Formal Total Synthesis of Manzacidin B via Sequential Diastereodivergent Henry Reaction

A formal total synthesis of manzacidin B is described. beta,beta-Disubstituted gamma-hydroxy-beta-aminoalcohol, the key structure of manzacidin B, is stereoselectively constructed via sequential Henry reactions. By taking advantage of noncovalent interactions, such as intramolecular hydrogen bonding and chelation, we could diastereodivergently control the stereoselectivity of the Henry reaction

Regulation of Antitumor Immune Responses by the IL-12 Family Cytokines, IL-12, IL-23, and IL-27

The interleukin (IL)-12 family, which is composed of heterodimeric cytokines including IL-12, IL-23, and IL-27, is produced by antigen-presenting cells such as macrophages and dendritic cells and plays critical roles in the regulation of helper T (Th) cell differentiation. IL-12 induces IFN-γ production by NK and T cells and differentiation to Th1 cells. IL-23 induces IL-17 production by memory T cells and expands and maintains inflammatory Th17 cells. IL-27 induces the early Th1 differentiation and generation of IL-10-producing regulatory T cells. In addition, these cytokines induce distinct immune responses to tumors. IL-12 activates signal transducers and activator of transcription (STAT)4 and enhances antitumor cellular immunity through interferon (IFN)-γ production. IL-27 activates STAT1, as does IFN-γ and STAT3 as well, and enhances antitumor immunity by augmenting cellular and humoral immunities. In contrast, although exogenously overexpressed IL-23 enhances antitumor immunity via memory T cells, endogenous IL-23 promotes protumor immunity through STAT3 activation by inducing inflammatory responses including IL-17 production

A Pivotal Role for Interleukin-27 in CD8+ T Cell Functions and Generation of Cytotoxic T Lymphocytes

Cytotoxic T lymphocytes (CTLs) play a critical role in the control of various cancers and infections, and therefore the molecular mechanisms of CTL generation are a critical issue in designing antitumor immunotherapy and vaccines which augment the development of functional and long-lasting memory CTLs. Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, acts on naive CD4+ T cells and plays pivotal roles as a proinflammatory cytokine to promote the early initiation of type-1 helper differentiation and also as an antiinflammatory cytokine to limit the T cell hyperactivity and production of pro-inflammatory cytokines. Recent studies revealed that IL-27 plays an important role in CD8+ T cells as well. Therefore, this article reviews current understanding of the role of IL-27 in CD8+ T cell functions and generation of CTLs

Serial MRI Features of Canine GM1 Gangliosidosis: A Possible Imaging Biomarker for Diagnosis and Progression of the Disease

GM1 gangliosidosis is a fatal neurodegenerative lysosomal storage disease caused by an autosomal recessively inherited deficiency of β-galactosidase activity. Effective therapies need to be developed to treat the disease. In Shiba Inu dogs, one of the canine GM1 gangliosidosis models, neurological signs of the disease, including ataxia, start at approximately 5 months of age and progress until the terminal stage at 12 to 15 months of age. In the present study, serial MR images were taken of an affected dog from a model colony of GM1 gangliosidosis and 4 sporadic clinical cases demonstrating the same mutation in order to characterize the MRI features of this canine GM1 gangliosidosis. By 2 months of age at the latest and persisting until the terminal stage of the disease, the MR findings consistently displayed diffuse hyperintensity in the white matter of the entire cerebrum on T2-weighted images. In addition, brain atrophy manifested at 9 months of age and progressed thereafter. Although a definitive diagnosis depends on biochemical and genetic analyses, these MR characteristics could serve as a diagnostic marker in suspect animals with or without neurological signs. Furthermore, serial changes in MR images could be used as a biomarker to noninvasively monitor the efficacy of newly developed therapeutic strategies

siRNAs Induce Efficient RNAi Response in Bombyx mori Embryos

Short interference RNA (siRNA) is widely used in mammalian cells. In insects, however, reports concerning the suitablility of siRNA in vivo is very limited compared with that of long dsRNA, which is thought to be more effective. There is insufficient information on the essential rules of siRNA design in insects, as very few siRNAs have been tested in this context. To establish an effective method of gene silencing using siRNA in vivo in insects, we determined the effects of siRNA on seven target genes. We designed siRNAs according to a new guideline and injected them into eggs of Bombyx mori. At the mRNA level, the expression of most of these genes was successfully silenced, down to less than half the constitutive level, which in some cases led to the development of distinctive phenotypes. In addition, we observed stronger effect of siRNA both on the mRNA level and the phenotype than that of long dsRNA under comparable conditions. These results indicate that direct injection of siRNA is an effective reverse-genetics tool for the analysis of embryogenesis in vivo in insects

Local coordination state of rare earth in eutectic scintillators for neutron detector applications.

Atomic distribution in phosphors for neutron detection has not been fully elucidated, although their ionization efficiency is strongly dependent on the state of the rare earth in the matrix. In this work, we examine optical properties of Eu-doped 80LiF-20CaF2 eutectics for neutron detector applications based on the Eu distribution. At low concentrations, aggregation of Eu cations is observed, whereas homogeneous atomic dispersion in the CaF2 layer, to substitute Ca(2+) ions, is observed in the eutectics at high concentrations. Eu LIII edge X-ray absorption fine structure (XAFS) analysis suggests that neutron responses do not depend on the amount of Eu(2+) ions. However, transparency, which depends on an ordered lamellar structure, is found to be important for a high light yield in neutron detection. The results confirm the effectiveness of the basic idea concerning the separation of radiation absorbers and activators in particle radiation scintillation and present potential for further improvement of novel bulk detectors