No abstract

The adipocyte-derived hormone adiponectin has been shown to play important roles in the regulation of energy homeostasis and insulin sensitivity. In this study, we analyzed globular domain adiponectin (gAd) transgenic (Tg) mice crossed with leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an unexpected similar body weight, gAd Tg ob/ob mice showed amelioration of insulin resistance and ␤-cell degranulation as well as diabetes, indicating that globular adiponectin and leptin appeared to have both distinct and overlapping functions. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved in fatty acid oxidation such as acyl-CoA oxidase, and molecules involved in energy dissipation such as uncoupling proteins 2 and 3 and increased fatty acid oxidation in skeletal muscle of gAd Tg ob/ob mice. Moreover, despite similar plasma glucose and lipid levels on an apoE-deficient background, gAd Tg apoE-deficient mice showed amelioration of atherosclerosis, which was associated with decreased expression of class A scavenger receptor and tumor necrosis factor ␣. This is the first demonstration that globular adiponectin can protect against atherosclerosis in vivo.In conclusion, replenishment of globular adiponectin may provide a novel treatment modality for both type 2 diabetes and atherosclerosis.

Interleukin 6 (IL-6) has been suggested to be involved in the pathogenesis of polyclonal and monoclonal plasma cell abnormalities. To address this possibility, transgenic mice carrying the human IL-6 genomic gene fused with a human immunoglobulin heavy chain enhancer were generated. High concentrations of human IL-6 and polyclonal increase in IgGi (120-to 400-fold) in sera of all transgenic mice were observed.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (T H 2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from T H 2 cells, is a potent pruritogenic cytokine, and its sys- First-line treatments of AD include the application of emollients for dry skin, topical steroids, and tacrolimus for skin inflammation, followed by second-line adjunct therapies such as systemic cyclosporine, short-term oral steroids, and ultraviolet radiation.

The NOD (non-obese diabetic) mouse spontaneously develops insulin-dependent diabetes mellitus (IDDM) characterized by autoimmune insulitis, involving lymphocytic infiltration around and into the islets followed by pancreatic beta (beta) cell destruction, similar to human IDDM. Genetic analysis in breeding studies between NOD and C57BL/6 mice has demonstrated that two recessive genes on independent chromosomes contribute to the development of insulitis. One of the two recessive diabetogenic genes was found to be linked to the major histocompatibility complex (MHC). This is of interest, because the NOD strain has a unique class II MHC: it does not express I-E molecules as no messenger RNA for the alpha-chain of I-E is visible in Northern blot analysis; I-A molecules are not detected with any available monoclonal antibodies or by allo-reactive or autoreactive T-cell clones, although their expression is demonstrated with a conventional antiserum to Ia antigens. To examine whether the unusual expression of class II MHC molecules may be responsible for the development of autoimmune insulitis, we attempted to express I-E molecules in NOD mice selectively, without introducing other genes on chromosome 17 by using I-E-expressing C57BL/6 (B6(E alpha d)) transgenic mice. We report here that the expression of I-E molecules in NOD mice can prevent the development of autoimmune insulitis.

We produced transgenic mice by microhijecting a partial tandem duplication of the complete hepatitis B virus (HBV) genome into fertilized eggs of C57BL/6 mice. One of eight transgenic mice was a high producer for HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) in the serum. The HBV genomes were transmitted to the next generation and these F1 mice also produced HBsAg and HBeAg. mRNAs of3.5, 2.1, and 0.8 kilobases were detected in the livers and the kidneys of these mice. In addition, a 0.8-kilobase RNA was detected in the testis. Single-standed and partially doublestranded HBV DNAs were shown to be produced in the cytoplasm of the liver and kidneys. These HBV DNAs were associated with the core particles, indi ble from nudeocapsid produced in an infected human liver. Viral genome DNA was detected in the serum. These results demonstrate that the HBV genome integrated into the mouse chromosome acted as a template for viral gene expression, allowing viral repliction. Thus, these tranic mice should be useful for detailed studies of the replication and expression of HBV and for pathological studies of hepatitis, including the development of hepatocellular carcinoma.Hepatitis B virus (HBV) is a causative agent of hepatitis. This viral genome DNA is a partially double-stranded circular molecule. After infection, it is converted into a covalently closed circular molecule (1), which is transcribed into two main species of mRNA, 2.1 and 3.5 kilobases (kb) in size (2). These molecules are then translated to produce viral proteins, HBV surface antigen (HBsAg) and HBV core antigen (HBcAg), and presumably other proteins called Pre-S, X, and Pol as inferred from the open reading frames. The 3.5-kb RNA, which is called pregenome RNA, is reverse transcribed (3) presumably by the viral polymerase (4), and the product, single-stranded minus DNA, then serves as a template for the synthesis of a plus strand. This reaction often terminates before completion, resulting in the formation of partially double-stranded DNA.HBV infection is linked to later development ofcirrhosis and hepatocellular carcinoma (HCC). Beasley etaL (5) showed from prospective epidemiological studies that the relative risk to HBsAg carriers ofdeveloping HCC was 217 times as compared with noncarriers. Despite the crucial role of HBV in human health problems, there is only limited knowledge of its mode of replication, integration, and tumor induction because the virus multiplies only in human and chimpanzee livers. Recently, cell culture systems have been established that allow expression and replication of the HBV genome following transfection with cloned HBV DNA (6-9). These systems have allowed detailed molecular and genetic studies of HBV replication and protein synthesis, but they are not suitable for studies on the outbreak of hepatitis and the induction of HCC. One approach to overcoming these problems is to make a transgenic animal carrying HBV DNA. In this approach the introduced DNAs are located on the same chromosomal site in all cell types ...

Nineteen DNA samples that carry integrated hepatitis B virus (HBV) DNA were isolated from seven independent human hepatomas by molecular cloning, and their structures were determined. The results, combined with reported data, were analyzed so that one can obtain insights into the mechanisms of integration of this virus DNA and possible rearrangements that occur subsequently. Recent studies have shown that the HBV genome carries four coding frames, all of which are located on the same DNA strand. The genome also carries a unique ~Present address: Institute for Bioscience, Nippon Zeon Co., Kawasaki, 210 Japan.