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BACKGROUND: Viral infection elicits the type I interferon (IFN-I) response in host cells and subsequently inhibits viral infection through inducing hundreds of IFN-stimulated genes (ISGs) that counteract many steps in the virus life cycle. However, most of ISGs have unclear functions and mechanisms in viral infection. Thus, more work is required to elucidate the role and mechanisms of individual ISGs against different types of viruses. RESULTS: Herein, we demonstrate that poliovirus receptor-like protein4 (PVRL4) is an ISG strongly induced by IFN-I stimulation and various viral infections. Overexpression of PVRL4 protein broadly restricts growth of enveloped RNA and DNA viruses, including vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whereas deletion of PVRL4 in host cells increases viral infections. Mechanistically, it suppresses viral entry by blocking viral-cellular membrane fusion through inhibiting endosomal acidification. The vivo studies demonstrate that Pvrl4-deficient mice were more susceptible to the infection of VSV and IAV. CONCLUSION: Overall, our studies not only identify PVRL4 as an intrinsic broad-spectrum antiviral ISG, but also provide a candidate host-directed target for antiviral therapy against various viruses including SARS-CoV-2 and its variants in the future.

CDK4/6 are important regulators of cell cycle and their inhibitors have been approved as anti-cancer drugs. Here, we report a STING-dependent anti-tumor immune mechanism responsible for tumor suppression by CDK4/6 blockade. Clinical datasets show that in human tissues, CDK4 and CDK6 are over-expressed and their expressions are negatively correlated with patients overall survival and T cell infiltration. Deletion of Cdk4 or Cdk6 in tumor cells significantly reduce tumor growth. Mechanistically, we find that Cdk4 or Cdk6 deficiency contributes to an increased level of endogenous DNA damage, which triggers the cGAS-STING signaling pathway to activate type I interferon response. Knockout of Sting is sufficient to reverse and partially reverse the anti-tumor effect of Cdk4 and Cdk6 deficiency respectively. Therefore, our findings suggest that CDK4/6 inhibitors may enhance anti-tumor immunity through the STING-dependent type I interferon response.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the global coronavirus disease 2019 (COVID-19) pandemic, contains a unique, four amino acid (aa) "PRRA" insertion in the spike (S) protein that creates a transmembrane protease serine 2 (TMPRSS2)/furin cleavage site and enhances viral infectivity. More research into immunogenic epitopes and protective antibodies against this SARS-CoV-2 furin cleavage site is needed.MethodsCombining computational and experimental methods, we identified and characterized an immunogenic epitope overlapping the furin cleavage site that detects antibodies in COVID-19 patients and elicits strong antibody responses in immunized mice. We also identified a high-affinity monoclonal antibody from COVID-19 patient peripheral blood mononuclear cells; the antibody directly binds the furin cleavage site and protects against SARS-CoV-2 infection in a mouse model.FindingsThe presence of "PRRA" amino acids in the S protein of SARS-CoV-2 not only creates a furin cleavage site but also generates an immunogenic epitope that elicits an antibody response in COVID-19 patients. An antibody against this epitope protected against SARS-CoV-2 infection in mice.InterpretationThe immunogenic epitope and protective antibody we have identified may augment our strategy in handling COVID-19 epidemic.FundingThe National Natural Science Foundation of China (82102371, 91542201, 81925025, 82073181, and 81802870), the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (2021-I2M-1-047 and 2022-I2M-2-004), the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2020-PT310-006, 2019XK310002, and 2018TX31001), the National Key Research and Development Project of China (2020YFC0841700), US National Institute of Health (NIH) funds grant AI158154, University of California Los Angeles (UCLA) AI and Charity Treks, and UCLA DGSOM BSCRC COVID-19 Award Program. H.Y. is supported by Natural Science Foundation of Jiangsu Province (BK20211554 andBE2022728).

Uranium ore is the main raw material in the front end of the nuclear fuel cycle in the production of yellowcake. The distribution pattern of rare earth element (REE) has regional characteristics, and it is generally believed that grinding process will not change this feature, so the fingerprint information of REE pattern has been applied in the nuclear verification traceability of yellowcake. In uranium hydrometallurgical plant, uranium ore not only needs to go through grinding, but also needs to go through complex processes such as leaching, extraction, reverse extraction and precipitation to get yellowcake products. In this process, the change of distribution pattern of REE remains to be studied. Therefore, from the perspective of production process, the applicability of the distribution pattern of REE in nuclear forensics traceability was studied. By tracking the production process from uranium ore to sodium diuranate in the conventional uranium hydrometallurgical plant in China, the samples of uranium ore, clarified leach solution, raffinate and sodium diuranate were pre-treated (acid dissolution methods) under the experimental conditions of low procedure background (less than 0.512 ng/mL) and low detection limit (less than 0.007 5 ng/mL). After the REE was separated by TRU resin, the content was accurately determined by inductively coupled plasma mass spectrometry (ICP-MS) and the distribution patterns of REE were drawn. The results show that after the separation of the four samples and removal of a large amount of uranium matrix, the contents of REE measured by ICP-MS are more accurate. The above four samples are enriched in light REE on the whole, with obvious Eu deficit, and the distribution pattern of REE generally presents a right-sloping deep valley. These indicate that uranium materials which have undergone traditional uranium hydrometallurgy process will retain the REE characteristics of uranium ore in general, and the distribution pattern of REE is helpful to identify the origin and history of uranium materials. In view of the obvious enrichment of Er in sodium diuranate sample, it is possible to further explore how the different chemical precipitations of leach ore cause the REE fractionation, so as to better explain how the production process and chemical history of the product affect the REE characteristics of yellowcake, which is also the basis for the use of REE in nuclear forensics traceability.

Introduction: The reservoir-forming rule in the paleo-slope zone outside petroliferous basins’ source kitchens of the eastern basin in China is unclear, manifested in the distribution of oil and gas in complex multi-layers. This study focuses on petroleum migration along faults and sandbodies to clarify this question and improve the exploration efficiency of petroleum in areas with similar geological conditions.Method: We summarized two models of petroleum migration based on two factors: the connected sandbodies and the vertical unsealing faults. Model I is conducive to the migration of hydrocarbons within a single layer, while Model II is conducive to the vertical migration of hydrocarbons across layers. Combining the means for evaluating fault sealing and sandbody connectivity, integrating these models could form a set of characterization methods for the distribution of the complex fluid migration pathways.Results: This method is applied to characterize the complex multilayer migration pathways distribution in the first and second members of the Shahejie Formation in the central-southern area of the Wen’an Slope in the Baxian Sag, Jizhong Depression, Bohai Bay Basin, China. The results show that, in the first and second members of the Shahejie Formation in the central-southern area of the Wen’an Slope, the area for Model II is mainly distributed in the central-eastern regions. The second member has a Model I area distributed in its western region, and the first member has a Model I area distributed in its centraleastern parts. The latter distribution area is larger than the former. According to hydrocarbon migration analysis, the first member is more conducive to large regional migration and accumulation of hydrocarbons than the second member.Discussion: The predicted result of petroleum migration is consistent with the hydrocarbon distribution found in the central-southern areas of the Wen’an Slope, which is that oil and gas distribution in the first member is significantly greater than that in the second member. Thus, our method is feasible for characterizing the regional distribution of complex multi-layer migration pathways in simple tectonic setting and oil source conditions. However, further research is still needed to increase the effectiveness of present petroleum migration analysis.