Non-toxic conformer of amyloid β may suppress amyloid β-induced toxicity in rat primary neurons: Implications for a novel therapeutic strategy for Alzheimer’s disease

The 42-mer amyloid β-protein (Aβ42) oligomers cause neurotoxicity and cognitive impairment in Alzheimer’s disease (AD). We previously identified the toxic conformer of Aβ42 with a turn at positions 22–23 (“toxic” turn) to form oligomers and to induce toxicity in rat primary neurons, along with the non-toxic conformer with a turn at positions 25–26. G25P-Aβ42 and E22V-Aβ42 are non-toxic mutants that disfavor the “toxic” turn. Here we hypothesize that these non-toxic mutants of Aβ42 could suppress Aβ42-induced neurotoxicity, and examined their effects on the neurotoxicity, aggregation, and levels of the toxic conformer, which was evaluated by dot blotting using a monoclonal antibody (11A1) against the toxic conformer. G25P-Aβ42 and E22V-Aβ42 suppressed the neurotoxicity and aggregation of Aβ42 as well as the formation of the toxic conformer. The neurotoxicity induced by Aβ42 was also significantly reduced by the treatment of 11A1, but not of Aβ-sequence specific antibodies (6E10 and 4G8). Since recent studies indicate that Aβ oligomers contain parallel β-sheet, the present results suggest that the non-toxic mutants of Aβ42 without the “toxic” turn could prevent the propagation process of the toxic conformer of Aβ42 resulting in suppression of the formation of the toxic oligomers. This could be a promising strategy for AD therapeutics.     

Inhibition of photophosphorylation by ATP and the role of magnesium in photophosphorylation

ATP and pyrophosphate at high concentration (> 1 mM) inhibited photophosphorylation of isolated spinach chloroplasts in the normal salt medium and did not cause stimulation of electron transport. The inhibition of photophosphorylation by ATP or pyrophosphate was shown to be abolished by the addition of excess MgCl₂, ADP and phosphate. It has been demonstrated that the rates of photophosphorylation in the absence and presence of ATP or pyrophosphate are determined similarly by the concentrations of magnesium-ADP (Mg · ADP^?) and magnesium-phosphate (Mg · P_i) complexes.It is highly probable that Mg · ADP^? and Mg · P_i, but not free ADP and free phosphate, are the active form of the substrates of photophosphorylation. This is in support of the view that ATP inhibits photophosphorylation by decreasing the concentration of Mg²⁺ which is available for the formation of the complex with ADP and phosphate.     

Role of gap junctional intercellular communication in radiation-induced bystander effects in human fibroblasts

Involvement of gap junctional intercellular communication (GJIC) in bystander responses of confluent human fibroblasts irradiated with a carbon-ion beam was investigated. It was found that the lower the radiation dose, the higher the yield of radiation-induced micronuclei per nuclear traversal, suggesting the existence of bystander effects. This low-dose sensitivity was increased when GJIC was enhanced by treating cells with 8-Br-cAMP, but it was partly reduced by treating cells with DMSO, an effective scavenger of reactive oxygen species (ROS). Moreover, no low-dose sensitivity was observed when cells were treated with 100 micro M lindane, an inhibitor of GJIC. The survival of irradiated cells was increased by DMSO but was not influenced significantly by cAMP or lindane. On the other hand, G(1)-phase arrest was detected in the irradiated cells, and it was enhanced by cAMP. In contrast, this arrest was reduced or almost eliminated by DMSO or lindane, respectively, even when cells were irradiated with such a high dose that each cell received five nuclear traversals on average. Thus the bystander responses occurred after both low-dose and relatively high-dose irradiation. Our results indicated that both GJIC and ROS contributed to the radiation-induced bystander effect, but gap junctional channels might play an essential role by modulating the release of radiation-induced signaling factors.     

Comparative genomic analysis of mammalian NKG2D ligand family genes provides insights into their origin and evolution

NKG2D is a major activating receptor of natural killer cells. Its ligands are major histocompatibility complex (MHC) class I-like molecules whose expression is induced by cellular stresses such as infections and tumorigenesis. Humans have two families of NKG2D ligands (NKG2DL): MHC class I-related chains (MIC) encoded in the MHC and UL16-binding proteins (ULBP) encoded outside the MHC. By contrast, mice have only the latter family of ligands; instead, they have non-MHC-encoded MILL molecules that are closely related to MIC, but do not function as NKG2DL. To gain insights into the origin and evolution of MIC, ULBP, and MILL gene families, we conducted comparative genomic analysis of NKG2DL family genes in five mammalian species. In the opossum MHC, we identified a ULBP-like gene adjacent to a previously described MIC-like gene, suggesting that ULBP genes were originally encoded in the MHC. The opossum genome also contained a transcribed MILL-like gene in a region syntenic to the rodent regions encoding MILL molecules. These observations indicate that MIC-, ULBP-, and MILL-like genes emerged before the divergence of placental and marsupial mammals. Comparison of the human, cattle, rat, mouse, and opossum genomes indicates that after emigration from the MHC, ULBP genes underwent extensive duplications in each species. In mice, some of the ULBP genes appear to have been translocated telomerically on the same chromosome, forming a major cluster of existent NKG2DL genes.     

Importance and usefulness of evaluating self-esteem in children

ABSTRACT: The Asian College of Psychosomatic Medicine (ACPM) was founded as the Asian Chapter of the International College of Psychosomatic Medicine (ICPM-AC) in Tokyo on April 12, 1982.The first president was Hitoshi ISHIKAWA (Japan), the vice-presidents were Mahalingam MAHADEVAN (Malaysia) and Burton G.BURTON-BRADLEY (Papua- New Guinea), and the general secretary was Sueharu TSUTSUI (Japan).Five years previously, preparation for creation of the ICPM-AC was started at the 4th World Congress of the International College of Psychosomatic Medicine (ICPM) held in Kyoto, Japan, September 5-9, 1977.The First Congress of the ICPM-AC was held by the President Yujiro IKEMI in Tokyo on May 19-20, 1984. The main members in the early stage were Y. IKEMI, H. ISHIKAWA, S. TSUTSUI, Taisaku KATSURA, Tetsuya NAKAGAWA. Hiroyuki SUEMATSU and others from Japan and Hsien RIN (Taiwan), Seock Young KANG (Korea), M. MAHADEVAN. B.G. BURTON-BRADLEY and others from other Asian countries.Thereafter, academic congresses of the ICPM-AC, the 2nd to the 9th, were held approximately every two years, in Japan, India, Malaysia, Taiwan, Korea, and China. The name was changed to the Asian College of Psychosomatic Medicine (ACPM), and the 10th to 14th congresses were held in Taiwan, Okinawa (Japan), Australia, Korea, and China.The current president of the Executive Board of ACPM is Chiharu KUBO, the Director of Kyushu University Hospital.The next academic congress is the 15th ACPM and will be hosted by Tserenkhuugyin LKHAGVASUREN in Ulaanbaatar, Mongolia from August 24-26, 2012.Participating countries have expanded to include Asian-Oceanic countries such as Mongolia, Micronesia, Australia and Sri Lanka.The main themes of the congresses have focused on psychosomatic disorders, culture - bound syndromes, oriental medicine, etc... To date,"Health promotion"by raising the level of mental health based on psychoneuroendocrinoimmunomodulation has been very important. Prevention is also important in the Asia - Oceana area, from the viewpoints of both psychosomatics and culture.Above all, an awareness of existential, authentic health is a sure way to promote healthy longevity and psychosomatic well - being.To pursue happiness and well-being subjectively, objectively, and ecologically will be the most important purposes of ACPM in the future.     

Capsaicin receptor expression in the rat temporomandibular joint

Experimentally, temporomandibular joint (TMJ) nerve units respond to capsaicin, which is used clinically to treat TMJ pain. However, the existence of capsaicin receptors in the TMJ has not previously been clearly demonstrated. Immunohistochemical analysis has revealed the presence of transient receptor potential vanilloid subtype 1 (TRPV1) expression in the nerves and synovial lining cells of the TMJ. TRPV1-immunoreactive nerves are distributed in the synovial membrane of the joint capsule and provide branches to the joint compartment. The disc periphery is supplied by TRPV1 nerves that are mostly associated with small arterioles, and occasional nerves penetrate to the synovial lining layer. Double immunofluorescence has shown that many TRPV1-immunoreactive nerves are labeled with neuropeptide calcitonin gene-related peptide, whereas few are labeled with IB4-lectin. The results provide evidence for the presence of TRPV1 in both nerves and synovial lining cells, which might thus be involved in the mechanism of nociception and inflammation in the TMJ. This study was supported by a grant-in-aid for Scientific Research (C), no. 15591938, from the Japanese Ministry of Education, Science, Sports, Culture, and Technology (to M.A.K.).     

Efficient production of androgenetic embryos by round spermatid injection

Mammalian androgenetic embryos can be produced by pronuclear exchange of fertilized oocytes or by dispermic in vitro fertilization of enucleated oocytes. Here, we report a new technique for producing mouse androgenetic embryos by injection of two round spermatid nuclei into oocytes, followed by female chromosome removal. We found that injection of round spermatids resulted in high rates of oocyte survival (88%). Androgenetic embryos thus produced developed into mid‐gestation fetuses at various rates, depending on the mouse strain used. All the fetuses examined maintained paternally specific genomic imprinting memories. This technique also enabled us to produce complete heterozygous F1 embryos by injecting two spermatids from different strains. The best rate of fetal survival (12% per embryos transferred) was obtained with C57BL/6 × DBA/2 androgenetic embryos. We also generated embryonic stem cell lines efficiently with the genotype of Mus musculus domesticus × M. m. molossinus. Thus, injection of two round spermatid nuclei followed by maternal enucleation is an effective alternative method of producing androgenetic embryos that consistently develop into blastocysts and mid‐gestation fetuses. genesis 47:155–160, 2009. © 2009 Wiley‐Liss, Inc.     

Bottromycin derivatives: Efficient chemical modifications of the ester moiety and evaluation of anti-MRSA and anti-VRE activities

Novel bottromycin derivatives were synthesized from bottromycin A₂ via a hydrazide derivative as a common intermediate. Seventeen derivatives were subjected to in vitro evaluation against drug-resistant gram-positive bacteria. Some compounds showed potent anti-MRSA and anti-VRE activity, as did bottromycin A₂. Notably, a propyl ketone derivative exhibited good antibacterial activity with excellent metabolite stability.     

Mechanism of Inhibition of the V-Type Molecular Motor by Tributyltin Chloride

Tributyltin chloride (TBT-Cl) is an endocrine disruptor found in many animal species, and it is also known to be an inhibitor for the V-ATPases that are emerging as potential targets in the treatment of diseases such as osteoporosis and cancer. We demonstrated by using biochemical and single-molecular imaging techniques that TBT-Cl arrests an elementary step for rotary catalysis of the V₁ motor domain. In the presence of TBT-Cl, the consecutive rotation of V₁ paused for a long duration (∼0.5 s), even at saturated ATP concentrations, and the pausing positions were localized at 120° intervals. Analysis of both the pausing time and moving time revealed that TBT-Cl has little effect on the binding affinity for ATP, but, rather, it arrests the catalytic event(s). This is the first report to demonstrate that an inhibitor arrests an elementary step for rotary catalysis of a V-type ATP-driven rotary motor.