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Abstract 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.

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.

Lactic acid from glycolytic metabolism of cancer cells has been associated with immune suppressive functions. Here authors show that lactate, when depart from the acidic protons, inhibits histone deacetylases in CD8 + T cells, which turns them into potent anti-tumour immune cells.

While recognized as the first effective immunotherapy for human cancer, IL-2 based immunotherapy still encounters several limitations in the clinic. Here, the authors design a cytokine receptor-masked IL-2 mutein prodrug that is selectively activated by matrix metalloproteinases in the tumor microenvironment, promoting anti-tumor immune response while minimizing systemic toxicity.

Background Cancer 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.Methods Tumor 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.Results Nanovaccine 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.Conclusions Our 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.

When mobile impurities are introduced and coupled to a Fermi sea, new quasiparticles known as Fermi polarons are formed. There are two interesting, yet drastically different regimes of the Fermi polaron problem: (i) the attractive polaron (AP) branch connected to pairing phenomena spanning the crossover from BCS superfluidity to the Bose-Einstein condensation of molecules and (ii) the repulsive branch (RP), which underlies the physics responsible for Stoner’s itinerant ferromagnetism. Here, we study Fermi polarons in two-dimensional systems, where many questions and debates regarding their nature persist. The model system we investigate is a doped MoSe_{2} monolayer. We find the observed AP-RP energy splitting and the quantum dynamics of attractive polarons agree with the predictions of polaron theory. As the doping density increases, the quantum dephasing of the attractive polarons remains constant, indicative of stable quasiparticles, while the repulsive polaron dephasing rate increases nearly quadratically. The dynamics of Fermi polarons are of critical importance for understanding the pairing and magnetic instabilities that lead to the formation of rich quantum phases found in a wide range of physical systems including nuclei, cold atomic gases, and solids.

The application of STING agonists and the blockade of the SIRPα–CD47 signaling axis are emerging immunotherapeutic strategies. Here the authors show that hybrid cellular membrane nanovesicles loaded with a STING agonist or overexpressing high-affinity SIRPα variants can be exploited to promote anti-tumor immune responses.

Interleukin-2 (IL-2) based cancer therapy is limited by severe toxicity and strong Treg amplification at the therapeutic dosage. Here, the authors develop a recombinant IL-2 immunocytokine which is comprised of a tumor-targeting antibody fused to a super mutant IL-2 and show in mouse models that this next-generation IL2 has reduced toxicity and enhanced antitumor activity.

Improper innate sensing within the tumor microenvironment limits immunotherapy success. Here, the authors show that targeting NQO1 triggers immunogenic innate sensing to reactivate T cells and overcome immune checkpoint blockade resistance.

Mammalian glycans have a role in host immunity but little is known about how they activate the host response in the context of autoimmune diseases. Here, the authors identify Manβ1-4GlcNAc as a novel innate immune modulator associated with chronic autoimmune diseases.

The Lower Jurassic Ahe Formation is an important exploration target for deep clastic reservoirs in the eastern Kuqa Depression. The Ahe Formation sandstones show heterogeneous porosity and permeability petrophysical properties. These properties have been poorly understood, limiting forecast of petroleum accumulations and making it difficult to develop the reservoirs. Based on cores, thin sections, SEM, and fluid inclusions, this study examined sandstone composition and texture and diagenetic heterogeneity at the core scale. The aim was to understand the influence of variations in detrital composition and texture on diagenetic and reservoir quality evolution. The Ahe Formation sandstones are dominantly fine- to coarse-grained litharenites, with minor feldspathic litharenites. In fining-up sand beds, detrital grain size determines the degree of mechanical compaction and, consequently, the abundance of porosity through ductile grains and muddy matrix. Local complete calcite cementation is a noticeable exception to this general trend. Three sandstone petrofacies have been defined based on texture and framework composition, detrital matrix, diagenesis, and pore types: (1) ductile-lean sandstone, (2) ductile-rich sandstone, and (3) tightly calcite-cemented sandstone. Different petrofacies experienced contrasting diagenetic and porosity evolution pathways. Ductile-lean sandstones underwent lower degree of compaction relative to ductile-rich sandstones during the eodiagenesis stage, and extensive grain dissolution occurred. The petrofacies remained relatively porous and permeable before early oil arrival. With continued burial, the porosity and permeability in the sandstones were further reduced by cementation. The petrofacies still had moderate porosity and permeability and were substantially charged when late petroleum migrated into the reservoirs. Thus, ductile-lean sandstones constitute effective reservoir rocks in deep reservoirs. By translating petrofacies to signatures of well logs, the effective properties of the reservoir rocks can be forecasted at the well scale.

Summary: 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. : 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). Keywords: glioma, glia, astrocyte, interaction, extracellular vesicle, tumor microenvironment, cell fusion, neuron, exosome

Based on the three-dimensional seismic interpretation data, this paper analyzed the formation mechanism and the growth process of the oblique anticline AE of the M region of the eastern Niger Delta, as well as the evolution process of the associated fault systems. The study results show that the stratigraphic sedimentary period between reflector H4-H6 of the middle and late Miocene was the initial fold-thrust stage, the anticline AE was a half-graben controlled by oblique extensional faults derived from the oblique extensional transfer structure formed by local initial differential fold-thrusting. At the same time the tear faults developed as a result of the differential sliding. During the stratigraphic sedimentary period between reflector H1-H4 of the late Miocene to Pliocene, the large-scale folding and thrusting occurred, differential contractional deformation resulted in the pre-existing extensional half-graben became AE anticline by oblique tectonic inversion, then the anticline grew continually and the crest of the anticline migrated gradually. The newly formed fault systems consist of a small number of associated tear-normal faults caused by differential thrusting and gravity-driven domino normal faults predominantly induced by the slope inclination of the anticline limb. During the stratigraphic sedimentary period between reflector H0-H1 of the Pleistocene to Holocene, as the growth of the anticline ceased, the area entered post-fold thrusting stage. The formation and distribution of conjugated faults were controlled by the local gravity return collapse, local differential sliding and reactivation of pre-existing positive inversion faults jointly. The research results of genetic mechanism of the oblique inversion anticline and evolution of associated faults are helpful to reveal the key factors controlling the accumulation and distribution of oil and gas. Key words: Niger Delta, gravity sliding, differential contractional deformation, oblique anticline, fault system, tectonic inversion, Paleogene, Neogene

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Faults have complex internal structures, which can be divided into the fault core and the damaged zone. During the fault formation process, the damaged zone will develop a large number of fractures cross cutting the adjacent host rocks, where the size and density of fractures would decrease as a function of distance from the fault core. Statistics show that compared with the host rocks, the rock’s secondary porosity may significantly get improved until it is 5%−10% higher than the host rock’s, and the permeability could be increased from zero to six orders of magnitude higher where fractures are developed. Based on the distribution of the fault core and damaged zone, we established an idealized geologic model to analyze the influence of the fault associated microstructures on the fluid flow efficiency. The results demonstrated that the reservoir property will be effectively improved when the fractures are developed to a certain magnitude, which will provide an advantageous conduit for fluid flow. The physical properties of wells are significantly different between the reservoirs transformed by the fractures and the reservoirs that have not been affected. The reservoir unit near faults has been modified by the associated fractures improving the reservoir quality. In addition, the portions of the reservoir farther from the fault core are less influenced and retain their initial poor characteristics. In order to evaluate the enhanced reservoir properties caused by faults and associated fractures, we performed statistical analysis of valid porosity ratio of the Nantun reservoirs as a function of the distance from 49 wells to faults in the research area. The results of this study demonstrated that connected fractures enhance the properties of the reservoirs and there is a distinct range that separates oil producing wells and water producing ones. This phenomenon verifies that faults are important and must be considered carefully during the exploration and production for hydrocarbon to provide higher quality reservoirs.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non–small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand–1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors. [ABSTRACT FROM AUTHOR]

This study was conducted to compare the efficacy and safety of ifosfamide plus etoposide plus platinum (IEP) to that of etoposide plus platinum (EP) in patients with previously untreated small-cell lung cancer (SCLC). The Cochrane Library, Embase, MEDLINE and Chinese Biomedical Literature databases were searched to identify all randomized controlled trials comparing IEP to EP in patients with histologically proven SCLC. Two investigators independently assessed the quality of the relevant trials and extracted data. We analyzed the data using Review Manager software, version 4.2.8. A total of 4 trials with 447 previously untreated SCLC patients were included in this meta-analysis. The results of the meta-analysis indicated that there were no significant differences in the overall response [relative risk (RR) = 1.07, 95% confidence interval (CI): 0.97-1.19], 1-year survival rate (RR=1.22, 95% CI: 0.96-1.55) and 2-year survival rate (RR=1.52, 95% CI: 0.75-3.07) between the IEP and EP regimens. However, there were significant differences between the IEP and EP regimens regarding the incidence of grade 3/4 neutropenia (RR=1.52, 95% CI: 1.07-2.17) and grade 3/4 vomiting (RR=1.78, 95% CI: 1.02-3.11). In conclusion, our results suggested that IEP is not superior to EP regimen for the treatment of previously untreated SCLC, whereas the IEP regimen is associated with more severe hematological and gastrointestinal toxicities compared to EP. Therefore, the use of ifosfamide in multimodality treatment regimens requires further investigation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]