Breaking tolerance in transgenic mice expressing the human TSH receptor A-subunit: thyroiditis, epitope spreading and adjuvant as a 'double edged sword'.

Transgenic mice with the human thyrotropin-receptor (TSHR) A-subunit targeted to the thyroid are tolerant of the transgene. In transgenics that express low A-subunit levels (Lo-expressors), regulatory T cell (Treg) depletion using anti-CD25 before immunization with adenovirus encoding the A-subunit (A-sub-Ad) breaks tolerance, inducing extensive thyroid lymphocytic infiltration, thyroid damage and antibody spreading to other thyroid proteins. In contrast, no thyroiditis develops in Hi-expressor transgenics or wild-type mice. Our present goal was to determine if thyroiditis could be induced in Hi-expressor transgenics using a more potent immunization protocol: Treg depletion, priming with Complete Freund's Adjuvant (CFA) + A-subunit protein and further Treg depletions before two boosts with A-sub-Ad. As controls, anti-CD25 treated Hi- and Lo-expressors and wild-type mice were primed with CFA+ mouse thyroglobulin (Tg) or CFA alone before A-sub-Ad boosting. Thyroiditis developed after CFA+A-subunit protein or Tg and A-sub-Ad boosting in Lo-expressor transgenics but Hi- expressors (and wild-type mice) were resistant to thyroiditis induction. Importantly, in Lo-expressors, thyroiditis was associated with the development of antibodies to the mouse TSHR downstream of the A-subunit. Unexpectedly, we observed that the effect of bacterial products on the immune system is a "double-edged sword". On the one hand, priming with CFA (mycobacteria emulsified in oil) plus A-subunit protein broke tolerance to the A-subunit in Hi-expressor transgenics leading to high TSHR antibody levels. On the other hand, prior treatment with CFA in the absence of A-subunit protein inhibited responses to subsequent immunization with A-sub-Ad. Consequently, adjuvant activity arising in vivo after bacterial infections combined with a protein autoantigen can break self-tolerance but in the absence of the autoantigen, adjuvant activity can inhibit the induction of immunity to autoantigens (like the TSHR) displaying strong self-tolerance

Metabolic Pathways Enhancement Confers Poor Prognosis in p53 Exon Mutant Hepatocellular Carcinoma.

RNA-Sequencing (RNA-Seq), the most commonly used sequencing application tool, is not only a method for measuring gene expression but also an excellent media to detect important structural variants such as single nucleotide variants (SNVs), insertion/deletion (Indels), or fusion transcripts. The Cancer Genome Atlas (TCGA) contains genomic data from a variety of cancer types and also provides the raw data generated by TCGA consortium. p53 is among the top 10 somatic mutations associated with hepatocellular carcinoma (HCC). The aim of the present study was to analyze concordant different gene profiles and the priori defined set of genes based on p53 mutation status in HCC using RNA-Seq data. In the study, expression profile of 11 799 genes on 42 paired tumor and adjacent normal tissues was collected, processed, and further stratified by the mutated versus normal p53 expression. Furthermore, we used a knowledge-based approach Gene Set Enrichment Analysis (GSEA) to compare between normal and p53 mutation gene expression profiles. The statistical significance (nominal P value) of the enrichment score (ES) genes was calculated. The ranked gene list that reflects differential expression between p53 wild-type and mutant genotypes was then mapped to metabolic process by KEGG, an encyclopedia of genes and genomes to assign functional meanings. These approaches enable us to identify pathways and potential target gene/pathways that are highly expressed in p53 mutated HCC. Our analysis revealed 2 genes, the hexokinase 2 (HK2) and Enolase 1 (ENO1), were conspicuous of red pixel in the heatmap. To further explore the role of these genes in HCC, the overall survival plots by Kaplan-Meier method were performed for HK2 and ENO1 that revealed high HK2 and ENO1 expression in patients with HCC have poor prognosis. These results suggested that these glycolysis genes are associated with mutated-p53 in HCC that may contribute to poor prognosis. In this proof-of-concept study, we proposed an approach for identifying novel potential therapeutic targets in human HCC with mutated p53. These approaches can take advantage of the massive next-generation sequencing (NGS) data generated worldwide and make more out of it by exploring new potential therapeutic targets

Transcription factor c-Myb promotes the invasion of hepatocellular carcinoma cells via increasing osteopontin expression

<p>Abstract</p> <p>Background</p> <p>Specific gene expression is tightly regulated by various transcription factors. Osteopontin (OPN) is a phosphoprotein that mediates hepatocellular carcinoma (HCC) progression and metastasis. However, the mechanism of OPN up-regulation in HCC metastasis remains to be clarified.</p> <p>Methods</p> <p>Oligonucleotide array-based transcription factor assays were applied to compare different activities of transcription factors in two human HCC cell lines with different OPN expression levels. The effects of one selected transcription factor on OPN expression were further evaluated.</p> <p>Results</p> <p>Eleven transcription factors were over-expressed in metastatic HCC cell line HCCLM6 cells whereas twelve transcription factors were down-regulated. Electrophoretic mobility shift assays (EMSA) and reporter gene assays showed that one of up-regulated transcription factors c-Myb could bind the OPN promoter and increase its transcription activity. In addition, small interfering RNA targeting c-Myb could inhibit OPN expression and significantly decrease migration and invasion of HCCLM6 cells <it>in vitro</it>.</p> <p>Conclusion</p> <p>Our data first demonstrate that c-Myb has a functionally important role in the regulation of OPN expression in HCC cells, suggesting that c-Myb might be a new target to control HCC metastasis.</p

3D Imaging of a Phase Object from a Single Sample Orientation Using an Optical Laser

Ankylography is a new 3D imaging technique, which, under certain circumstances, enables reconstruction of a 3D object from a single sample orientation. Here, we provide a matrix rank analysis to explain the principle of ankylography. We then present an ankylography experiment on a microscale phase object using an optical laser. Coherent diffraction patterns are acquired from the phase object using a planar CCD detector and are projected onto a spherical shell. The 3D structure of the object is directly reconstructed from the spherical diffraction pattern. This work may potentially open the door to a new method for 3D imaging of phase objects in the visible light region. Finally, the extension of ankylography to more complicated and larger objects is suggested.Comment: 22 pages 5 figure

Comparison Electrochemical Performances of Spherical LiFePO4/C Cathode Materials at Low and High Temperatures

AbstractThe spherical LiFePO4/C composite material was prepared by the solid-state method and a spray dry method. The surface modification was conducted on spherical LFP/C composite by using 3wt.% Li4Ti5O12 (LTO) to improve the rate capability and cycle stability properties at a low temperature of -20oC and a high temperature of 55oC. The characteristic properties were examined by X-ray diffraction (XRD), micro-Raman, scanning electron microscopy (SEM), AC impedance method, and galvanostatic charge-discharge method. For comparison, the as-prepared LiFePO4/C cathode, SP LFP/C composite, and 3%LTO-modified spherical LiFePO4/C composite are studied and compared. As a result, the LTO-modified spherical LiFePO4/C composite displays the discharge capacities of 150, 145, 135, 110, 95 and 90 mAh g-1 at 0.1C, 0.2C, 0.5C, 1C, 3C and 5C rates, respectively. It is demonstrated that the LTO-modified spherical LiFePO4/C composite material exhibit a good candidate for application in Li ion batteries

Structure of Co-2 × 2 nanoislands grown on Ag/Ge(111)-√3 × √3 surface studied by scanning tunneling microscopy

We have found that Co-2 × 2 islands grown on an Ag/Ge(111)-√3 × √3 surface have hcp structure with the (11-20) orientation. The island evolution involves transformation of the unit cell shape from parallelogram into rectangular, which is accompanied by the island shape transformation from hexagonal into stripe-like. Identified are two crystallographic directions for the island growth, the pseudo-[0001] and the pseudo-[1-100]. We have observed the occurrence of a lateral shift between the topmost and the underlying bilayers in the case of the island growth along the pseudo-[0001] direction. In contrast, the topmost and the underlying bilayers are unshifted for the growth along the pseudo-[1-100] direction

{μ-6,6′-Dimeth­oxy-2,2′-[ethane-1,2-diylbis(nitrilo­methyl­idyne)]diphenolato}-μ-nitrato-dinitratoeuropium(III)zinc(II)

In the title heteronuclear ZnII–EuIII complex [systematic name: {6,6′-dimeth­oxy-2,2′-[ethane-1,2-diylbis(nitrilo­methyl­idyne)]diphenolato-κ4 O 1,O 1′,O 6,O 6′:2κ4 O 1,N,N′,O 1′}-μ-nitrato-1:2κ2 O:O′-dini­trato-1κ4 O,O′-europium(III)zinc(II)], [EuZn(C18H18N2O4)(NO3)3], with the hexa­dentate Schiff base compartmental ligand N,N′-bis­(3-methoxy­salicyl­idene)ethyl­enediamine (H2 L), the Eu and Zn atoms are triply bridged by two phenolate O atoms of the Schiff base ligand and one nitrate ion. The five-coordinate Zn atom is in a square-pyramidal geometry with the donor centers of two imine N atoms, two phenolate O atoms and one of the bridging nitrate O atoms. The EuIII center has a ninefold coordination environment of O atoms, involving the phenol­ate O atoms, two meth­oxy O atoms, two O atoms from two nitrate ions and one from the bridging nitrate ion. Weak inter­molecular C—H⋯O inter­actions generate a two-dimensional double-layer structure