Identification of prognostic biomarkers for breast cancer brain metastases based on the bioinformatics analysis

PurposeThe prognosis of breast cancer (BC) patients who develop into brain metastases (BMs) is very poor. Thus, it is of great significance to explore the etiology of BMs in BC and identify the key genes involved in this process to improve the survival of BC patients with BMs.Patients and methodsThe gene expression data and the clinical information of BC patients were downloaded from TCGA and GEO database. Differentially expressed genes (DEGs) in TCGA-BRCA and GSE12276 were overlapped to find differentially expressed metastatic genes (DEMGs). The protein-protein interaction (PPI) network of DEMGs was constructed via STRING database. ClusterProfiler R package was applied to perform the gene ontology (GO) enrichment analysis of DEMGs. The univariate Cox regression analysis and the Kaplan-Meier (K-M) curves were plotted to screen DEMGs associated with the overall survival and the metastatic recurrence survival, which were identified as the key genes associated with the BMs in BC. The immune infiltration and the expressions of immune checkpoints for BC patients with brain relapses and BC patients with other relapses were analyzed respectively. The correlations among the expressions of key genes and the differently infiltrated immune cells or the differentially expressed immune checkpoints were calculated. The gene set enrichment analysis (GSEA) of each key gene was conducted to investigate the potential mechanisms of key genes involved in BC patients with BMs. Moreover, CTD database was used to predict the drug-gene interaction network of key genes.ResultsA total of 154 DEGs were identified in BC patients at M0 and M1 in TCGA database. A total of 667 DEGs were identified in BC patients with brain relapses and with other relapses. By overlapping these DEGs, 17 DEMGs were identified, which were enriched in the cell proliferation related biological processes and the immune related molecular functions. The univariate Cox regression analysis and the Kaplan-Meier curves revealed that CXCL9 and GPR171 were closely associated with the overall survival and the metastatic recurrence survival and were identified as key genes associated with BMs in BC. The analyses of immune infiltration and immune checkpoint expressions showed that there was a significant difference of the immune microenvironment between brain relapses and other relapses in BC. GSEA indicated that CXCL9 and GPR171 may regulate BMs in BC via the immune-related pathways.ConclusionOur study identified the key genes associated with BMs in BC patients and explore the underlying mechanisms involved in the etiology of BMs in BC. These findings may provide a promising approach for the treatments of BC patients with BMs.     

Potential generation in bilayer lipid membranes in the NADH-flavin mononucleotide-ubiquinone-6-O2 system

Membrane conductance and generation of transmembrane potential by the NADH oxidation reactions in the NADH-flavin mononucleotide-ubiquinone-6-O₂ system have been studied. It has been shown that in solutions of a relatively low buffer capacity at pH 5.8 in the presence of a proton carrier, a potential is generated, the value of which depends on the concentration of the reducer and amounts to 40–60 mV. In the absence of a proton carrier at pH 8, a potential arises, which suggests a transmembrane negative charge transfer. Bilayer lipid membranes have been shown to possess proton selectivity if the reaction is run at pH 3.7. At a pH higher than 5.8 the proton selectivity disappears. Schemes of potential generation in lipid bilayers in different conditions are suggested and discussed.     

Interplay of four auxiliary factors is required for the assembly of photosystem I reaction center subcomplex

The photosystem I (PSI) complex consisting of reaction center (RC) subunits, several peripheral subunits and many co-factors, is present in the thylakoid membranes of chloroplasts and cyanobacteria. The assembly of RC subunits (PsaA/B) that bind electron transfer co-factors and antenna pigments is an intricate process, and is mediated by several auxiliary factors such as Ycf3, Y3IP1/CGL59, Ycf4 and Ycf37/PYG7/CGL71. However, their precise molecular mechanisms in RC assembly remain to be addressed. Here we purified four PSI auxiliary factors by affinity chromatography, and characterized co-purified PSI assembly intermediates. We suggest that Ycf3 assists the initial assembly of newly synthesized PsaA/B subunits into an RC subcomplex, while Y3IP1 may be involved in transferring the RC subcomplex from Ycf3 to the Ycf4 module that stabilizes it. CGL71 may form an oligomer that transiently interacts with the PSI RC subcomplex, physically protecting it under oxic conditions until association with the peripheral PSI subunits occurs. Together, our results reveal the interplay among four auxiliary factors required for the stepwise assembly of the PSI RC.     

Proliferative stem cells maintain quiescence of their niche by secreting the Activin inhibitor Follistatin

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Variant enterovirus A71 found in immune-suppressed patient binds to heparan sulfate and exhibits neurotropism in B-cell-depleted mice

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Regulation of humoral immune responses by a bone marrow-derived glycolipid-like molecule

Bone marrow cells have been shown to nonspecifically suppress primary in vitro antibody responses. This suppression appears to be mediated by a low-molecular-weight soluble factor, B-SF which was released from a fraction of cells of similar size to the suppressor as obtained by velocity sedimentation. Like the suppressor cell, B-SF was also shown to be effective very early in the immune response. It was produced by all strains of mice tested and functioned across strain barriers. Characterization of the active suppressor molecule showed it to be a highly heat-stable, nonsialic acid-containing glycolipid of 1000 to 35000 daltons in molecular weight. Recovery of the purified suppressor from thin-layer chromatography plates was achieved indicating that the major glycolipid component visualized on TLC is likely the active suppressor molecule. The characteristics of this suppressor may show it to be a fundamental immune regulatory mechanism.     

Animal models of enterovirus 71 infection: applications and limitations

Human enterovirus 71 (EV71) has emerged as a neuroinvasive virus that is responsible for several outbreaks in the Asia-Pacific region over the past 15 years. Appropriate animal models are needed to understand EV71 neuropathogenesis better and to facilitate the development of effective vaccines and drugs. Non-human primate models have been used to characterize and evaluate the neurovirulence of EV71 after the early outbreaks in late 1990s. However, these models were not suitable for assessing the neurovirulence level of the virus and were associated with ethical and economic difficulties in terms of broad application. Several strategies have been applied to develop mouse models of EV71 infection, including strategies that employ virus adaption and immunodeficient hosts. Although these mouse models do not closely mimic human disease, they have been applied to determine the pathogenesis of and treatment and prevention of the disease. EV71 receptor-transgenic mouse models have recently been developed and have significantly advanced our understanding of the biological features of the virus and the host-parasite interactions. Overall, each of these models has advantages and disadvantages, and these models are differentially suited for studies of EV71 pathogenesis and/or the pre-clinical testing of antiviral drugs and vaccines. In this paper, we review the characteristics, applications and limitation of these EV71 animal models, including non-human primate and mouse models.