Significant role for Fas in the pathogenesis of autoimmune diabetes

Programmed cell death represents an important pathogenic mechanism in various autoimmune diseases. Type I diabetes mellitus (IDDM) is a T cell-dependent autoimmune disease resulting in selective destruction of the beta cells of the islets of Langerhans. beta cell apoptosis has been associated with IDDM onset in both animal models and newly diagnosed diabetic patients. Several apoptotic pathways have been implicated in beta cell destruction, including Fas, perforin, and TNF-alpha. Evidence for Fas-mediated lysis of beta cells in the pathogenesis of IDDM in nonobese diabetic (NOD) mice includes: 1) Fas-deficient NOD mice bearing the lpr mutation (NOD-lpr/lpr) fail to develop IDDM; 2) transgenic expression of Fas ligand (FasL) on beta cells in NOD mice may result in accelerated IDDM; and 3) irradiated NOD-lpr/lpr mice are resistant to adoptive transfer of diabetes by cells from NOD mice. However, the interpretation of these results is complicated by the abnormal immune phenotype of NOD-lpr/lpr mice. Here we present novel evidence for the role of Fas/FasL interactions in the progression of NOD diabetes using two newly derived mouse strains. We show that NOD mice heterozygous for the FasL mutation gld, which have reduced functional FasL expression on T cells but no lymphadenopathy, fail to develop IDDM. Further, we show that NOD-lpr/lpr mice bearing the scid mutation (NOD-lpr/lpr-scid/scid), which eliminates the enhanced FasL-mediated lytic activity induced by Fas deficiency, still have delayed onset and reduced incidence of IDDM after adoptive transfer of diabetogenic NOD spleen cells. These results provide evidence that Fas/FasL-mediated programmed cell death plays a significant role in the pathogenesis of autoimmune diabetes.     

云南普洱市菝葜属植物资源调查

经调查鉴定,云南普洱市有菝葜属植物18种,其中菝葜、小叶菝葜、光叶菝葜(土茯苓)分布较广。介绍了它们的地理分布等,为普洱市菝葜属植物资源的综合利用和深入研究提供一定的依据。     

Inferring Protective CD8+ T-Cell Epitopes for NS5 Protein of Four Serotypes of Dengue Virus Chinese Isolates Based on HLA-A, -B and -C Allelic Distribution: Implications for Epitope-Based Universal Vaccine Design

Dengue is one of the most globally serious vector-borne infectious diseases in tropical and subtropical areas for which there are currently no effective vaccines. The most highly conserved flavivirus protein, NS5, is an indispensable target of CD8⁺ T-cells, making it an ideal vaccine design target. Using the Immune Epitope Database (IEDB), CD8⁺ T-cell epitopes of the dengue virus (DENV) NS5 protein were predicted by genotypic frequency of the HLA-A,-B, and-C alleles in Chinese population. Antigenicity scores of all predicted epitopes were analyzed using VaxiJen v2.0. The IEDB analysis revealed that 116 antigenic epitopes for HLA-A (21),-B (53), and-C (42) had high affinity for HLA molecules. Of them, 14 had 90.97–99.35% conversancy among the four serotypes. Moreover, five candidate epitopes, including ²⁰⁰NS5²¹⁰ (94.84%, A*11:01), ⁵¹⁵NS5⁵²⁵ (98.71%, A*24:02), ²²⁵NS5²³² (99.35%, A*33:03), ⁵¹⁶NS5⁵²³ (98.71%, A*33:03), and ²⁸⁴NS5²⁹¹ (98.06%, A*33:03), were presented by HLA-A. Four candidate epitopes, including ²³⁴NS5²⁴¹ (96.77%, B*13:01), ⁹²NS5⁹⁹ (98.06%, B*15:01, B*15:02, and B*46:01), ²⁶²NS5²⁶⁹ (92.90%, B*38:02), and ⁵³⁸NS5⁵⁴⁷ (90.97%, B*51:01), were presented by HLA-B. Another 9 candidate epitopes, including ⁵¹⁴NS5⁵²² (98.71%, C*01:02), ⁵¹⁴NS5⁵²⁴ (98.71%, C*01:02 and C*14:02), ⁹²NS5⁹⁹ (98.06%, C*03:02 and C*15:02), ³⁶²NS5³⁶⁹ (44.84%, C*03:04 and C*08:01), ²²⁵NS5²³² (99.35%, C*04:01), ²³⁴NS5²⁴¹(96.77%, C*04:01), ³⁶¹NS5³⁶⁹ (94.84%, C*04:01), ⁵¹⁵NS5⁵²² (98.71%, C*14:02), ⁵¹⁵NS5⁵²⁴ (98.71%, C*14:02), were presented by HLA-C. Further data showed that the four-epitope combination of ⁹²NS5⁹⁹ (B*15:01, B*15:02, B*46:01, C*03:02 and C*15:02), ²⁰⁰NS5²¹⁰ (A*11:01), ³⁶²NS5³⁶⁹ (C*03:04, C*08:01), and ⁵¹⁴NS5⁵²⁴ (C*01:02, C*14:02) could vaccinate >90% of individuals in China. Further in vivo study of our inferred novel epitopes will be needed for a T-cell epitope-based universal vaccine development that may prevent all four China-endemic DENV serotypes.     

MiR-133a Is Functionally Involved in Doxorubicin-Resistance in Breast Cancer Cells MCF-7 via Its Regulation of the Expression of Uncoupling Protein 2

The development of novel targeted therapies holds promise for conquering chemotherapy resistance, which is one of the major hurdles in current breast cancer treatment. Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells. In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7. We postulated that miR133a might play a functional role in the development of Doxorubicin-resistant in breast cancer cells. In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2. These findings provided direct evidences that the miR133a/UCP-2 axis might play an essential role in the development of Doxorubicin-resistance in breast cancer cells, suggesting that the miR133a/UCP-2 signaling cohort could be served as a novel therapeutic target for the treatment of chemotherapy resistant in breast cancer.     

Narrowband Light Total Antireflection and Absorption in Metal Film–Array Structures by Plasmonic Near-Field Coupling

We study the cooperative effects between plasmon gap modes and optical cavity modes of a novel triple-layer structure consisting of double continuous gold films separated by a gold nanosphere array. Narrowband near-perfect antireflection of optical field is achieved for the first time due to the strong near-field light–matter interaction within the deep sub-wavelength gaps between adjacent nanospheres combined with the spatial field confinement effects of the optical cavity built by the double gold films. The coexistence cooperation of near-field dipole plasmon resonances and spatial optical field confinement presents more efficient light modification than that of the individual subsystem and may open a new approach to manage light flow. By varying the period of nanosphere array, the diameter of nanospheres, and the distance between the array and the film, optical behaviors of the proposed structure can be tuned in a wide range. High environmental sensitivity and large figure of merit factor are obtained using this structure as the detecting substrate. Furthermore, ultra-compact structure and high conduction suggest the proposed structure being a good candidate for potential applications in highly integrated optoelectronic devices, such as plasmonic filters and sensors.     

Genome engineering of Agrobacterium tumefaciens using the lambda Red recombination system

Agrobacterium tumefaciens has been widely used as a tool for transgenesis in plants. The availability of its genome sequence should facilitate the directed engineering of improved properties; however, the current genome engineering options are laborious. Here, we investigated whether the lambda R ed operon can be applied for recombineering of the A. tumefaciens genome. First, we built an expression plasmid for A. tumefaciens employing a tetracycline-inducible promoter to regulate the Red operon. This multicopy plasmid was then itself modified in A. tumefaciens to verify that the Red operon was functional. Then, we modified the endogenous A. tumefaciens tumor-inducing plasmid and the linear chromosome. These results extend recombineering technology to a new host and indicate a fast and convenient way to engineer the A. tumefaciens genome for functional genomics and strain improvements.