Glycans from microbial pathogens are well known pathogen-associated molecular patterns that are recognized by the host immunity; however, little is known about whether and how mammalian self-glycans ...activate the host immune response, especially in the context of autoimmune disease. Using biochemical fractionation and two-dimensional HPLC, we identify an abundant and bioactive free glycan, the Manβ1-4GlcNAc disaccharide in TREX1-associated autoimmune diseases. We report that both monosaccharide residues and the β1-4 linkage are critical for bioactivity of this disaccharide. We also show that Manβ1-4GlcNAc is produced by oligosaccharyltransferase hydrolysis of lipid-linked oligosaccharides in the ER lumen, followed by ENGase and mannosidase processing in the cytosol and lysosomes. Furthermore, synthetic Manβ1-4GlcNAc disaccharide stimulates a broad immune response in vitro, which is in part dependent on the STING-TBK1 pathway, and enhances antibody response in vivo. Together, our data identify Manβ1-4GlcNAc as a novel innate immune modulator associated with chronic autoimmune diseases.
Fewer studies have focused on subsurface deformation bands than deformation bands in outcrops. In this work, we studied the subsurface deformation bands in high-porosity sandstones from the Shulu ...borehole in the Bohai Bay Basin. The Shulu borehole was drilled through the Xicaogu normal fault with a displacement of 140 m, and the recovered core contains deformation bands and fractures in the damage zones. This study focused on the structural characteristics of subsurface deformation bands with burial depths between 2504.4 m and 2506.2 m. The critical porosity limit of host sandstone for the formation of deformation bands and fractures was determined. The host sandstones in the Shulu borehole are predominantly arkose. The subsurface deformation bands in the Shulu borehole are suggested to be compactional shear bands. We find that the subsurface deformation bands have identical characteristics to those in outcrops, except that they do not show strong positive reliefs. These bands are characterized by protocataclasis and cataclasis and organized into localized and conjugate networks. Compared to the host rocks, the subsurface deformation bands show porosity reductions of 7.7–27.7% and permeability reductions of 1–3 orders of magnitude. Three porosity intervals of the host-rock with different deformation styles can be identified in the Shulu borehole core: 1) host sandstone with porosities greater than 14.3%, which develop deformation bands exclusively; 2) host sandstone with porosities less than 10.8%, which develop fractures; and 3) the transition zone, where the porosities of host sandstone are 10.8–14.3%, and the deformation styles are characterized by both deformation bands and fractures. The critical porosity limit of host rocks in terms of the formation of deformation bands and fractures suggests that porosity is a major factor controlling the formation of fractures and deformation bands. Deformation bands and fractures have counteracting effects on the fluid flow in the transition zone.
•Subsurface deformation bands were investigated from in an across-fault borehole.•Compactional shear bands with protocataclasis and cataclasis are defined in the Shulu borehole.•Three host-rock porosity intervals with different deformation styles were identified.•Deformation bands and fractures could coexist in transition zones with porosities ranging 10.8–14.3%.•Deformation bands and fractures have counteracting effects on fluid flow in the transition zone.
In the history of vaccine development, the synthetic vaccine is a milestone that is in stark contrast with traditional vaccines based on live-attenuated or inactivated microorganisms. Synthetic ...vaccines not only are safer than attenuated or inactivated microorganisms but also provide the opportunity for vaccine design for specific purposes. The first generation of synthetic vaccines has been largely based on DNA recombination technology and genetic manipulation. This de novo generation is occasionally time consuming and costly, especially in the era of genomics and when facing pandemic outbreaks of infectious diseases. To accelerate and simplify the R&D process for vaccines, we developed an improved method of synthetic vaccine construction based on protein assembly. We optimized and employed the recently developed SpyTag/SpyCatcher technique to establish a protein assembly system for vaccine generation from pre-prepared subunit proteins. As proof of principle, we chose a dendritic cell (DC)-targeting molecule and specific model antigens to generate desired vaccines. The results demonstrated that a new vaccine generated in this way does not hamper the individual function of different vaccine components and is efficient in inducing both T and B cell responses. This protein assembly strategy may be especially useful for high-throughput antigen screening or rapid vaccine generation.
The respiratory system, especially the lung, is the key site of pathological injury induced by SARS-CoV-2 infection. Given the low feasibility of targeted delivery of antibodies into the lungs by ...intravenous administration and the short half-life period of antibodies in the lungs by intranasal or aerosolized immunization, mRNA encoding broadly neutralizing antibodies with lung-targeting capability can perfectly provide high-titer antibodies in lungs to prevent the SARS-CoV-2 infection. Here, we firstly identify a human monoclonal antibody, 8-9D, with broad neutralizing potency against SARS-CoV-2 variants. The neutralization mechanism of this antibody is explained by the structural characteristics of 8-9D Fabs in complex with the Omicron BA.5 spike. In addition, we evaluate the efficacy of 8-9D using a safe and robust mRNA delivery platform and compare the performance of 8-9D when its mRNA is and is not selectively delivered to the lungs. The lung-selective delivery of the 8-9D mRNA enables the expression of neutralizing antibodies in the lungs which blocks the invasion of the virus, thus effectively protecting female K18-hACE2 transgenic mice from challenge with the Beta or Omicron BA.1 variant. Our work underscores the potential application of lung-selective mRNA antibodies in the prevention and treatment of infections caused by circulating SARS-CoV-2 variants.
Emerging evidence suggests that crosstalk between glioma cells and the brain microenvironment may influence brain tumor growth. To date, known reciprocal interactions among these cells have been ...limited to the release of paracrine factors. Combining a genetic strategy with longitudinal live imaging, we find that individual gliomas communicate with distinct sets of non-glioma cells, including glial cells, neurons, and vascular cells. Transfer of genetic material is achieved mainly through extracellular vesicles (EVs), although cell fusion also plays a minor role. We further demonstrate that EV-mediated communication leads to the increase of synaptic activity in neurons. Blocking EV release causes a reduction of glioma growth in vivo. Our findings indicate that EV-mediated interaction between glioma cells and non-glioma brain cells alters the tumor microenvironment and contributes to glioma development.
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•Distinct types of gliomas interact with different sets of brain cells•Glioma cells use extracellular vesicles to achieve the glioma-brain-cell crosstalk•EV-mediated communication alters neuronal activity in the labeled neurons
Non-glioma cells form a unique tumor microenvironment and are critical for glioma progression. Gao et al. find that individual gliomas communicate with distinct sets of non-glioma cells, including glial cells, neurons, and vascular cells. Transfer of genetic material is achieved mainly through extracellular vesicles (EVs).
MicroRNAs (miRs) are short, highly conserved small noncoding RNA molecules with fundamental roles in regulating gene expression. To identify miR biomarkers associated with idiopathic pulmonary ...fibrosis (IPF), the expression pattern of miRs in exosomes from bronchoalveolar lavage fluid (BALF) of elderly patients with IPF were evaluated. High‑throughput quantitative detection of miR expression using a microarray indicated that miR‑125b, miR‑128, miR‑21, miR‑100, miR‑140‑3p and miR‑374b were upregulated in patients with IPF, while let‑7d, miR‑103, miR‑26 and miR‑30a‑5p were downregulated. The expression level of miR‑30a‑5p was further examined, and its potential target genes were predicted using target gene prediction analysis software. A direct regulatory association was confirmed between miR‑30a‑5p and TGF‑β activated kinase 1/MAP3K7 binding protein 3 (TAB3) via a dual‑luciferase reporter assay. Overexpression of miR‑30a‑5p decreased TAB3, α‑smooth muscle actin and fibronectin expression in A549 cells with or without transforming growth factor‑β1 treatment. The decreased expression of miR‑30a in the BALF of patients with IPF, along with the consequential increase in TAB3 expression, may be a crucial factor in IPF progression.
Peer-to-peer (P2P) lending is a fintech innovation that provides loans to individuals and businesses without the need for additional intermediaries. However, if the borrower fails to repay the loan ...on time, the bank suffers a financial loss due to the borrower's default. At present, many studies are trying to improve the accuracy of credit default risk prediction models to reduce the risk of financial institutions' loan business, but it is also a meaningful study to focus on improving the recall rate of model prediction results. In the related research field of credit default risk prediction, improving the recall rate is crucial for banks and other lending institutions. The recall rate refers to the proportion of all true positive examples that are correctly identified as positive examples. In credit default risk prediction, true positive cases refer to the cases where borrowers default, while being correctly identified as positive cases means that the model can accurately predict which borrowers may default. If banks' risk prediction models can improve recall rates, this can help them better assess risk, formulate appropriate lending policies, and minimize default losses. This study aims to further improve the recall and AUC metrics (area under the ROC curve) of P2P credit default prediction using the lending dataset from Lending Club using an improved machine learning model fusion algorithm. Our proposed algorithm consists of two machine learning algorithms. The improved LightGBM algorithm and the improved XGBoost algorithm are used for model fusion to obtain the LGB-XGB-Stacking model. By optimizing the evaluation metrics in the training phase of these two algorithms, we have achieved significant improvement in results, especially in the recall rate of defaulted customers and the overall AUC metrics. After comparing the predictive performance of the models, our proposed predictive model is improved in the following aspects. First, the recall of our proposed prediction model is significantly better than other models. Second, it also outperforms other machine learning models on the AUC metric. Among them, the recall rate of the positive sample (default customer) is 24.43% higher than that of the XGBoost model, and the overall AUC index is 6.71% higher. In the end, it was found that XGBoost, LightGBM, and CatBoost models performed very well in terms of accuracy rate improvement. The accuracy rates of these three models are very close, and they are all higher than other models. Therefore, it is found that machine learning models are still an effective method for credit default prediction research, especially tree models. Although the accuracy of our model is slightly lower than the above models, our proposed model outperforms the above models in identifying defaulting customers. Our model can more accurately identify defaulting customers and minimize the risk of bad debts for financial institutions.
•We use improved model fusion algorithms to build credit risk forecasting models.•Use a novel model fusion method to improve the recall rate and AUC value of default users.•Our method greatly reduces the cost of credit risk assessment for P2P lending platforms.
BackgroundCancer vaccines are able to achieve tumor-specific immune editing in early-phase clinical trials. However, the infiltration of cytotoxic T cells into immune-deserted tumors is still a major ...limiting factor. An optimized vaccine approach to induce antigen-specific T cells that can perform robust tumor infiltration is important to accelerate their clinical translation. We previously developed a STING-activating PC7A nanovaccine that produces a strong anti-tumor T cell response on subcutaneous injection. This study systematically investigated the impact of administration methods on the performance of nanovaccines.MethodsTumor growth inhibition by intratumoral delivery and subcutaneous delivery of nanovaccine was investigated in TC-1 human papillomavirus-induced cancer model and B16-OVA melanoma model. Nanovaccine distribution in vivo was detected by clinical camera imaging, systemic T cell activation and tumor infiltration were tested by in vivo cytotoxicity killing assay and flow cytometry. For mechanism analysis, T cell recruitment was investigated by in vivo migration blocking assay, multiplex chemokine array, flow cytometry, RT-qPCR, chemotaxis assay and gene knockout mice.ResultsNanovaccine administration was found to alter T cell production and infiltration in tumors. Intratumoral delivery of nanovaccines displayed superior antitumor effects in multiple tumor models compared with subcutaneous delivery. Mechanistic investigation revealed that intratumoral administration of the nanovaccine significantly increased the infiltration of antigen-specific T cells in TC-1 tumors, despite the lower systemic levels of T cells compared with subcutaneous injection. The inhibition of tumor growth by nanovaccines is primarily dependent on CD8+ cytotoxic T cells. Nanovaccine accumulation in tumors upregulates CXCL9 expression in myeloid cells in a STING dependent manner, leading to increased recruitment of IFNγ-expressing CD8+ T cells from the periphery, and IFNγ reciprocally stimulates CXCL9 expression in myeloid cells, resulting in positive feedback between myeloid-CXCL9 and T cell-IFNγ to promote T cell recruitment. However, the STING agonist alone could not sustain this effect in the presence of a systemic deficiency in antigen-specific T cells.ConclusionsOur results demonstrate that intratumoral administration of PC7A nanovaccine achieved stronger antitumor immunity and efficacy over subcutaneous injection. These data suggest intratumoral administration should be included in the therapeutic design in the clinical use of nanovaccine.
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