Positive selection of Tcrb-V10b+ T cells

The Tcrb-V10b⁺ T cell population has been examined with a newly established antibody, KT10b, specific for Tcrb-V10b but not Tcrb-V10a. H-2E⁺ mice have higher levels of Tcrb-V10b⁺ T cells (4.3%–11.%) than H-2E^– mice (2.2%–4.9%). This difference appears to be determined by levels of Tcrb-V10b⁺ T cells in the CD4 population. F₁ mice between H-2E⁺ and H-2E^– mice dominantly express higher levels of Tcrb-V10b⁺ T cells. [NOD (E–) x (NOD x A (E⁺))F₁] backcross mice show positive selection of Tcrb-V10b⁺ CD4⁺ T cells by H-2E. On the other hand other backcross analyses reveal positive selection of Tcrb-V10b⁺ CD8⁺ T cells by certain major histocompatibility class I molecules. Involvement of non-H-2 antigens in these positive selections remain to be determined. Address correspondence and offprint requests to: K. Tomonari.     

T-cell receptor expressed on an autoreactive T-cell clone, clone 4. I. Induction of various T-receptor functions by anti-T idiotypic antibodies

Three monoclonal antibodies (1G3, 2H11, and 3G12) specific for a syngeneic Ek-specific T-cell clone, clone 4, have been established. The antibodies specifically blocked not only the activation of the clone in response to the specific antigen Ek but also the activation by IL-2. Kinetic studies of the blocking activity revealed that the antibodies blocked activation not only through steric hindrance of the antigen-binding site of the receptor but also via inhibition of DNA synthesis. The antibodies induced unresponsiveness of the clone to the specific antigen Ek, but not to nonspecific activation by IL-2. The state of unresponsiveness induced by 1G3 continued for 14 days, the longest time so far examined. The recovery from the unresponsiveness (tolerance) was not observed unless the clone cells proliferated vigorously in response to IL-2. The idiotope recognised by 1G3 was different from that by 2H11 and/or 3G12. This might explain some functional differences elicited by the antibodies.     

Identification of a new pharmacological activity of the phenylpiperazine derivative naftopidil: tubulin-binding drug

The phenylpiperazine derivative naftopidil is an α₁-adrenoceptor (AR) antagonist that has been used clinically to treat benign prostatic hyperplasia. In our drug repositioning research, naftopidil shows the unique growth-inhibitory effects. Naftopidil inhibits cell cycle progression not only in cancer cells, but also in fibroblasts and vascular endothelial cells. Naftopidil-inhibited cell cycle progression is independent of α₁-AR expression in cells. Therefore, the antiproliferative effects of naftopidil may be due to the off-target effects of the drug. In this study, we attempted to identify the off-target molecules of naftopidil using the magnetic nanobeads, ferrite glycidyl metharcrylate (FG) beads. Similar to naftopidil, its derivatives TG09-01 and TG09-02, which were introduced with amino groups for immobilizing to FG beads, inhibited cell growth in human HT29 colon adenocarcinoma cells. Both derivatives were associated with inhibition of cell cycle progression in HT29 cells. This observation is consistent with that seen with naftopidil. Using TG09-02-immobilized FG beads, α- and β-tubulins were identified as the specific binding proteins of naftopidil. The tubulin polymerization assay clearly indicated that naftopidil bound directly to tubulin and inhibited the polymerization of tubulin. Other phenylpiperazine derivatives, such as RS100329, BMY7378, and KN-62, also inhibited the polymerization of tubulin. These results suggest that phenylpiperazine derivatives including naftopidil may have broad spectrum of cellular cytotoxicity in various types of cells. In addition, the tubulin polymerization-inhibiting activity of phenylpiperazine derivatives may be a specific feature of the phenylpiperazine-based structure. These findings can allow us to design and synthesize new tubulin-binding drugs derived from naftopidil as a lead compound.     

Seasonal and diel changes in cetacean vocalizations monitored by passive acoustic methods in Nemuro Strait adjacent to the Shiretoko World Natural Heritage Site

UNESCO World Natural Heritage sites are established to ensure the long-term conservation of natural areas. Nemuro Strait in northern Japan is adjacent to the Shiretoko World Natural Heritage Site, and attracts various trophic levels of marine species, including marine mammals. Although the coexistence of humans and marine mammals is an important issue in this area, the temporal habitat use of cetaceans in this area is unknown. Here, we document seasonal and diel changes in cetacean vocalizations collected using passive acoustic recording devices during November 2012–March 2014. Killer whale calls occurred in spring and summer, and sperm whale clicks were detected in summer. Pacific white-sided dolphin calls were recorded in summer and late fall. No cetaceans were recorded during the sea ice period in February and March. The dolphin calls and unknown click trains were significantly more frequent at night. In contrast, marginal diel changes in killer whale calls were detected. Our results suggest that the majority of cetaceans utilize Nemuro Strait at night during the ice-free period, and we provide new insights into the habitat use and diversity of marine mammals in the Strait.     

Generalizable brain network markers of major depressive disorder across multiple imaging sites

Many studies have highlighted the difficulty inherent to the clinical application of fundamental neuroscience knowledge based on machine learning techniques. It is difficult to generalize machine learning brain markers to the data acquired from independent imaging sites, mainly due to large site differences in functional magnetic resonance imaging. We address the difficulty of finding a generalizable marker of major depressive disorder (MDD) that would distinguish patients from healthy controls based on resting-state functional connectivity patterns. For the discovery dataset with 713 participants from 4 imaging sites, we removed site differences using our recently developed harmonization method and developed a machine learning MDD classifier. The classifier achieved an approximately 70% generalization accuracy for an independent validation dataset with 521 participants from 5 different imaging sites. The successful generalization to a perfectly independent dataset acquired from multiple imaging sites is novel and ensures scientific reproducibility and clinical applicability.

Biomarkers for psychiatric disorders based on neuroimaging data have yet to be put to practical use. This study overcomes the problems of inter-site differences in fMRI data by using a novel harmonization method, thereby successfully constructing a generalizable brain network marker of major depressive disorder across multiple imaging sites.     

Phototrophic bacterial production of oleic acid in an illuminated upflow anaerobic sludge blanket reactor

Phototrophic bacterial cells in the effluent from a lighted upflow anaerobic sludge blanket reactor supplied with a medium containing 142 mg S (as SO₄ ^2–) l^–1 accumulated a 6.8% w/w oleic acid content in cells and 19 mg cell-bound oleic acid l^–1 in the effluent. Pure cultures of Rhodopseudomonas palustris and Blastochloris sulfoviridis isolated from the effluent also accumulated 5.1 and 6.4% w/w oleic acid contents in cells, respectively. The oleic acid content in the cells recovered from the LUASB reactor effluent was related to the phototrophic bacterial population in the LUASB reactor. The inverse relationship was observed in the LUASB reactor between phototrophic bacterial growth and sulfate concentration in the influent.