ZNF131 facilitates the growth of hepatocellular carcinoma by acting as a transcriptional activator of SMC4 expression.

ZNF131 is a Zinc finger protein that acts as a transcription factor with oncogenic effects in multiple cancers. In this study, we aimed to explore the alternative splicing profile of ZNF131 in hepatocellular carcinoma (HCC), its regulatory effects on cell-cycle progression, and the downstream effectors. ZNF131 transcriptional profile and HCC survival analysis were conducted using data from the Cancer Genome Atlas (TCGA)-Liver Hepatocellular Cancer (LIHC) dataset. Chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays were utilized to explore transcriptional regulation. CCK-8, colony formation and xenograft tumor models were used to study HCC tumor growth. Results showed that ZNF131 isoform 2 is upregulated in HCC tissues and its upregulation was associated with unfavorable overall survival (OS) and progression-free interval (PFI). Knockdown of endogenous ZNF131 inhibits HCC cell growth and induces G2/M cell-cycle arrest. ZNF131 binds to the SMC4 promoter by interacting with ZBTB33 and the ZBTB33 recognizing motif. ZNF131 transcriptionally activates SMC4 expression in HCC cells. The tumor-suppressive effects of ZNF131 shRNA could be partially reversed by enforced SMC4 overexpression. In summary, this study highlights the ZNF131/ZBTB33/SMC4 axis as a driver of pathological cell cycling and proliferation in HCC.

SIRT5-mediated PRKAA2 succinylation ameliorates apoptosis of human placental trophoblasts in hypertensive disorder complicating pregnancy.

PURPOSE: Hypertensive disorder complicating pregnancy (HDCP) is a serious clinical disorder syndrome during pregnancy. This study aims at finding novel targets for HDCP therapy. METHODS: HDCP-related mRNAs were firstly screened out and subjected to gene enrichment analysis. We chose protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) as the research object. Thirty-nine HDCP patients at 32 to 40 weeks of gestation were selected as the HDCP group, and 39 normal controls who received cesarean section delivery at 37-42 weeks of pregnancy were enrolled in this study. Chorionic villi samples were collected within 30 min of delivery. The apoptosis of isolated placental trophoblasts was monitored to investigate the regulatory role of PRKAA2. RESULTS: PRKAA2 expression was further proven to be enhanced in the placental tissues of HDCP patients compared with that of normal puerpera. Subsequently, the results of flow cytometry analysis and western blot indicated that PRKAA2 overexpression accelerated primary placental cell apoptosis, while its knockdown attenuated cell apoptosis. Mechanistically, we determined that the level of PRKAA2 succinylation was elevated in the placental tissue of HDCP patients. Through in vitro succinylation assay and mutagenesis, we confirmed that sirtuin 5 (SIRT5) interacts with PRKAA2 at K69 and K260 to induce PRKAA2 desuccinylation. SIRT5 regulated primary HDCP cell apoptosis through PRKAA2. Finally, the animal study revealed that PRKAA2 elevates the systolic blood pressure of HDCP rat model. CONCLUSION: Our findings indicated that SIRT5-mediated PRKAA2 succinylation modulates placental cell apoptosis in HDCP, suggesting that PRKAA2 is a potential therapeutic target for HDCP treatment.

Toll9 from Bombyx mori functions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals.

Toll/Toll-like receptors (TLRs) are key regulators of the innate immune system in both invertebrates and vertebrates. However, while mammalian TLRs directly recognize pathogen-associated molecular patterns, the insect Toll pathway is thought to be primarily activated by binding Spätzle cytokines that are processed from inactive precursors in response to microbial infection. Phylogenetic and structural data generated in this study supported earlier results showing that Toll9 members differ from other insect Tolls by clustering with the mammalian TLR4 group, which recognizes lipopolysaccharide (LPS) through interaction with myeloid differentiation-2 (MD-2)-like proteins. Functional experiments showed that BmToll9 from the silkmoth Bombyx mori also recognized LPS through interaction with two MD-2-like proteins, previously named BmEsr16 and BmPP, that we refer to in this study as BmMD-2A and BmMD-2B, respectively. A chimeric BmToll9-TLR4 receptor consisting of the BmToll9 ectodomain and mouse TLR4 transmembrane and Toll/interleukin-1 (TIR) domains also activated LPS-induced release of inflammatory factors in murine cells but only in the presence of BmMD-2A or BmMD-2B. Overall, our results indicate that BmToll9 is a pattern recognition receptor for LPS that shares conserved features with the mammalian TLR4-MD-2-LPS pathway.

The role of lncRNAKCNQ1OT1/miR-301b/Tcf7 axis in cardiac hypertrophy.

OBJECTIVE: Cardiac hypertrophy, acting as a pathologic process of chronic hypertension and coronary disease, and its underlying mechanisms still need to be explored. Long non-coding RNA (LncRNA) potassium voltage-gated channel subfamily Q member 1 Transcript 1 (KCNQ1OT1) has been implicated in myocardial infarction. However, its role in cardiac hypertrophy remains reported. METHOD: To explore the regulated effect of lncRNAKCNQ1OT1 and miR-301b in cardiac hypertrophy, gain-and-lose function assays were tested. The expression of lncRNAKCNQ1OT1 and miR-301b were tested by quantitative real time polymerase chain reaction (qRT-PCR). The levels of transcription factor 7 (Tcf7), Proto-oncogene c-myc (c-myc), Brainnatriureticpeptide (BNP) and ß-myosin heavy chain (ß-MHC) were detected by Western blot. Additionally, luciferase analysis revealed interaction between lncRNAKCNQ1OT1, BNPß-MHCmiR-301b, and Tcf7. RESULT: LncRNAKCNQ1OT1 overexpression significantly induced cardiac hypertrophy. Furthermore, lncRNAKCNQ1OT1 acts as a sponge for microRNA-301b, which exhibited lower expression in cardiac hypertrophy model, indicating an anti-hypertrophic role. Furthermore, the BNP and ß-MHC expression increased, as well as cardiomyocyte surface area, with Ang II treatment, while the effect was repealed by miR-301b. Moreover, the protein expression of Tcf7 was inversely regulated by miR-301b and Antisense miRNA oligonucleotides (AMO)-301b. CONCLUSION: Our study has shown that overexpression of lncRNAKCNQ1OT1 could promote the development of cardiac hypertrophy by regulating miR-301b and Tcf7. Therefore, inhibition of lncRNAKCNQ1OT1 might be a potential therapeutic strategy for cardiac hypertrophy.

Therapeutic drug monitoring of free vancomycin concentration in practice: A new analytical technique based on the HFCF-UF sample separation method.

The aim of this study was to establish a method for free vancomycin concentration determination in human plasma and apply it to clinical therapeutic drug monitoring (TDM). The unbound vancomycin in plasma was separated by the hollow fiber centrifugal ultrafiltration (HFCF-UF) technique and analyzed by HPLC. Chromatographic conditions were optimized, the specificity, linearity, precision, recovery and stability of the method were examined, and plasma samples of patients were measured. The standard curve for free vancomycin is y = 0.0277x - 0.0080 with good linearity within 0.25-50 µg·mL-1 . The relative and absolute recovery rates for vancomycin were 98.63-101.0% and 88.41-101.2%, respectively. The intraday and interday precision RSDs were <10%. Plasma was stable under several conditions. The TDM value of the free vancomycin concentration of 20 patients was 0.99-38.51 µg·mL-1 , and the correlation between the free and total concentrations was not significant. The unbound fraction of vancomycin ranged from 25.5 to 84.8%, with large variation. The operation of free vancomycin separation by HFCF-UF was simple and suitable for TDM in practice. The unbound fraction of vancomycin in clinical samples varied significantly between individuals. It is recommended to perform free concentration TDM in critically ill patients.

Efficacy and evaluation of therapeutic exercises on adults with Parkinson's disease: a systematic review and network meta-analysis.

BACKGROUND: Exercises are an effective treatment in Parkinson's disease (PD), but there is still controversy over which types should be used. We aimed to compare and rank the types of exercise that improve PD symptoms by quantifying information from randomised controlled trials. METHODS: We performed a systematic review and network meta-analysis and searched PubMed, MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and China National Knowledge Infrastructure (CNKI) from their inception date to June 30, 2022. We included randomized controlled trials of 24 types of exercise for the interventional treatment of adults (≥ 50 years old) with PD. Effect size measures were standardized mean differences (SMDs) with 95% credible intervals (CrIs). The confidence of evidence was examined using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We identified 10 474 citations and included 250 studies involving 13 011 participants. Results of NMA showed that power training (PT) had the best benefits for motor symptoms compared with the control group (CON), with SMDs (95% CrI) (-1.46, [-2.18 to -0.74]). Body weight support treadmill training (BWS_TT) showed the best improvement in balance (1.55, [0.72 to 2.37]), gait velocity (1.15 [0.57 to 1.31]) and walking distance (1.96, [1.18 to 2.73]), and robotic assisted gait training (RA_GT) had the most benefits for freezing of gait (-1.09, [-1.80 to -0.38]). For non-motor symptoms, Dance showed the best benefits for depression (-1.71, [-2.79 to -0.73]). Only Yoga significantly reduced anxiety symptom compared with CON (-0.53, [0.96 to -0.11]). Only resistance training (RT) significantly enhanced sleep quality and cognition (-1.42, [-2.60 to -0.23]; 0.51, [0.09 to 0.94]). For muscle strength, PT showed the best advance (1.04, [0.64 to 1.44]). For concern of falling, five types of exercise were more effective than CON. CONCLUSIONS: There is low quality evidence that PT, Yoga, BWS_TT, Dance, and RT are the most effective treatments, pending outcome of interest, for adults with PD. TRIAL REGISTRATION: PROSPERO (CRD42021220052).

Immune infiltration profiling in gastric cancer and their clinical implications.

The abundance and type of immune cells in the tumor microenvironment (TME) significantly influence immunotherapy and tumor progression. However, the role of immune cells in the TME of gastric cancer (GC) is poorly understood. We studied the correlations, proportion, and infiltration of immune and stromal cells in GC tumors. Data analyses showed a significant association of infiltration levels of specific immune cells with the pathological characteristics and clinical outcomes of GC. Furthermore, based on the difference in infiltration levels of immune and stromal cells, GC patients were divided into two categories, those with "immunologically hot" (hot) tumors and those with "immunologically cold" (cold) tumors. The assay for transposase-accessible chromatin using sequencing and RNA sequencing analyses revealed that the hot and cold tumors had altered epigenomic and transcriptional profiles. Claudin-3 (CLDN3) was found to have high expression in the cold tumors and negatively correlated with CD8+ T cells in GC. Overexpression of CLDN3 in GC cells inhibited the expression of MHC-I and CXCL9. Finally, the differentially expressed genes between hot and cold tumors were utilized to generate a prognostic model, which predicted the overall survival of GC as well as patients with immunotherapy. Overall, we undertook a comprehensive analysis of the immune cell infiltration pattern in GC and provided an accurate model for predicting the prognosis of GC patients.

Effect of mutations in capsid shell protein on the assembly of BmCPV virus-like particles.

Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) is a typical single-layer capsid dsRNA virus belonging to the genus Cypovirus in the family Reoviridae. The results of cryo-electron microscopy showed that the BmCPV capsid consists of 60 asymmetric units, and each asymmetric unit contains one turret protein (TP), two large protrusion proteins (LPP) and two capsid shell proteins (CSP). CSP has the ability to self-assemble into virus-like particles (VLPs), and the small protrusion domain (SPD) in CSP may play an essential role in the assembly of viral capsids. In this study, three critical amino acid sites, D828, S829 and V945, in the SPD were efficiently mutated (point mutation) based on the principle of PCR circular mutagenesis. Moreover, a multi-gene expression system, Ac-MultiBac baculovirus, was used to produce eight different recombinant VLPs in vitro. Transmission electron microscopy showed that the single site and double site mutations had little effect on the efficiency and morphology of the assembly of VLPs. Still, the simultaneous mutation of the three sites had a significant impact. The experimental results demonstrate that the SPD of CSP plays an essential role in assembly of the viral capsid, which lays the foundation for further analysis of the molecular and structural mechanism of BmCPV capsid assembly.

Smart Materials for Dynamic Thermal Radiation Regulation.

Thermal radiation in the mid-infrared region profoundly affects human lives in various fields, including thermal management, imaging, sensing, camouflage, and thermography. Due to their fixed emissivities, radiance features of conventional materials are usually proportional to the quadruplicate of surface temperature, which set the limit, that one type of material can only present a single thermal function. Therefore, it is necessary and urgent to design materials for dynamic thermal radiation regulations to fulfill the demands of the age of intelligent machines. Recently, the ability of some smart materials to dynamically regulate thermal radiation has been evaluated. These materials are found to be competent enough for various commands, thereby, providing better alternatives and tremendously promoting the commercial potentials. In this review, the dynamic regulatory mechanisms and recent progress in the evaluation of these smart materials are summarized, including thermochromic materials, electrochromic materials, mechanically and humidity responsive materials, with the potential applications, insufficient problems, and possible strategies highlighted.

Transcriptome analysis reveals GPNMB as a potential therapeutic target for gastric cancer.

Gastric cancer has the fifth highest incidence of disease and is the third leading cause of cancer-associated mortality in the world. The etiology of gastric cancer is complex and needs to be fully elucidated. Thus, it is necessary to explore potential pathogenic genes and pathways that contribute to gastric cancer. Gene expression profiles of the GSE33335 and GSE54129 datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were compared and identified using R software. The DEGs were then subjected to gene set enrichment analysis and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Survival analyses based on The Cancer Genome Atlas database were used to further screen the essential DEGs. A knockdown assay was performed to determine the function of the candidate gene in gastric cancer. Finally, the association between the candidate gene and immune-related genes was investigated. We found that GPNMB serves as an essential gene, with a high expression level, and predicts a worse outcome of gastric cancer. Knockdown of GPNMB inhibited gastric cancer cell proliferation and migration. In addition, GPNMB may augment the immunosuppressive ability of gastric cancer by recruiting immunosuppressive cells and promoting immune cell exhaustion through PI3K/AKT/CCL4 signaling axis. Collectively, these data suggest that GPNMB acts as an important positive mediator of tumor progression in gastric cancer, and GPNMB could exert multimodality modulation of gastric cancer-mediated immune suppression.

A ceRNA network and a potential regulatory axis in gastric cancer with different degrees of immune cell infiltration.

Immune cell infiltration is an important indicator of whether tumor patients will benefit from immunotherapy. Gastric cancer is one of the most common tumors in the world, and new indicators of immunotherapy are urgently needed. The aim of this study was to construct ceRNA networks in gastric cancer with different degrees of immune cell infiltration. We analyzed the expression profiles of different gastric cancer with different degrees of immune cell infiltration retrieved from The Cancer Genome Atlas (TCGA) database and found differentially expressed lncRNAs, mRNAs, and miRNAs. A ceRNA regulatory network of gastric cancer with different degrees of immune cell infiltration was constructed using functional annotation, RNA-RNA interaction prediction, correlation analysis, survival analysis, and other comprehensive bioinformatics methods. The interaction and correlation between ceRNAs were verified using experiments on tumor tissues and cell lines. Cell line experiments showed a potential RP11-1094M14.8/miR-1269a/CXCL9 axis that was consistent with the ceRNA theory. qRT-PCR results showed that RP11-1094M14.8 knockdown significantly reduced the expression of CXCL9, and RP11-1094M14.8 overexpression had the opposite effect. The results of clinical analysis of gastric cancer samples showed that RP11-1094M14.8 and CXCL9 were highly expressed in hot tumors, and CXCL9 was positively correlated with a better prognosis for patients. The constructed novel ceRNA network and the potential regulatory axis may provide a comprehensive understanding of the potential mechanisms of development in gastric cancer with different degrees of immune cell infiltration. The RP11-1094M14.8/miR-1269a/CXCL9 axis may serve as a potential immune-therapeutic target for gastric cancer with different degrees of immune cell infiltration.

Antiviral defense against Cypovirus 1 (Reoviridae) infection in the silkworm, Bombyx mori.

Recent years have shown a large increase in studies of infection of the silkworm (Bombyx mori) with Cypovirus 1 (previously designated as B. mori cytoplasmic polyhedrosis virus), that causes serious damage in sericulture. Cypovirus 1 has a single-layered capsid that encapsulates a segmented double-strand RNA (dsRNA) genome which are attractive features for the establishment of a biotechnological platform for the production of specialized gene silencing agents, either as recombinant viruses or as viral-like particles with nonreplicative dsRNA cargo. For both combatting viral disease and application of Cypovirus-based pest control, however, a better understanding is needed of the innate immune response caused by Cypovirus infection of the midgut of lepidopteran larvae. Studies of deep sequencing of viral small RNAs have indicated the importance of the RNA interference pathway in the control of Cypovirus infection although many functional aspects still need to be elucidated and conclusive evidence is lacking. A considerable number of transcriptome studies were carried out that revealed a complex response that hitherto remains uncharacterized because of a dearth in functional studies. Also, the uptake mechanism of Cypovirus by the midgut cells remains unclarified because of contrasting mechanisms revealed by electron microscopy and functional studies. The field will benefit from an increase in functional studies that will depend on transgenic silkworm technology and reverse genetics systems for Cypovirus 1.

Public Mental Health in Post-COVID-19 Era.

Transmission of the 2019 novel coronavirus (COVID-19) has now rapidly spread around the world, which has alarming implications for individuals and communities, in particular for public mental health. Significant progress has been made in the prevention and control of the COVID-19 pandemic in China, but the psychological crisis caused by the epidemic is still not over and may continue to exist. The public mental health in the post-COVID-19 era should not be ignored. This article provides early warning for the public's mental health in the post-COVID-19 era by listing the characteristics and duration of the public mental health crisis following the SARS outbreak. In addition, based on the current situation, specific methods and measures are proposed in order to provide effective reference for the prevention and control of psychological crisis caused by the COVID-19 epidemic.

Integrated Metabolomics and Lipidomics Analyses Reveal Metabolic Reprogramming in Human Glioma with IDH1 Mutation.

Mutations in isocitrate dehydrogenase ( IDH) 1 are high-frequency events in low-grade glioma and secondary glioblastoma, and IDH1 mutant gliomas are vulnerable to interventions. Metabolic reprogramming is a hallmark of cancer. In this study, comprehensive metabolism investigation of clinical IDH1 mutant glioma specimens was performed to explore its specific metabolic reprogramming in real microenvironment. Massive metabolic alterations from glycolysis to lipid metabolism were identified in the IDH1 mutant glioma tissue when compared to IDH1 wild-type glioma. Of note, tricarboxylic acid (TCA) cycle intermediates were in similar levels in both groups, with more pyruvate found entering the TCA cycle in IDH1 mutant glioma. The pool of fatty acyl chains was also reduced, displayed as decreased triglycerides and sphingolipids, although membrane phosphatidyl lipids were not changed. The lower fatty acyl pool may be mediated by the lower protein expression levels of long-chain acyl-CoA synthetase 1 (ACSL1), ACSL4, and very long-chain acyl-CoA synthetase 3 (ACSVL3) in IDH1 mutant glioma. Lower ACSL1 was further found to contribute to the better survival of IDH1 mutant glioma patients based on the The Cancer Genome Atlas (TCGA) RNA sequencing data. Our research provides valuable insights into the tissue metabolism of human IDH1 mutant glioma and unravels new lipid-related targets.

The R132H mutation in IDH1 promotes the recruitment of NK cells through CX3CL1/CX3CR1 chemotaxis and is correlated with a better prognosis in gliomas.

Mutations in the isocitrate dehydrogenase (IDH) 1 gene, especially the R132H mutation, have been reported to be associated with a better prognosis in glioma patients. However, the underlying molecular mechanisms are not yet well understood. Many factors may contribute to differences in the survival of IDH1 wild-type and IDH1 mutant glioma patients, in which immune components play a potentially important role. In this study, we analyzed The Cancer Genome Atlas (TCGA), and the Chinese Glioma Genome Atlas (CGGA) databases, as well as glioma patient-derived tumor samples. We found that there was a higher infiltration of natural killer (NK) cells in IDH1 mutant glioma patients, and this was correlated with a better prognosis. We also showed that IDH1-R132 tumor cells had higher expression levels of the chemokine CX3CL1. This arises as a result of the conversion of α-ketoglutarate to R(-)-2-hydroxyglutarate by the IDH1 mutant and the resultant phosphorylation of nuclear factor kappa B. Knockdown of CX3CL1 decreased the migration of NK cells. In addition, the high levels of expression of CX3CL1 were positively correlated with glioma patient survival in the TCGA and CGGA databases, and in the clinical samples. Overall, our data have identified a novel mechanism in which R132H mutation of the IDH1 gene serves as a tumor suppressor by promoting the recruitment of NK cells through CX3CL1/CX3CR1 chemotaxis.

Transcriptional response of immune-related genes after endogenous expression of VP1 and exogenous exposure to VP1-based VLPs and CPV virions in lepidopteran cell lines.

In insects, RNAi is considered the major antiviral immune defense pathway. DsRNAs produced during viral infection are processed by Dicer enzymes into small RNAs that function as specificity determinants to silence viral genes. By contrast, in mammals, recognition of molecules associated with viral infection, such as dsRNA, by pattern recognition receptors (PRRs) initiates a signaling cascade that culminates in the production and release of signaling proteins with antiviral function such as interferons. However, in insects, the hypothesis that components of virions can be recognized as pathogen-activated molecular patterns (PAMPs) to activate the innate immune response has not been investigated systematically. In this study, the potential of VP1, that constitutes the major capsid protein of cytoplasmic polyhedrosis virus (CPV; Reoviridae), to activate a collection of immune-related genes was examined in silkworm-derived Bm5 cells. Two different methods of VP1 administration were tested, either through endogenous expression in transformed cell lines, or through addition of purified VP1-based viral-like particles to the extracellular medium. In addition, exposure to CPV virions isolated from purified polyhedra was also performed. In general, our results do not show a robust transcriptional response of immune-related genes to VP1 or CPV virions, but two exceptions were noted. First, the expression of the antimicrobial peptide (AMP) gene Attacin was strongly induced after 24 h of exposure to VP1-based VLPs. Second, the expression levels of dcr-2, an essential gene in the RNAi pathway, were greatly increased in VP1-expressing transformed Sf21 cells but not transformed Bm5 cells, indicating the existence of species-specific effects. However, the increased expression of dcr-2 did not result in increased silencing efficiency when tested in an RNAi reporter assay. Our study indicates that the capsid protein VP1 of CPV has the potential to act as a PAMP and to induce a transcriptional response in insect cells that relate both to RNAi and protein effectors such as AMPs. The identity of the PRRs and the signaling cascade that are potentially triggered by VP1 remain to be elucidated in future experiments. While this study was performed on a small scale, it can encourage more comprehensive studies with high-throughput approaches (microarray, deep sequencing) to search more systematically whether viral capsid proteins can act as PAMPs in insects and whether their production results in the induction of immune-related genes with potential antiviral function.

An efficient method for multigene co-interference by recombinant Bombyx mori nucleopolyhedrovirus.

Bombyx mori Nucleopolyhedrovirus (BmNPV), which is a member of the Baculoviridae family, is a significant pathogen of the silkworm. The infection of BmNPV is often lethal and causes about 20% loss of cocoon in the silk industry annually. To explore the effects of different gene inhibition strategies on the replication cycle of baculovirus, we constructed the mutant virus to infect BmN cells directly and further identified ie0, ie1, and gp64 as the essential viral genes of BmNPV. To elucidate the significance of the inhibition effect of different interference strategies, we characterized and constructed the recombinant BmNPV that carried a single or multigene-interfering cassette. The results showed that the inhibition effect of dsie1 on target gene expression, virus titer, and silkworm mortality was significantly better than that of dsie0 and dsgp64. It also showed that the dsie1 interference produced fewer progeny virions and was less lethal, which indicates that ie1 played a more critical role in the BmNPV replication cycle. Furthermore, the inhibitory effect of the virus titer and mortality indicated that the multigene co-interference constructed by the baculovirus expression system was significantly better than the interference of any single-gene (p < 0.05). In summary, the strategy of multigene synergy can achieve the function of continuous interference and provide a new platform for the breeding of silkworm disease resistant. In addition, this strategy improves the various traits of the silkworm.

4.1B suppresses cancer cell proliferation by binding to EGFR P13 region of intracellular juxtamembrane segment.

BACKGROUND: Gastric cancer (GC) has high incidence and mortality worldwide. However, the underlying mechanisms that regulate gastric carcinogenesis are largely undefined. 4.1B is an adaptor protein found at the interface of membrane and the cytoskeleton. Previous studies demonstrated that 4.1B serves as tumor suppressor. RESULTS: We showed that 4.1B expression was decreased or lost in most GC patients. The expression pattern of it was tightly correlated with tumor size, TNM stage and overall survival (OS). We further showed that 4.1B inhibited the proliferation of two GC cell lines, MGC-803 and MKN-45, by impeding the EGFR/MAPK/ERK1/2 and PI3K/AKT pathways. A similar phenotype was also observed in immortalized mouse embryonic fibroblasts (MEF) derived from wild type (WT) and 4.1B knock-out (BKO) mice. Additionally, immunofluorescence (IF) staining and Co-IP showed that protein 4.1B bound to EGFR. Furthermore, the FERM domain of 4.1B interacted with EGFR through the initial 13 amino acids (P13) of the intracellular juxtamembrane (JM) segment of EGFR. The binding of 4.1B to EGFR inhibited dimerization and autophosphorylation of EGFR. CONCLUSION: Our present work revealed that 4.1B plays important regulatory roles in the proliferation of GC cells by binding to EGFR and inhibiting EGFR function through an EGFR/MAPK/ERK1/2 pathway. Our results provide novel insight into the mechanism of the development and progression of GC.

Genetic variants in Forkhead box O1 associated with predisposition to sepsis in a Chinese Han population.

BACKGROUND: Genetic variant is one of the causes of sepsis patients' mortality. Now, many studies have identified several SNPs related to sepsis. However, none of these studies were identified in a genome-wide way. We aimed to detect genetic polymorphisms of sepsis patients. METHODS: The blood samples of eight normal controls and ten sepsis patients were collected for whole exome sequencing. Then, Single Nucleotide Polymorphisms (SNPs) were selected according to quality score and number of sepsis patients who had this variants. Synonymous mutations were removed. Genes including these remaining variants were used for functional analyses. After analyses, the remaining SNPs and indels were validated in 149 normal controls and 156 sepsis patients. Finally, serum levels of proteins coded by genes including these SNPs were evaluated. RESULTS: After whole exome sequencing, 97 SNPs and one indel site were left. Then, functional screening was performed. Only seven SNPs were used for further validation. As a result, the rs2721068 in dominant model and rs17446614 in recessive model were associated with sepsis, and the ORs of these two SNPs were 3.24 (95%CI, 1.25, 8.44) and 0.47 (0.026, 0.88), respectively. These two SNPs were both located in Forkhead box O1 (FOXO1) gene. For rs2721068 (T/T, T/C-C/C) and rs17446614 (A/A-A/G, G/G), serum levels of foxo1 in sepsis patients were both significantly lower in normal controls. CONCLUSIONS: We firstly reported that the rs2721068 and rs17446614 were correlated to genetic predisposition to sepsis.

Chichen type III interferon produced by silkworm bioreactor induces ISG expression and restricts ALV-J infection in vitro.

Type III interferon (IFN-λ) has recently been shown to exert a significant antiviral impact against viruses in vertebrates. Avian leukosis virus subgroup J (ALV-J), which causes tumor disease and immunosuppression in infected chicken, is a retrovirus that is difficult to prevent and control because of a lack of vaccines and drugs. Here, we obtained chicken IFN-λ (chIFN-λ) using a silkworm bioreactor and demonstrated that chIFN-λ has antiviral activity against ALV-J infection of both chicken embryo fibroblast cell line (DF1) and epithelial cell line (LMH). We found that chIFN-λ triggered higher levels of particular type III interferon-stimulated genes (type III ISGs) including myxovirus resistance protein (Mx), viperin (RSAD2), and interferon-inducible transmembrane protein 3 (IFITM3) in DF1 and LMH cells. Furthermore, over-expression of Mx, viperin, and IFITM3 could inhibit ALV-J infection in DF1 and LMH cells. Therefore, these results suggested that the anti-ALV-J function of chIFN-λ was specifically implemented by induction of expression of type III ISGs. Our data identified chIFN-λ as a critical antiviral agent of ALV-J infection and provides a potentially and attractive platform for the production of commercial chIFN-λ.