Operational status of TAMA300 with the seismic attenuation system (SAS)

TAMA300 has been upgraded to improve the sensitivity at low frequencies after the last observation run in 2004. To avoid the noise caused by seismic activities, we installed a new seismic isolation system —- the TAMA seismic attenuation system (SAS). Four SAS towers for the test-mass mirrors were sequentially installed from 2005 to 2006. The recycled Fabry–Perot Michelson interferometer was successfully locked with the SAS. We confirmed the reduction of both length and angular fluctuations at frequencies higher than 1 Hz owing to the SAS

Differential tumor surveillance by natural killer (NK) and NKT cells

Natural tumor surveillance capabilities of the host were investigated in six different mouse tumor models where endogenous interleukin (IL)-12. does or does not dictate the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis. In the models examined, CD3(-) NK cells were responsible for tumor rejection and protection from metastasis in models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12, A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity. In particular, T cell receptor J alpha 281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide

Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice

<div><p>Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.</p></div

The Japanese space gravitational wave antenna; DECIGO

DECi-hertz Interferometer Gravitational wave Observatory (DECIGO) is the future Japanese space gravitational wave antenna. DECIGO is expected to open a new window of observation for gravitational wave astronomy especially between 0.1 Hz and 10 Hz, revealing various mysteries of the universe such as dark energy, formation mechanism of supermassive black holes, and inflation of the universe. The pre-conceptual design of DECIGO consists of three drag-free spacecraft, whose relative displacements are measured by a differential Fabry– Perot Michelson interferometer. We plan to launch two missions, DECIGO pathfinder and pre- DECIGO first and finally DECIGO in 2024

Natural killer cells are crucial for the efficacy of Icon (factor VII/human IgG1 Fc) immunotherapy in human tongue cancer

<p>Abstract</p> <p>Background</p> <p>Icon is a novel, dual neovascular- and cancer cell-targeting immunotherapeutic agent and has shown efficacy in the treatment of cancer, wet form macular degeneration and endometriosis. However, its underlying mechanism remains to be investigated. The objective of this study is to elucidate the mechanism of Icon immunotherapy in cancer using a squamous carcinoma human tongue cancer line TCA8113 <it>in vitro </it>and <it>in vivo </it>in severe combined immunodeficiency (SCID) mice.</p> <p>Results</p> <p>We showed that Icon, as a chimeric factor VII and human IgG1 Fc immunoconjugate, could separately induce murine natural killer (NK) cells and activate complement to kill TCA8113 cancer cells <it>in vitro </it>via antibody dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, Icon-NK ADCC had a significantly stronger effect than that of Icon-CDC. Moreover, Icon could completely eradicate established human tongue tumour xenografts <it>in vivo </it>in the CB-17 strain of SCID mice that have functional NK cells at a normal level, whereas it was less effective in SCID/Beige mice that do not have functional NK cells.</p> <p>Conclusions</p> <p>We conclude that NK cells are crucial for the efficacy of Icon immunotherapy in the treatment of cancer. The results also suggest that impaired NK level/activity could contribute to the resistance to therapeutic antibodies that are currently under investigation in preclinical and clinical studies.</p

Chicken CRTAM Binds Nectin-Like 2 Ligand and Is Upregulated on CD8⁺ αβ and γδ T Lymphocytes with Different Kinetics

During a search for immunomodulatory receptors in the chicken genome, we identified a previously cloned chicken sequence as CRTAM homologue by its overall identity and several conserved sequence features. For further characterization, we generated a CRTAM specific mab. No staining was detectable in freshly isolated cell preparations from thymus, bursa, caecal tonsils, spleen, blood and intestine. Activation of splenocytes with recombinant IL-2 increased rapid CRTAM expression within a 2 h period on about 30% of the cells. These CRTAM+ cells were identified as CD8+ γδ T lymphocytes. In contrast, CRTAM expression could not be stimulated on PBL with IL-2, even within a 48 h stimulation period. As a second means of activation, T cell receptor (TCR) crosslinking using an anti-αβ-TCR induced CRTAM on both PBL and splenocytes. While CRTAM expression was again rapidly upregulated on splenocytes within 2 h, it took 48 h to reach maximum levels of CRTAM expression in PBL. Strikingly, albeit the stimulation of splenocytes was performed with anti-αβ-TCR, CRTAM expression after 2 h was mainly restricted to CD8+ γδ T lymphocytes, however, the longer anti-TCR stimulation of peripheral blood lymphocytes (PBL) resulted in CRTAM expression on αβ T lymphocytes. In order to characterize the potential ligand we cloned and expressed chicken Necl-2, a member of the nectin and nectin-like family which is highly homologous to its mammalian counterpart. Three independent assays including a reporter assay, staining with a CRTAM-Ig fusion protein and a cell conjugate assay confirmed the interaction of CRTAM with Necl-2 which could also be blocked by a soluble CRTAM-Ig fusion protein or a CRTAM specific mab. These results suggest that chicken CRTAM represents an early activation antigen on CD8+ T cells which binds to Necl-2 and is upregulated with distinct kinetics on αβ versus γδ T lymphocytes

T Helper 1 (Th1) and Th2 Characteristics Start to Develop During T Cell Priming and Are Associated with an Immediate Ability to Induce Immunoglobulin Class Switching

The respective production of specific immunoglobulin (Ig)G2a or IgG1 within 5 d of primary immunization with Swiss type mouse mammary tumor virus [MMTV(SW)] or haptenated protein provides a model for the development of T helper 1 (Th1) and Th2 responses. The antibody-producing cells arise from cognate T cell B cell interaction, revealed by the respective induction of Cγ2a and Cγ1 switch transcript production, on the third day after immunization. T cell proliferation and upregulation of mRNA for interferon γ in response to MMTV(SW) and interleukin 4 in response to haptenated protein also starts during this day. It follows that there is minimal delay in these responses between T cell priming and the onset of cognate interaction between T and B cells leading to class switching and exponential growth. The Th1 or Th2 profile is at least partially established at the time of the first cognate T cell interaction with B cells in the T zone

Direct TLR2 Signaling Is Critical for NK Cell Activation and Function in Response to Vaccinia Viral Infection

Natural killer (NK) cells play an essential role in innate immune control of poxviral infections in vivo. However, the mechanism(s) underlying NK cell activation and function in response to poxviruses remains poorly understood. In a mouse model of infection with vaccinia virus (VV), the most studied member of the poxvirus family, we identified that the Toll-like receptor (TLR) 2-myeloid differentiating factor 88 (MyD88) pathway was critical for the activation of NK cells and the control of VV infection in vivo. We further showed that TLR2 signaling on NK cells, but not on accessory cells such as dendritic cells (DCs), was necessary for NK cell activation and that this intrinsic TLR2-MyD88 signaling pathway was required for NK cell activation and played a critical role in the control of VV infection in vivo. In addition, we showed that the activating receptor NKG2D was also important for efficient NK activation and function, as well as recognition of VV-infected targets. We further demonstrated that VV could directly activate NK cells via TLR2 in the presence of cytokines in vitro and TLR2-MyD88-dependent activation of NK cells by VV was mediated through the phosphatidylinositol 3-kinase (PI3K)-extracellular signal-regulated kinase (ERK) pathway. Taken together, these results represent the first evidence that intrinsic TLR signaling is critical for NK cell activation and function in the control of a viral infection in vivo, indicate that multiple pathways are required for efficient NK cell activation and function in response to VV infection, and may provide important insights into the design of effective strategies to combat poxviral infections