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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially described to target the respiratory system and now has been reported to infect a variety of cell types, including cardiomyocytes, neurons, hepatocytes, and gut enterocytes. However, it remains unclear whether the virus can directly infect human embryonic stem cells (hESCs) or early embryos. Herein, we sought to investigate this question in a cell-culture system of hESCs. Both the RNA and S protein of SARS-CoV-2 were detected in the infected hESCs and the formation of syncytium was observed. The increased level of subgenomic viral RNA and the presence of dsRNA indicate active replication of SARS-CoV-2 in hESCs. The increase of viral titers in the supernatants revealed virion release, further indicating the successful life cycle of SARS-CoV-2 in hESCs. Remarkably, immunofluorescence microscopy showed that only a small portion of hESCs were infected, which may reflect low expression of SARS-CoV-2 receptors. By setting |log2 (fold change)| > 0.5 as the threshold, a total of 1,566 genes were differentially expressed in SARS-CoV-2-infected hESCs, among which 17 interferon-stimulated genes (ISGs) were significantly upregulated. Altogether, our results provide novel evidence to support the ability of SARS-CoV-2 to infect and replicate in hESCs.

SARS-CoV-2 is evolving with mutations throughout the genome all the time and a number of major variants emerged, including several variants of concern (VOC), such as Delta and Omicron variants. In this study, we demonstrated that mutations in the regions corresponding to the sequences of the probes and 3’-end of primers have a significant impact on qPCR detection efficiency. We also found that the G28916T mutation of the N gene accounts for 78.78% sequenced genomes of Delta variant. It was found that detection sensitivity of G28916T mutant was 2.35 and 1.74 times less than that of the wt sequence and detection limit was reduced from 1 copy/μl to 10 copies/μl for the commercially available CP3 and CP4 primer/probe sets. These results indicate that the detection probes and primers should be optimized to keep maximal detection efficiency in response to the emergence of new variants.

Interferon-inducible p200 family protein IFI204 was reported to be involved in DNA sensing, and subsequently induces the production of type I interferons and proinflammatory mediators. However, its function in the regulation of antiviral innate immune signaling pathway remains unclear. Here we reported a novel role of IFI204 that specifically inhibits the IRF7-mediated type I interferons response during viral infection. IFI204 and other p200 family proteins are highly expressed in mouse hepatitis coronavirus-infected bone marrow-derived dendritic cells. The abundant IFI204 could significantly interact with IRF7 in nucleus by its HIN domain and prevent the binding of IRF7 with its corresponding promoter. Moreover, other p200 family proteins that possess HIN domain could also inhibit the IRF7-mediated type I interferons. These results reveal that, besides the positive regulation function in type I interferon response at the early stage of DNA virus infection, the interferon-inducible p200 family proteins such as IFI204 could also negatively regulate the IRF7-mediated type I interferon response after RNA virus infection to avoid unnecessary host damage from hyper-inflammatory responses.

IntroductionBrodifacoum is a highly potent superwarfarin rodenticide that leads to coagulopathy. Although the effect of warfarin during pregnancy is well understood, reports on superwarfarin poisoning, like brodifacoum, during pregnancy are scarce.Case PresentationWe report a case involving a woman with a singleton pregnancy who experienced sudden nasal hemorrhage accompanied by hematuria at 34 weeks and 3 days of gestation, with no apparent etiology. It was ultimately diagnosed as acquired coagulopathy resulting from brodifacoum poisoning. Fetal ultrasonography revealed significant intracranial hemorrhage, leading to intrauterine fetal demise and subsequent pregnancy termination. Following the correction of the patient’s coagulation profile through intravenous and oral administration of vitamin K1, tailored to the serum levels of brodifacoum, diligent monitoring confirmed that the patient was in stable condition.ConclusionThe primary hazard associated with the ingestion of brodifacoum is hemorrhage, with clinical presentations varying from asymptomatic cases to overt bleeding, which may present as hematuria, epistaxis, menometrorrhagia, and intracranial hemorrhage. Therefore, the diagnosis and management of this type of poisoning pose significant challenges. Prompt recognition and ongoing care for pregnant individuals affected by rodenticide toxicity are crucial for optimizing maternal health outcomes.

Abstract Along with the rapid development of a new round of scientific and technological revolution and industrial transformation, digital manufacturing, artificial intelligence, the Internet and other emerging fields marked by digitalization and intelligence are experiencing widespread penetration, cross-integration and constantly emerged crossover innovation. New technology development is a process of continuous increase of resource heterogeneity characterized by high fuzziness and uncertainty. However, it is difficult to meet the requirements of the development of emerging technologies only by the innovative resources and capabilities of the enterprises themselves. The limitation of innovation resources urges emerging technology enterprises to actively or passively exchange various innovation resources with other innovation subjects across organizational, technological or industry boundaries, and promotes the rapid rise of crossover innovation networks of emerging technologies, which has become an important way for emerging technology enterprises to avoid innovation risks and improve innovation efficiency. To explore the crossover innovation network of emerging technologies and its evolution path, this paper uses social network analysis to build the IPC co-occurrence network, patentee cooperative innovation network and patent citation network by stages by taking the invention patent data of self-driving car technology from 2006 to 2020 as samples, analyzes the subject cooperation, knowledge flow and technology convergence in the process of crossover innovation, explores the evolution process of crossover innovation network of emerging technologies and its characteristics in each stage, and then draws relevant enlightenment.

China’s urban–rural dichotomy has resulted in a widening gap between urban and rural areas, posing significant challenges to rural development. This study aims to investigate the spatio-temporal differentiation and driving mechanisms of rural industry integration within the Chengdu–Chongqing Economic Circle in China. Using panel data from 2011 to 2020, we employed the entropy weight TOPSIS method to construct a comprehensive index that charts the evolution of rural industry integration across various districts and counties. Additionally, we utilized fixed-effect and spatio-temporally weighted regression models to analyze the underlying driving forces behind this integration. Our findings reveal a dynamic and varied landscape of rural industry integration, with different levels of depth and breadth across various subsystems. Spatially, we observed a transition from a dispersed to a more concentrated agglomeration pattern within the Chengdu–Chongqing Economic Circle. This shift suggests a diffusion effect emanating from core metropolitan areas, as well as an attracting force exerted by adjacent metropolitan circles. In terms of drivers, market demand, openness level, financial development, policy support, and agricultural insurance breadth significantly contribute to rural industry integration. However, technological progress and rural human capital exhibit a weaker correlation. Notably, our models identified pronounced spatial–temporal heterogeneity among these influencing factors, highlighting a nuanced and dynamic relationship between them. Overall, our study emphasizes the crucial role of rural industry integration in bridging the urban–rural divide and fostering sustainable agricultural development and rural revitalization. The insights gained from this research provide valuable guidance for policymakers and stakeholders seeking to optimize rural development strategies and unlock the potential of integrated rural industries.

Tuberculosis (TB) remains one of the world’s deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.

Bioactive secondary metabolites from Streptomycetes are important sources of lead compounds in current drug development. Streptomyces costaricanus SCSIO ZS0073, a mangrove-derived actinomycete, produces actinomycin D, a clinically used therapeutic for Wilm’s tumor of the kidney, trophoblastic tumors and rhabdomyosarcoma. In this work, we identified the actinomycin biosynthetic gene cluster (BGC) acn by detailed analyses of the S. costaricanus SCSIO ZS0073 genome. This organism produces actinomycin D with a titer of ~69.8 μg mL−1 along with traces of actinomycin Xoβ. The acn cluster localized to a 39.8 kb length region consisting of 25 open reading frames (ORFs), including a set of four genes that drive the construction of the 4-methyl-3-hydroxy-anthranilic acid (4-MHA) precursor and three non-ribosomal peptide synthetases (NRPSs) that generate the 4-MHA pentapeptide semi-lactone, which, upon dimerization, affords final actinomycin D. Furthermore, the acn cluster contains four positive regulatory genes acnWU4RO, which were identified by in vivo gene inactivation studies. Our data provide insights into the genetic characteristics of this new mangrove-derived actinomycin D bioproducer, enabling future metabolic engineering campaigns to improve both titers and the structural diversities possible for actinomycin D and related analogues.

RNA interference (RNAi) is a process of eukaryotic posttranscriptional gene silencing that functions in antiviral immunity in plants, nematodes, and insects. However, recent studies provided strong supports that RNAi also plays a role in antiviral mechanism in mammalian cells. To combat RNAi-mediated antiviral responses, many viruses encode viral suppressors of RNA silencing (VSR) to facilitate their replication. VSRs have been widely studied for plant and insect viruses, but only a few have been defined for mammalian viruses currently. We identified a novel VSR from coronaviruses, a group of medically important mammalian viruses including Severe acute respiratory syndrome coronavirus (SARS-CoV), and showed that the nucleocapsid protein (N protein) of coronaviruses suppresses RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. Mouse hepatitis virus (MHV) is closely related to SARS-CoV in the family Coronaviridae and was used as a coronavirus replication model. The replication of MHV increased when the N proteins were expressed in trans, while knockdown of Dicer1 or Ago2 transcripts facilitated the MHV replication in mammalian cells. These results support the hypothesis that RNAi is a part of the antiviral immunity responses in mammalian cells. IMPORTANCE RNAi has been well known to play important antiviral roles from plants to invertebrates. However, recent studies provided strong supports that RNAi is also involved in antiviral response in mammalian cells. An important indication for RNAimediated antiviral activity in mammals is the fact that a number of mammalian viruses encode potent suppressors of RNA silencing. Our results demonstrate that coronavirus N protein could function as a VSR through its double-stranded RNA binding activity. Mutational analysis of N protein allowed us to find out the critical residues for the VSR activity. Using the MHV-A59 as the coronavirus replication model, we showed that ectopic expression of SARS-CoV N protein could promote MHV replication in RNAi-active cells but not in RNAi-depleted cells. These results indicate that coronaviruses encode a VSR that functions in the replication cycle and provide further evidence to support that RNAi-mediated antiviral response exists in mammalian cells. [ABSTRACT FROM AUTHOR]