Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, smooth muscle cell proliferation, cell apoptosis, necrosis, fibrosis, and local inflammation. Immune and ...inflammatory responses have significant effects on every phase of atherosclerosis, and increasing evidence shows that immunity plays a more important role in atherosclerosis by tightly regulating its progression. Therefore, understanding the relationship between immune responses and the atherosclerotic microenvironment is extremely important. This article reviews existing knowledge regarding the pathogenesis of immune responses in the atherosclerotic microenvironment, and the immune mechanisms involved in atherosclerosis formation and activation.
Rhynchophorus ferrugineus, the red palm weevil, is a key pest that attacks many economically important palm species and that has evolved a sensitive and specific olfactory system to seek palm hosts. ...Odorant-binding proteins not only play crucial roles in its olfactory perception process but are also important molecular targets for the development of new approaches for pest management.
Analysis of the tissue expression profiles of RferOBP8 and RferOBP11 revealed that these two RferOBPs exhibited high expression in the antennae and showed sexual dimorphism. We analyzed the volatiles of seven host plants by gas chromatography-mass spectrometry and screened 13 potential ligands by molecular docking. The binding affinity of two recombinant OBPs to aggregation pheromones and 13 palm odorants was tested by fluorescence competitive binding assays. The results revealed that 8 tested palm volatiles and ferrugineol have high binding affinities with RferOBP8 or RferOBP11. Behavioral trials showed that these 8 odor compounds could elicit an attraction response in adult RPW. RNAi analysis indicated that the reduction in the expression levels of the two RferOBPs led to a decrease in behavioral responses to these volatiles.
These results suggest that RferOBP8 and RferOBP11 are involved in mediating the responses of RPW to palm volatiles and to aggregation pheromones and may play important roles in RPW host-seeking. This study also provides a theoretical foundation for the promising application of novel molecular targets in the development of new behavioral interference strategies for RPW management in the future. This article is protected by copyright. All rights reserved.
The nucleus is considered the ideal target for anti‐tumor therapy because DNA and some enzymes in the nucleus are the main causes of cell canceration and malignant proliferation. However, nuclear ...target drugs with good biosafety and high efficiency in cancer treatment are rare. Herein, a nuclear‐targeted material MeTPAE with aggregation‐induced emission (AIE) characteristics was developed based on a triphenylamine structure skeleton. MeTPAE can not only interact with histone deacetylases (HDACs) to inhibit cell proliferation but also damage telomere and nucleic acids precisely through photodynamic treatment (PDT). The cocktail strategy of MeTPAE caused obvious cell cycle arrest and showed excellent PDT anti‐tumor activity, which offered new opportunities for the effective treatment of malignant tumors.
A nuclear‐targeted material MeTPAE with AIE characteristics was developed. MeTPAE can not only interact with HDACs to inhibit cell proliferation, but also damage telomere and nucleic acids precisely through photodynamic treatment. The cocktail strategy of MeTPAE caused obvious cell cycle arrest and showed excellent photodynamic therapy (PDT) anti‐tumor activity, which offered new opportunities for the effective treatment of malignant tumors.
Statin use decreases the risk of decompensation and mortality in patients with cirrhosis due to hepatitis C virus (HCV). Whether this beneficial effect can be extended to cirrhosis in the general ...population or cirrhosis due to other causes, such as hepatitis B virus (HBV) infection or alcohol, remains unknown. Statin use also decreases the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV and HCV infection. It is unclear whether the effect can be observed in patients with pre‐existing cirrhosis. The goal of this study was to determine the effect of statin use on rates of decompensation, mortality, and HCC in HBV‐, HCV‐, and alcohol‐related cirrhosis. Patients with cirrhosis were identified from a representative cohort of Taiwan National Health Insurance beneficiaries from 2000 to 2013. Statin users, defined as having a cumulative defined daily dose (cDDD) ≥28, were selected and served as the case cohort. Statin nonusers (<28 cDDD) were matched through propensity scores. The association between statin use and risk of decompensation, mortality, and HCC were estimated. A total of 1350 patients with cirrhosis were enrolled. Among patients with cirrhosis, statin use decreased the risk of decompensation, mortality, and HCC in a dose‐dependent manner (P for trend <0.0001, <0.0001, and 0.009, respectively). Regression analysis revealed a lower risk of decompensation among statin users with cirrhosis due to chronic HBV (adjusted hazard ratio HR, 0.39; 95% confidence interval CI, 0.25‐0.62) or HCV infection (HR, 0.51; 95% CI, 0.29‐0.93). The lowered risk of decompensation was of borderline significance among statin users with alcohol‐related cirrhosis (HR, 0.69; 95% CI, 0.45‐1.07). Conclusion: Statin use decreases the decompensation rate in both HBV‐ and HCV‐related cirrhosis. Of borderline significance is a decreased decompensation rate in alcohol‐related cirrhosis. (Hepatology 2017;66:896–907).
Immune thrombocytopenia (ITP) is the most common acquired thrombocytopenia after chemotherapy-induced thrombocytopenia. Existing guidelines describe the management and treatment of most patients who, ...overall, do well, even if they present with chronic disease, and they are usually not at a high risk for bleeding; however, a small percentage of patients is refractory and difficult to manage. Patients classified as refractory have a diagnosis that is not really ITP or have disease that is difficult to manage. ITP is a diagnosis of exclusion; no specific tests exist to confirm the diagnosis. Response to treatment is the only affirmative confirmation of diagnosis. However, refractory patients do not respond to front-line or other treatments; thus, no confirmation of diagnosis exists. The first section of this review carefully evaluates the diagnostic considerations in patients with refractory ITP. The second section describes combination treatment for refractory cases of ITP. The reported combinations are divided into the era before thrombopoietin (TPO) and rituximab and the current era. Current therapy appears to have increased effectiveness. However, the definition of refractory, if it includes insufficient response to TPO agents, describes a group with more severe and difficult-to-treat disease. The biology of refractory ITP is largely unexplored and includes oligoclonality, lymphocyte pumps, and other possibilities. Newer treatments, especially rapamycin, fostamatinib, FcRn, and BTK inhibitors, may be useful components of future therapy given their mechanisms of action; however, TPO agents, notwithstanding failure as monotherapy, appear to be critical components. In summary, refractory ITP is a complicated entity in which a precise specific diagnosis is as important as the development of effective combination treatments.
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During translation, a conserved GTPase elongation factor-EF-G in bacteria or eEF2 in eukaryotes-translocates tRNA and mRNA through the ribosome. EF-G has been proposed to act as a flexible motor that ...propels tRNA and mRNA movement, as a rigid pawl that biases unidirectional translocation resulting from ribosome rearrangements, or by various combinations of motor- and pawl-like mechanisms. Using time-resolved cryo-EM, we visualized GTP-catalyzed translocation without inhibitors, capturing elusive structures of ribosome•EF-G intermediates at near-atomic resolution. Prior to translocation, EF-G binds near peptidyl-tRNA, while the rotated 30S subunit stabilizes the EF-G GTPase center. Reverse 30S rotation releases Pi and translocates peptidyl-tRNA and EF-G by ~20 Å. An additional 4-Å translocation initiates EF-G dissociation from a transient ribosome state with highly swiveled 30S head. The structures visualize how nearly rigid EF-G rectifies inherent and spontaneous ribosomal dynamics into tRNA-mRNA translocation, whereas GTP hydrolysis and Pi release drive EF-G dissociation.
The emergence and spread of antibiotic resistance has posed a major threat to both human health and environmental ecosystem. Although the disinfection has been proved to be efficient to control the ...occurrence of pathogens, little effort is dedicated to revealing potential impacts of disinfection on transmission of antibiotic resistance genes (ARGs), particularly for free-living ARGs in final disinfected effluent of urban wastewater treatment plants (UWWTP). Here, we investigated the effects of chlorine disinfection on the occurrence and concentration of both extracellular ARGs (eARGs) and intracellular ARGs (iARGs) in a full-scale UWWTP over a year. We reported that the concentrations of both eARGs and iARGs would be increased by the disinfection with chlorine dioxide (ClO2). Specifically, chlorination preferentially increased the abundances of eARGs against macrolide (ermB), tetracycline (tetA, tetB and tetC), sulfonamide (sul1, sul2 and sul3), β-lactam (ampC), aminoglycosides (aph(2’)-Id), rifampicin (katG) and vancomycin (vanA) up to 3.8 folds. Similarly, the abundances of iARGs were also increased up to 7.8 folds after chlorination. In terms of correlation analyses, the abundance of Escherichia coli before chlorination showed a strong positive correlation with the total eARG concentration, while lower temperature and higher ammonium concentration were assumed to be associated with the concentration of iARGs. This study suggests the chlorine disinfection could increase the abundances of both iARGs and eARGs, thereby posing risk of the dissemination of antibiotic resistance in environments.
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•Impact of chlorination on eARGs pollution in UWWTPs were for the first time reported.•Chlorination disinfection enhanced both eARGs and iARGs pollution.•Extracellular tetM and sul1 were the most dominant eARGs in the final effluent.•E. coli showed a positive correlation with the total eARG concentration after chlorination.
Structure-based stabilization of protein–protein interactions (PPIs) is a promising strategy for drug discovery. However, this approach has mainly focused on the stabilization of native PPIs, and ...non-native PPIs have received little consideration. Here, we identified a non-native interaction interface on the three-dimensional dimeric structure of the N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD). The interface formed a conserved hydrophobic cavity suitable for targeted drug screening. By considering the hydrophobic complementarity during the virtual screening step, we identified 5-benzyloxygramine as a new N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities. X-ray crystallography and small-angle X-ray scattering showed that 5-benzyloxygramine stabilizes the N-NTD dimers through simultaneous hydrophobic interactions with both partners, resulting in abnormal N protein oligomerization that was further confirmed in the cell. This unique approach based on the identification and stabilization of non-native PPIs of N protein could be applied toward drug discovery against CoV diseases.
Most genome‐wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are for recurrence and mortality. We conducted a GWAS on breast cancer survival ...after diagnosis in estrogen receptor‐positive patients, including 953 Taiwanese patients with 159 events. Through Cox proportional hazard models estimation, we identified 24 risk SNPs with p < 1 × 10−5. Based on imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, p = 2.43 × 10−5) was found to be a functional variant associated with breast cancer survival and XCL1 gene expression. A series of experimental approaches, including cell‐based analyses and CRISPR/Cas9 genome‐editing system, were then used and identified the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer survival, which promoted XCL1 expression, but not to the G allele of rs1024176. The chemokine XCL1 attracts type 1 dendritic cells (DC1s) to the tumor microenvironment. In breast cancer tissues, we applied a two‐step Mendelian randomization analysis, using expression quantitative trait loci as instrumental variables, to confirm higher XCL1 expression was correlated with higher DC1 signatures and favorable disease progression, through the causal effect of rs1024176‐A allele. Our study supports the genetic effect on preventing breast cancer survival through XCL1‐induced DC1 recruitment in tumor microenvironment.
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Although many prognostic predictors have been identified, the factors that determine patient differences in breast cancer progression and survival are not fully understood. This study addresses the important role of cancer immune control in promoting human breast cancer survival. Using genetic, cell‐based, and multi‐omic analyses, the authors find that one of the most significant SNP, rs1024176 at 1q24.2 could be a functional variant regulating XCL1 gene expression and thus recruiting type 1 dendritic cells to the breast tumor microenvironment. These findings reveal a pathway to prevent breast cancer progression through XCL1‐induced type 1 dendritic cells recruitment in the tumor microenvironment.
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