TRAIL-transduced dendritic cells protect mice from acute graft-versus-host disease and leukemia relapse

TRAIL preferentially induces apoptotic cell death in a wide variety of transformed cells, whereas it induces no apoptosis, but inhibits activation of Ag-specific T cells via blockade of cell cycle progression. Although accumulating results suggest that TRAIL is involved in the maintenance of immunological homeostasis under steady state conditions as well as in the initiation and progression of immunopathologies, the potential regulatory effect of TRAIL on immune responses and its therapeutic potential in immunological diseases remains unclear. We report in this study the potential usefulness of TRAIL-transduced dendritic cells (DCs) for the treatment of lethal acute graft-vs-host disease (GVHD) and leukemia relapse. DCs genetically modified to express TRAIL showed potent cytotoxicity against both alloreactive T cells and leukemic cells through the induction of apoptosis. In addition, treatment with genetically modified DCs expressing TRAIL of allogeneic BM transplants recipients with leukemia was effective for protection against acute GVHD and leukemia relapse. Thus, gene transfer of TRAIL to DCs is a novel modality for the treatment of acute GVHD and leukemia relapse by selective targeting of pathogenic T cells and leukemic cells.     

Inhibition of hepatocyte growth factor induction in human dermal fibroblasts by interleukin-1 and its prevention by interferon-gamma

Hepatocyte growth factor (HGF) is one of the vital factors for liver regeneration. HGF production is induced by the activation of protein kinase A and protein kinase C-mediated pathways, interleukin (IL)-1, tumor necrosis factor (TNF)-alpha, and epidermal growth factor (EGF) in mesenchymal cells. We here report that IL-1 and TNF-alpha, hitherto regarded as HGF inducers, potently inhibited HGF production stimulated by other HGF inducers. IL-1alpha, IL-1beta, and TNF-alpha alone had minimal stimulating effects on HGF production in human dermal fibroblasts, but they strongly inhibited production of HGF induced by cholera toxin, 8-bromo-cAMP, EGF, and phorbol 12-myristate 13-acetate (PMA). Moreover, although the high level of HGF production in MRC-5 cells was enhanced by PMA and less markedly by IL-1beta, HGF production in MRC-5 cells treated with PMA plus IL-1beta was less than that in the cells treated with PMA alone. In the presence of interferon (IFN)-gamma, however, cholera toxin- and 8-bromo-cAMP-induced HGF production was not inhibited by IL-1beta. Pretreatment of cells with IL-1beta suppressed the phosphorylation of cAMP-responsive element-binding protein induced by cholera toxin but not that induced by 8-bromo-cAMP. Taken together, our results indicate that IL-1 inhibited HGF production stimulated by various inducers, including protein kinase A-activating agents, and that IFN-gamma overcame this inhibition of induction of HGF production.     

Molecular characterization of a Cryptosporidium isolate from a banded mongoose Mungos mungo

Cryptosporidium spp. has been found in more than 150 species of mammals, but there has been no report in mongooses. In this study, we report the isolation of Cryptosporidium sp. in a banded mongoose Mungos mungo, which was brought from Tanzania to Japan; the isolate was analyzed genetically to validate the occurrence of a new, host-adapted genotype. Cryptosporidium diagnostic fragments of 18S ribosomal RNA and 70-kDa heat shock protein genes were amplified from this isolate and compared with the other Cryptosporidium species and genotypes reported previously. Analyses showed that the mongoose isolate represents a new genotype, closely related to that of bears.     

Modeling of hemodynamics arising from malaria infection

We propose a numerical model of hemodynamics arising from malaria infection. This model is based on a particle method, where all the components of blood are represented by the finite number of particles. A two-dimensional spring network of membrane particles is employed for expressing the deformation of malaria infected red blood cells (IRBCs). Malaria parasite within the IRBC is modeled as a rigid object. This model is applied to the stretching of IRBCs by optical tweezers, the deformation of IRBCs in shear flow, and the occlusion of narrow channels by IRBCs. We also investigate the effects of IRBCs on the rheological property of blood in micro-channels. Our results indicate that apparent viscosity is drastically increased for the period from the ring stage and the trophozoite stage, whereas it is not altered in the early stage of infection.     

Stereoselective reduction of ketones by various vegetables

Reduction of (+)-and (−)-camphorquinones (1a, 1b) by various vegetables (carrot, potato, sweet potato, apple, Japanese radish, cucumber, burdock and onion) gave -hydroxycamphor selectively. Using burdock, (+)-camphorquinone was reduced to give (−)-3S-exo-hydroxycamphor (4a) as major product in high stereoselectivity with high yield. Moreover, 1,2-cyclohexanedione (1c) and 2-methylcyclohexanone (1d) with various vegetables afford enantiomerically pure trans- and/or cis-alcohol, respectively. Various vegetable reduction gave a new idea of a biotechnological process.     

Computational analysis of blood flow in an integrated model of the left ventricle and the aorta

To study the effects of intraventricular flow dynamics on the aortic flow, we created an integrated model of the left ventricle and aorta and conducted a computer simulation of diastolic and systolic blood flow within this model. The results demonstrated that the velocity profile at the aortic annulus changed dynamically, and was influenced by the intraventricular flow dynamics. The profile was almost flat in early systole but became nonuniform as systole progressed, and was skewed toward the posterior side in midsystole and toward the anterior side in later systole. At a distance from the aortic annulus, a different velocity profile was induced by the twisting and torsion of the aorta. In the ascending aorta, the fastest flow was initially located in the posteromedial sector, and it moved to the posterior section along the circumference as systole progressed. The nonuniformity of the aortic inflow gave rise to a complex wall shear stress (WSS) distribution in the aorta. A comparison of the WSS distribution obtained in this integrated analysis with that obtained in flow calculations using an isolated aorta model with Poiseuille and flat inlet conditions showed that intraventricular flow affected the WSS distribution in the ascending aorta. These results address the importance of an integrated analysis of flow in the left ventricle and aorta.     

Characterization of cyanobacteriochrome TePixJ from a thermophilic cyanobacterium Thermosynechococcus elongatus strain BP-1

A putative photoreceptor gene, TepixJ, of a thermophilic cyanobacterium is homologous to SypixJ1 that mediates positive phototaxis in the unicellular motile cyanobacterium Synechocystis sp. PCC 6803. The putative chromophore-binding GAF domain of TePixJ protein was overexpressed as a fusion with a polyhistidine tag (His-TePixJ_GAF) in Synechocystis cells and isolated to homogeneity. The photoreversible conversion of His-TePixJ_GAF showed peaks at 531, 341 and 266 nm for the green light-absorbing form (Pg form), and peaks at 433 and 287 nm for the blue light-absorbing form (Pb form). At 77K, the Pg form fluoresced at 580 nm, while the Pb form did not emit any fluorescence. Mass spectrometry of the tryptic chromopeptide demonstrated that a phycocyanobilin isomer binds to the conserved cysteine at ring A via a thioether bond. It is established that TePixJ and SyPixJ1 are novel photoreceptors in cyanobacteria ('cyanobacteriochromes') that are similar, but distinct from the phytochromes and bacteriophytochromes.     

Aerobic removal of technetium by a marine Halomonas strain

A novel strain of Halomonas (Tc-202), which has the capability of removing Tc(VII) from solid- and aqueous-phase material aerobically, was isolated from the marine environment. Tc-202 removed 55% of the total 99Tc in solutions at 15 degrees C by reducing Tc(VII) to Tc(V), but other Halomonas strains did not.     

Histone acetyltransferase 1 is dispensable for replication-coupled chromatin assembly but contributes to recover DNA damages created following replication blockage in vertebrate cells

Histone acetyltransferase 1 (HAT1) is implicated for diacetylation of Lys-5 and Lys-12 of newly synthesized histone H4, the biological significance of which remains unclear. To investigate the in vivo role of HAT1, we generated HAT1-deficient DT40 clone (HAT1(-/-)). HAT1(-/-) cells exhibited greatly reduced diacetylation levels of Lys-5 and Lys-12, and acetylation level of Lys-5 of cytosolic and chromatin histones H4, respectively. The in vitro nucleosome assembly assay and in vivo MNase digestion assay revealed that HAT1 and diacetylation of Lys-5 and Lys-12 of histone H4 are dispensable for replication-coupled chromatin assembly. HAT1(-/-) cells had mild growth defect, conferring sensitivities to methyl methanesulfonate and camptothecin that enforce replication blocks creating DNA double strand breaks. Such heightened sensitivities were associated with prolonged late-S/G2 phase. These results indicate that HAT1 participates in recovering replication block-mediated DNA damages, probably through chromatin modulation based on acetylation of Lys-5 and Lys-12 of histone H4.