Structural basis for the immune recognition and selectivity of the immune receptor PVRIG for ligand Nectin-2.

Nectin and nectin-like (Necl) co-receptor axis, comprised of receptors DNAM-1, TIGIT, CD96, PVRIG, and nectin/Necl ligands, is gaining prominence in immuno-oncology. Within this axis, the inhibitory receptor PVRIG recognizes Nectin-2 with high affinity, but the underlying molecular basis remains unknown. By determining the crystal structure of PVRIG in complex with Nectin-2, we identified a unique CC' loop in PVRIG, which complements the double-lock-and-key binding mode and contributes to its high affinity for Nectin-2. The association of the corresponding charged residues in the F-strands explains the ligand selectivity of PVRIG toward Nectin-2 but not for Necl-5. Moreover, comprehensive comparisons of the binding capacities between co-receptors and ligands provide innovative insights into the intra-axis immunoregulatory mechanism. Taken together, these findings broaden our understanding of immune recognition and regulation mediated by nectin/Necl co-receptors and provide a rationale for the development of immunotherapeutic strategies targeting the nectin/Necl axis.

A versatile upconversion-based multimode lateral flow platform for rapid and ultrasensitive detection of microRNA towards health monitoring.

MicroRNAs are small single-stranded RNA molecules associated with gene expression and immune response, suggesting their potential as biomarkers for health monitoring. Herein, we designed a novel upconversion-based multimode lateral flow assay (LFA) system to detect microRNAs in body fluids by simultaneously producing three unique signals within a detection strip. The core-shell Au-DTNB@Ag nanoparticles act as both the Raman reporters and acceptors, quenching fluorescence from upconversion nanoparticles (UCNPs, NaYF4: Yb3+, Er3+) via the Förster resonance energy transfer mechanism. Using microRNA-21 as a representative analyte, the LFA system offers remarkable detection range from 2 nM to 1 fM, comparable to outcomes from signal amplification methods, due to the successful single-layer self-assembly of UCNPs on the NC membrane, which greatly enhances both the convenience and sensitivity of the LFA technique. Additionally, our proprietary fluorescence-Raman detection platform simplifies result acquisition by reducing procedural intricacies. The biosensor, when evaluated with diverse bodily fluids, showed remarkable selectivity and sustained stability. Importantly, our LFA biosensor effectively identified periodontitis and lung cancer patients from healthy subjects in genuine samples, indicating significant potential for disease prediction, early diagnosis, and progression tracking. This system holds promise as a multifunctional tool for various biomarker assays.

Rational design of a 'two-in-one' immunogen DAM drives potent immune response against mpox virus.

The global outbreak of the mpox virus (MPXV) in 2022 highlights the urgent need for safer and more accessible new-generation vaccines. Here, we used a structure-guided multi-antigen fusion strategy to design a 'two-in-one' immunogen based on the single-chain dimeric MPXV extracellular enveloped virus antigen A35 bivalently fused with the intracellular mature virus antigen M1, called DAM. DAM preserved the natural epitope configuration of both components and showed stronger A35-specific and M1-specific antibody responses and in vivo protective efficacy against vaccinia virus (VACV) compared to co-immunization strategies. The MPXV-specific neutralizing antibodies elicited by DAM were 28 times higher than those induced by live VACV vaccine. Aluminum-adjuvanted DAM vaccines protected mice from a lethal VACV challenge with a safety profile, and pilot-scale production confirmed the high yield and purity of DAM. Thus, our study provides innovative insights and an immunogen candidate for the development of alternative vaccines against MPXV and other orthopoxviruses.

Investigation of rare earth-based magnetic nanocomposites for specific enrichment of exosomes from human plasma.

Exosomes, also known as small extracellular vesicles, are widely present in a variety of body fluids (e.g., blood, urine, and saliva). Exosomes are becoming an alternative promising source of diagnostic markers for disease rich in cargo of metabolites, proteins, and nucleic acids. However, due to the low abundance and structure similarity with protein complex, the efficient isolation of exosomes is one of the most important issues for biomedical applications. With a higher order of f-orbitals in rare earth element, it will have strong adsorption toward the phosphate group on the surface of the phospholipid bilayer of exosomes. In this study, we systematically investigated the ability of various rare earths interacting with phosphate-containing molecules and plasma exosomes. One of the best binding europium was selected and used to synthesize core-shell magnetic nanomaterials (Fe3O4@SiO2@Eu2O3) for the enrichment of exosomes from human plasma. The developed nanomaterials exhibited higher enrichment capacity, less time consumption and more convenient handling compared to commonly used ultracentrifugation method. The nanomaterials were applied to separate exosomes from the plasma of patients with hepatocellular carcinoma and healthy controls for metabolomics study with high-resolution mass spectrometry, where 70 differentially expressed metabolites were identified, involving amino acid and lipid metabolic pathway. We anticipated the rare earth-based materials to be an alternative approach on exosome isolation for disease diagnosis or postoperative clinical monitoring.

A Wearable Healthcare Platform Integrated with Biomimetical Ions Conducted Metal-Organic Framework Composites for Gas and Strain Sensing in Non-Overlapping Mode.

Intelligent wearable devices are essential for telemedicine healthcare as they enable real-time monitoring of physiological information. Elaborately constructing synapse-inspired materials provides a crucial guidance for designing high-performance sensors toward multiplex stimuli response. However, a realistic mimesis both in the "structure and sense" of biological synapses to obtain advanced multi-functions is still challenging but essential for simplifying subsequent circuit and logic programs. Herein, an ionic artificial synapse integrated with Ti3 CNTx nanosheets in situ grown with zeolitic imidazolate framework flowers (ZIF-L@Ti3 CNTx composite) is constructed to concurrently mimic the structure and working mechanism of the synapse. The flexible sensor of the bio-inspired ZIF-L@Ti3 CNTx composite exhibits excellent dual-mode dimethylamine (DMA) and strain-sensitive response with non-overlapping resistance variations. The specific ions conduction working principle triggered by DMA gas or strain with the assistance of humidity is confirmed by the density functional theory simulation. Last, an intelligent wearable system is self-developed by integrating the dual-mode sensor into flexible printed circuits. This device is successfully applied in pluralistic monitoring of abnormal physiological signals of Parkinson's sufferers, including real-time and accurate assessment of simulated DMA expiration and kinematic tremor signals. This work provides a feasible routine to develop intelligent multifunctional devices for upsurging telemedicine diagnosis.

Opal photonic crystal-enhanced upconversion turn-off fluorescent immunoassay for salivary CEA with oral cancer.

The point-of-care test of tumor markers in saliva with high specificity and sensitivity for early diagnosis of oral cancer is of great interest and significance, but remaining a daunting challenge due to the low concentration of such biomarkers in oral fluid. Herein, a turn-off biosensor based on opal photonic crystal (OPC) enhanced upconversion fluorescence is proposed to detect the carcinoembryonic antigen (CEA) in saliva by applying fluorescence resonance energy transfer sensing strategy. Hydrophilic PEI ligands are modified on upconversion nanoparticles to enhance the sensitivity of biosensor by promoting sufficient contact between saliva and detection region. As a substrate for the biosensor, OPC can also provide a local-field effect for greatly enhanced upconversion fluorescence by coupling the stop band and excitation light, and a 66-fold amplification of the upconversion fluorescence signal was obtained. For the CEA detection in spiked saliva, such sensors showed a favorable linear relationship at 0.1-2.5 ng mL-1 and more than 2.5 ng mL-1, respectively. The limit of detection was down to 0.1 ng mL-1. Moreover, by monitoring real saliva, the effective discrepancy between patients and healthy people was confirmed, indicating remarkable practical application value in clinical early diagnosis and home-based self-monitoring of tumors.

Influence of microplastics on microbial anaerobic detoxification of chlorophenols.

Microplastics (MPs) can absorb halogenated organic compounds and transport them into marine anaerobic zones. Microbial reductive dehalogenation is a major process that naturally attenuates organohalide pollutants in anaerobic environments. Here, we aimed to determine the mechanisms through which MPs affect the microbe-mediated marine halogen cycle by incubating 2,4,6-trichlorophenol (TCP) dechlorinating cultures with various types of MPs. We found that TCP was dechlorinated to 4-chlorophenol in biotic control and polypropylene (PP) cultures, but essentially terminated at 2,4-dichlorophenol in polyethylene (PE) and polyethylene terephthalate (PET) cultures after incubation for 20 days. Oxygen-containing functional groups such as peroxide and aldehyde were enriched on PE and PET after incubation and corresponded to elevated levels of intracellular reactive oxygen species (ROS) in the microorganisms. Adding PE or PET to the cultures exerted limited effects on hydrogenase and ATPase activities, but delayed the expression of the gene encoding reductive dehalogenase (RDase). Considering the limited changes in the microbial composition of the enriched cultures, these findings suggested that microbial dechlorination is probably affected by MPs through the ROS-induced inhibition of RDase synthesis and/or activity. Overall, our findings showed that extensive MP pollution is unfavorable to environmental xenobiotic detoxification.

Antibacterial PDT nanoplatform capable of releasing therapeutic gas for synergistic and enhanced treatment against deep infections.

Antibacterial photodynamic therapy (aPDT) has emerged as an attractive treatment option for efficient removal of pathogenic bacteria. However, aPDT in deep tissue will encounter difficulties such as limited light penetration depth, insufficient oxygen (O2) supply and inability to eliminate inflammation introduced by bacteria, which hinders its clinical application. Herein, the near infrared (NIR) strategy of simultaneously generating O2 and CO was developed for aPDT based antibacterial therapy and mitigation of deep infection inflammation. Methods: We prepared NIR-mediated multifunctional aPDT nanoplatform (POS-UCNPs/ICG) producing therapeutic gas of O2 and CO. The CO, O2 and ROS generation of the nanoplatform were characterized by dye probes, respectively. The antibacterial activity and anti-inflammation of POS-UCNPs/ICG were demonstrated in vitro and in vivo. In addition, the therapeutic effects in vivo were serially analyzed by immunofluorescence staining, Masson's staining, hematoxylin and eosin staining, colony formation units (CFU) and so on. Results: NIR-mediated multifunctional aPDT nanoplatform was realized by combining the up-conversion nanoparticles (UCNPs) and partially oxidized SnS2 (POS) nanosheets (NSs) as well as indocyanine green (ICG). Using a single 808 nm light, aPDT can be achieved via ICG molecules, meanwhile, O2/CO can be generated by POS NSs through upconversion light excitation. During the aPDT process, O2 can enhance aPDT, while CO can regulate inflammation through the PI3K/NF-κB pathway. Therefore, POS-UCNPs/ICG groups had a highest percentage of healing area up to 91.55±1.26% in mouse abscess model. Conclusion: Due to enhanced aPDT and anti-inflammatory collaborative therapy, the POS-UCNPs/ICG composites showed remarkably accelerated recovery in animal abscess models. Such NIR light responsive nanoplatform with optimized antibacterial capacity and immunomodulatory functions is promising for clinical therapeutics of bacteria-induced infections.

Additional mitral valve procedure and coronary artery bypass grafting versus isolated coronary artery bypass grafting in the management of significant functional ischemic mitral regurgitation: a meta-analysis.

INTRODUCTION: Functional ischemic mitral regurgitation (IMR) is commonly present following acute myocardial infarction (AMI) and tightly associated with a poorer prognosis. The optimal surgical strategy for the management of significant IMR (≥2+ grade) remains controversial and mitral valve surgery (MVS) at the time of coronary artery bypass grafting (CABG) is still debated. The primary objective of this meta-analysis was to clarify the effects of additional MVS on the prognosis in the patients with significant IMR, compared with isolated CABG. EVIDENCE ACQUISITION: A meta-analysis of eligible studies, reporting concomitant MVS and CABG in comparison with CABG alone in respects to in-hospital mortality, survival and postoperative residual mitral regurgitation (MR) and cardiac functional status, was carried out. The outcomes of interest included in-hospital mortality, one-, three- and five-year survival and postoperative New York Heart Association (NYHA) class, residual MR and left ventricular ejection fraction (LVEF). EVIDENCE SYNTHESIS: Pooling 2 randomized controlled trials (RCTs) (N.=175) and 11 observational studies (N.=2661) demonstrated that additional MVS did not significantly influence in-hospital mortality (odds ratio [OR]=1.45, 95% confidence interval [CI] 0.93-2.28, P=0.10) and one- (OR=0.89, 95%CI 0.68-1.15, P=0.37), three- (OR=1.10, 95%CI 0.79-1.55, P=0.56) and five- (OR=0.93, 95%CI 0.73-1.18, P=0.55) year survival in comparison with isolated CABG. And pooling neither RCTs nor observational studies alone presented any evidence of significant difference in in-hospital mortality and survival between the two groups. Additionally, concomitant MVS was associated with increased postoperative LVEF (standard mean differences [SMD]=0.28, 95%CI 0.10-0.46, P<0.01) and decreased postoperative residual MR (SMD=-4.22, 95%CI -6.48 to -1.97, P<0.0001). Similar outcomes were obtained when either RCTs or observational studies were pooled alone. Additional MVS appeared to decrease postoperative NYHA functional class (SMD=-0.48, 95%CI -0.97-0.00, P=0.05) with evident heterogeneity (I2=87.5%, P<0.0001). In the subgroup analysis, MVS significantly reduced postoperative NYHA functional class in RCTs (SMD=-1.32, 95%CI -1.67 to -0.97, P<0.0001) whereas it did not among observational studies (SMD=-0.08, 95%CI -0.27-0.11, P=0.42), and heterogeneity was completely eliminated (for RCTs, I2=0%, P=0.49; for observational studies, I2=0%, P=0.40). CONCLUSIONS: Concomitant MVS at the time of CABG is associated with greater improvement in postoperative residual MR and LVEF in the patients with significant IMR. However, the evidence is still lacking of advantages of combined surgery over CABG alone regarding in-hospital mortality, survival and postoperative NYHA function class. Additional RCTs are needed to assess the safety and efficacy outcomes of adding mitral valve procedure in the surgical intervention of significant IMR.

[Clinicopathological diagnosis of IgG4-related disease: report of eight cases].

OBJECTIVE: To evaluate the clinical and pathological features of IgG4-related disease (IgG4RD). METHODS: The clinical data, laboratory profiles, radiological, pathological and therapeutic features of eight cases of IgG4RD were analyzed. This cohort included two cases of common bile duct and partial hepatectomy specimens, two of submandibular gland excision specimens, one from lung biopsy specimen, one from open lung biopsy specimen, one from renal biopsy specimen, and one from renal excision specimen. In all cases, adequate lesion tissues were obtained. They were paraffin embedded, HE stained, and additional special stains and immunohistochemistry performed (MaxVision method). RESULTS: This series consisted of five males and three females, with a mean age of onset of 60 years. Five cases were suspected to be malignant pre-operatively, including two cases suspected of common bile duct carcinoma, two suspected of salivary gland tumor, and one suspected of renal pelvic carcinoma. Elevated serum levels of IgG4 and IgE were detected in five cases and eosinophilia in four cases. Multi-organ involvement was noted in four cases. The major histopathological features associated with IgG4-RD were: dense lymphoplasmacytic infiltrate, with lymphoid follicle formation. Extensive eosinophilic infiltrate (> 10/HPF) was seen in four cases; fibrosis that was arranged at least focally in a storiform pattern was also noted. The numbers of IgG4 positive plasma cells were > 20-50/HPF, while the IgG4 to IgG ratio was more than 40%. Obliterative phlebitis was present in four cases. Other pathological changes such as necrotizing vasculitis or lymphoma were not found. Five patients responded well to glucocorticoids. CONCLUSIONS: IgG4RD has relatively specific histopathological features; accurate evaluation of the absolute and relative number of IgG4 positive plasma cells in lesional tissue, combining with clinical examination and exclusion of other causes of elevated IgG4, allows the diagnosis of IgG4RD. IgG4RD has complicated clinical manifestation, and glucocorticoids therapy is efficacious.