Search

In the context of the normalization of COVID-19 epidemic, China has vigorously promoted COVID-19 vaccination, and the vaccination rate will have a profound impact on China's social economy.This topic in bengbu in anhui province as an example, through field investigation and data statistics, questionnaire survey method, based on the theory of a large number of bengbu enterprise economic data, the education scientific research development dynamics, and through the establishment of regression model, the new crown vaccination rates as independent variables, social economic level as the dependent variable, the concrete analysis of the new champions league vaccination rates to bengbu the influence of social economy, And then put forward constructive suggestions on the adverse effects of the high herd immunity threshold on the social and economic level.

Biosynthesis of gold nanoparticles (AuNPs) for antimicrobial and chemotherapeutic applications is a well-established process in microbial hosts such as bacterial, fungi, and plants. However, reports on AuNPs biosynthesis in mammalian cells are scarce. In this study, bovine aortic endothelial cells (BAECs) and bovine aortic smooth muscle cells (BASMCs) were examined for their ability to synthesize AuNPs in vitro. Cell culture conditions such as buffer selection, serum concentration, and HAuCl4 concentration were optimized before the biosynthesized AuNPs were characterized through visible spectrometry, transmission electron microscopy, X-ray diffraction, and Fourier transform infrared (FTIR) spectroscopy. BAECs and BASMC produced small, spherical AuNPs that are semi-crystalline with a similar diameter (23 ± 2 nm and 23 ± 4 nm). Hydrogen peroxide pretreatment increased AuNPs synthesis, suggesting that antioxidant enzymes may reduce Au3+ ions as seen in microbial cells. However, buthionine sulfoximine inhibition of glutathione synthesis, a key regulator of oxidative stress, failed to affect AuNPs generation. Taken together, these results show that under the right synthesis conditions, non-tumor cell lines can produce detectable concentrations of AuNPs in vitro.

According to our prior findings, ARID1A expression is decreased in colon cancer, which has a poor prognosis. In this study, we investigated the ARID1A-VIM/CDH1 signalling axis's role in colon cancer proliferation and migration. The differentially expressed genes in cells that might be controlled by ARID1A were discovered by a database screening for ARID1A knockout. qPCR was used to analyse ARID1A and EMT markers expression levels in colon cancer. We utilized siRNA RID1A to explore the influence of ARID1A silencing on EMT in CRC cells. The function of ARID1A in the colon was investigated utilizing the wound healing, transwell and CCK-8 WST- assays. The molecular mechanism by which ARID1A regulates VIM and CDH1 was elucidated using chip-qPCR. Numerous genes involved in EMT were dysregulated in the absence of ARID1A. VIM expression increased in cells lacking ARID1A expression and vice versa. Many COAD samples with high ARID1A mRNA expression had low VIM mRNA expression, despite the relevance. CDH1 gene was positively correlated with ARID1A. Moreover, siRNA-ARID1A-transfected cells accelerated cell migration and invasion and increased cell proliferation rate in vitro. Chip-qPCR analysis showed that ARID1A binds to the promoters of both genes and changes their expression in colon cancer. ARID1A inactivation is associated with VIM activation and CDH1 suppression, which might serve as crucial molecules influencing COAD prognosis, accelerate tumour progression, and shorten patients' survival time, and promote metastases of COAD. Thus, depletion of ARID1A can be therapeutically exploited by targeting downstream effects to improve cancer treatment-related outcomes.

We performed a differential analysis, enrichment analysis, and immune-infiltration analysis of the thyroid-associated ophthalmopathy (TAO) gene using data from the Gene Expression Omnibus (GEO) database to provide a theoretical basis for understanding the immune-related mechanisms of TAO.We searched the GEO database for "Graves disease" and selected the genes expressed in the lacrimal gland of thyroid-related eye disease patients as the test group and the genes expressed in the lacrimal gland of normal subjects as the control group. Immune-related differentially expressed genes (irDEGs), gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein-protein interaction, gene-gene interaction (GGI) network, pivotal gene identification, and immune-infiltration analyses were carried out, and finally, risk-prediction models were constructed.The GSE105149 and GSE58331 data sets contained 200 DEGs, of which 15 were immune-related. In relation to the GO biological processes (BPs), the main pathways included the interleukin (IL)-27-mediated signaling pathway, the IL-35-mediated signaling pathway, cytokine activity, T helper 17 cell differentiation, the phosphatidylinositol-3-kinase and protein kinase B signaling pathway, cytokine-cytokine receptor interaction, the Janus kinase and signal transducer and activator of transcription signaling pathway, and other KEGG pathways. Cluster of differentiation (CD)4In TAO, various types of immune cells infiltrate to different degrees, and the immune response and inflammatory response are throughout the disease. Our constructed risk-prediction models provide a reference for predicting TAO.

Considering the existing indicators are not sufficient to predict the patient's response to immune checkpoint inhibitors (ICIs), we conducted this study to evaluate the efficacy and safety of ICIs in advanced non-small cell lung cancer (NSCLC) patients, and to determine prognostic factors of ICIs. In this study, 61 patients diagnosed with advanced NSCLC who underwent ICIs were recruited. The univariate analysis revealed the number of metastatic sites, immune-related adverse events (irAEs) (≥ G2) and best response were significantly associated with both progression-free survival (PFS) and overall survival (OS). Peripheral blood biomarkers, including post-treatment neutrophil-to-lymphocyte ratio (NLR) and CEA levels were also associated with PFS, but not OS. The irAEs (≥ G2), best response and age were confirmed as independent predictors of a prolonged survival by multivariate analysis. The development of irAEs ≥ G2 correlated with a survival benefit in patients with advanced NSCLC (median PFS: 7.1 months vs. 4.6 months, P = 0.013). Thus, we concluded that identifying predictors of benefit from ICIs treatment will help to further extend patient survival in advanced NSCLC.

Biosynthesis of gold nanoparticles (AuNPs) for antimicrobial and chemotherapeutic applications is a well-established process in microbial hosts such as bacterial, fungi, and plants. However, reports on AuNPs biosynthesis in mammalian cells are scarce. In this study, bovine aortic endothelial cells (BAECs) and bovine aortic smooth muscle cells (BASMCs) were examined for their ability to synthesize AuNPs

AT-rich interaction domain 1A (ARID1A) is a tumor suppressor gene that mutates in several cancer types, including breast cancer, ovarian cancer, and colorectal cancer (CRC). In colon adenocarcinoma (COAD), the low expression of ARID1A was reported but the molecular reason is unclear. We noticed that ARID1A low expression was associated with increased levels of miR-185 in the COAD. Therefore, this study aims to explore ncRNA-dependent mechanism that regulates ARID1A expression in COAD regarding miR-185. The expression of ARID1A was tested in COAD cell line under the effect of miR-185 mimics compared with inhibitor. The molecular features associated with loss of ARID1A and its association with tumor prognosis were analyzed using multi-platform data from The Cancer Genome Atlas (TCGA), and gene set enrichment analysis (GSEA) to identify potential signaling pathways associated with ARID1A alterations in colon cancer. Kaplan-Meier survival curve showed that a low level of ARID1A was closely related to low survival rate in patients with COAD. Results showed that inhibiting miR-185 expression in the COAD cell line significantly restored the expression of ARID1A. Further, the increased expression of ARID1A significantly improved the prolonged overall survival of COAD. We noticed that there is a possible relationship between ARID1A high expression and tumor microenvironment infiltrating immune cells. Furthermore, the increase of ARID1A in tumor cells enhanced the response of inflammatory chemokines. In conclusion, this study demonstrates that ARID1A is a direct target of miR-185 in COAD that regulates the immune modulations in the microenvironment of COAD.

Summary DNA-induced liquid-liquid phase separation of cyclic GMP-AMP synthase (cGAS) triggers a potent response to detect pathogen infection and promote innate immune signaling. Whether and how pathogens manipulate cGAS-DNA condensation to mediate immune evasion is unknown. We report the identification of a structurally related viral tegument protein family, represented by ORF52 and VP22 from gamma- and alpha-herpesvirinae, respectively, that employs a conserved mechanism to restrict cGAS-DNA phase separation. ORF52/VP22 proteins accumulate into, and effectively disrupt, the pre-formed cGAS-DNA condensation both in vitro and in cells. The inhibition process is dependent on DNA-induced liquid-liquid phase separation of the viral protein rather than a direct interaction with cGAS. Moreover, highly abundant ORF52 proteins carried within viral particles are able to target cGAS-DNA phase separation in early infection stage. Our results define ORF52/VP22-type tegument proteins as a family of inhibitors targeting cGAS-DNA phase separation and demonstrate a mechanism for how viruses overcome innate immunity.

The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum (ER) is a key biological process mediated by the signal recognition particle (SRP). In eukaryotes, the SRP68–SRP72 (SRP68/72) heterodimer plays an essential role in protein translocation. However, structural information on the two largest SRP proteins, SRP68 and SRP72, is limited, especially regarding their interaction. Herein, we report the first crystal structures of human apo-SRP72 and the SRP68/72 complex at 2.91Å and 1.7Å resolution, respectively. The SRP68-binding domain of SRP72 contains four atypical tetratricopeptide repeats (TPR) and a flexible C-terminal cap. Apo-SRP72 exists mainly as dimers in solution. To bind to SRP68, the SRP72 homodimer disassociates, and the indispensable C-terminal cap undergoes a pronounced conformational change to assist formation of the SRP68/72 heterodimer. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 through its unusually hydrophobic and extended surface. Structural, biophysical, and mutagenesis analyses revealed that cancer-associated mutations disrupt the SRP68–SRP72 interaction and their co-localization with ER in mammalian cells. The results highlight the essential role of the SRP68–SRP72 interaction in SRP-mediated protein translocation and provide a structural basis for disease diagnosis, pathophysiology, and drug design.

Summary: Zinc-finger antiviral protein (ZAP) is a host antiviral factor that specifically restricts a wide range of viruses. ZAP selectively binds to CG-dinucleotide-enriched RNA sequences and recruits multiple RNA degradation machines to degrade target viral RNA. However, the molecular mechanism and structural basis for ZAP recognition of specific RNA are not clear. Here, we report the crystal structure of the ZAP N-terminal domain bound to a CG-rich single-stranded RNA, providing the molecular basis for its specific recognition of a CG dinucleotide and additional guanine and cytosine. The four zinc fingers of ZAP adopt a unique architecture and form extensive interactions with RNA. Mutations of both protein and RNA at the RNA-ZAP interacting surface reduce the in vitro binding affinity and cellular antiviral activity. This work reveals the molecular mechanism of ZAP recognition of specific target RNA and also provides insights into the mechanism by which ZAP coordinates downstream RNA degradation processes. : ZAP is a host antiviral factor that specifically restricts a wide range of viruses. Luo et al. determine the structural and molecular basis for the specific recognition of a CG dinucleotide and additional guanine and cytosine by ZAP. Keywords: ▪▪▪

Human non-small cell lung carcinoma (NSCLC) is one of the most common cancer worldwide. In previous studies, lovastatin, acting as an inhibitor of 3-hydroxy-3-methylglutaryl Co A (HMG-CoA) reductase, exhibited significant antitumor activity during tumorigenesis. However, whether or not this effect is mediated through changes in minichromosome maintenance (MCM) 2 expression remains unclear. The present study investigated whether lovastatin inhibits proliferation due to MCM2 in NSCLCs. We first assessed the effects of lovastatin on cell anti-proliferation, cell cycle progression and apoptosis in NSCLC cells. We found, by quantitative RT-PCR and western blot analysis, that lovastatin treatment markedly and consistently inhibited the expression of MCM2. Then, to further explore the anticancer mechanism of lovastatin involving MCM2, we silenced MCM2 by siRNA in two cell lines (A549 and GLC-82). Silencing of MCM2 triggered G1/S arrest. Following further examination of cell cycle-related factors, MCM2 knockdown inhibited protein retinoblastoma (Rb), cyclin D1 and CDK4 expression, but increased p21 and p53 expression, suggesting that siMCM2 indeed triggered cell cycle arrest. In addition, siMCM2 induced apoptosis. Finally, lovastatin treatment increased p-JNK, which is involved in the downregulation of MCM2. In conclusion, our data suggest that MCM2 may be a novel therapeutic target of lovastatin treatment in NSCLCs.

Endoribonuclease (NendoU) is unique and conserved as a major genetic marker in nidoviruses that infect vertebrate hosts. Arterivirus nonstructural protein 11 (nsp11) was shown to have NendoU activity and play essential roles in the viral life cycle. Here, we report three crystal structures of porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV) nsp11 mutants. The structures of arterivirus nsp11 contain two conserved compact domains: the N-terminal domain (NTD) and C-terminal domain (CTD). The structures of PRRSV and EAV endoribonucleases are similar and conserved in the arterivirus, but they are greatly different from that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoV), representing important human pathogens in the Nidovirales order. The catalytic center of NendoU activity is located in the CTD, where a positively charged groove is next to the key catalytic residues conserved in nidoviruses. Although the NTD is nearly identical, the catalytic region of the arterivirus nsp11 family proteins is remarkably flexible, and the oligomerization may be concentration dependent. In summary, our structures provide new insight into this key multifunctional NendoU family of proteins and lay a foundation for better understanding of the molecular mechanism and antiviral drug development. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus are two major members of the arterivirus family. PRRSV, a leading swine pathogen, causes reproductive failure in breeding stock and respiratory tract illness in young pigs. Due to the lack of a suitable vaccine or effective drug treatment and the quick spread of these viruses, infected animals either die quickly or must be culled. PRRSV costs the swine industry around $644 million annually in the United States and almost €1.5 billion in Europe every year. To find a way to combat these viruses, we focused on the essential viral nonstructural protein 11 (nsp11). nsp11 is associated with multiple functions, such as RNA processing and suppression of the infected host innate immunity system. The three structures solved in this study provide new insight into the molecular mechanisms of this crucial protein family and will benefit the development of new treatments against these deadly viruses.

The central region of MDM2 is critical for p53 activation and tumor suppression. Upon ribosomal stress, this region is bound by ribosomal proteins, particularly ribosomal protein L11 (RPL11), leading to MDM2 inactivation and subsequent p53 activation. Here, we solved the complex structure of human MDM2–RPL11 at 2.4 Å. MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers. Formation of the MDM2–RPL11 complex induces substantial conformational changes in both proteins. RPL11, unable to bind MDM2 mutants, fails to induce the activation of p53 in cells. MDM2 mimics 28S rRNA binding to RPL11. The C4 zinc finger determines RPL11 binding to MDM2 but not its homolog, MDMX. Our results highlight the essential role of the RPL11–MDM2 interaction in p53 activation and tumor suppression and provide a structural basis for potential new anti-tumor drug development.

Little is known about the prognostic factors for small cell lung cancer (SCLC) in Chinese patients. The aim of this retrospective study was to improve our understanding of overall survival (OS) and progression-free survival (PFS) prognostic factors in Chinese patients with SCLC. A retrospective analysis of 999 SCLC cases was performed. Patient characteristics, treatments, and laboratory data, including platelet counts and serum lactate dehydrogenase (LDH) and serum sodium levels, were collected. Potential prognostic factors for OS and PFS were evaluated by univariate and multivariate analyses. The median OS and PFS were 10.6 and 7.0 months, respectively. The multivariate Cox proportional hazards model was used to identify stage, serum LDH, and several therapy-relevant factors, including the initial chemotherapy regimen, number of initial chemotherapy cycles and combination therapy, as independent prognostic factors for OS. Furthermore, female sex, normal LDH levels, a response to therapy, receiving six cycles of initial chemotherapy, and receiving chemotherapy combined with radiotherapy and/or surgery were favorable prognostic factors for PFS. In addition, patients with hyponatremia had a worse OS; therefore, hyponatremia could not influence survival when a good response to therapy was achieved, and it failed to predict PFS. This study demonstrated that several factors, including patient, tumor and treatment characteristics and serum LDH levels are independent prognostic factors for OS and PFS in Chinese patients with SCLC. The identification of such factors will help physicians compare different populations and to interpret the contribution of treatment to differences in survival among groups. This article is protected by copyright. All rights reserved.

Flexibility is an intrinsic property of proteins and essential for their biological functions. However, because of structural flexibility, obtaining high-quality crystals of proteins with heterogeneous conformations remain challenging. Here, we show a novel approach to immobilize traditional precipitants onto molecularly imprinted polymers (MIPs) to facilitate protein crystallization, especially for flexible proteins. By applying this method, high-quality crystals of the flexible N-terminus of human fragile X mental retardation protein are obtained, whose absence causes the most common inherited mental retardation. A novel KH domain and an intermolecular disulfide bond are discovered, and several types of dimers are found in solution, thus providing insights into the function of this protein. Furthermore, the precipitant-immobilized MIPs (piMIPs) successfully facilitate flexible protein crystal formation for five model proteins with increased diffraction resolution. This highlights the potential of piMIPs for the crystallization of flexible proteins.

The present study aimed to ascertain whether suppression of midkine (MK) expression in pancreatic cancer cells inhibits metastasis to the liver. Human pancreatic cancer AsPC-1 cells were transfected with small interfering RNA (siRNA) targeting MK. siRNA against MK was observed to reduce the expression of MK mRNA and protein in a concentration- and time-dependent manner, and to decrease the number of migrating and tissue-penetrating cells in a concentration-dependent manner (P