インフルエンザウイルスゲノムの変異の傾向

博士（医学）神戸大

A Comprehensive Study of Short Bursts from SGR 1806-20 and SGR 1900+14 Detected by HETE-2

We present the results of temporal and spectral studies of the short burst (less than a few hundred milliseconds) from the soft gamma repeaters (SGRs) 1806-20 and 1900+14 using the HETE-2 samples. In five years from 2001 to 2005, HETE-2 detected 50 bursts which were localized to SGR 1806-20 and 5 bursts which were localized to SGR 1900+14. Especially SGR 1806-20 was active in 2004, and HETE-2 localized 33 bursts in that year. The cumulative number-intensity distribution of SGR 1806-20 in 2004 is well described by a power law model with an index of -1.1+/-0.6. It is consistent with previous studies but burst data taken in other years clearly give a steeper distribution. This may suggest that more energetic bursts could occur more frequently in periods of greater activity. A power law cumulative number-intensity distribution is also known for earthquakes and solar flares. It may imply analogous triggering mechanisms. Although spectral evolution during bursts with a time scale of > 20 ms is not common in the HETE-2 sample, spectral softening due to the very rapid (< a few milliseconds) energy reinjection and cooling may not be excluded. The spectra of all short bursts are well reproduced by a two blackbody function (2BB) with temperatures ~4 and ~11 keV. From the timing analysis of the SGR 1806-20 data, a time lag of 2.2+/-0.4 ms is found between the 30-100 keV and 2-10 keV radiation bands. This may imply (1) a very rapid spectral softening and energy reinjection, (2) diffused (elongated) emission plasma along the magnetic field lines in pseudo equilibrium with multi-temperatures, or (3) a separate (located at < 700 km) emission region of softer component (say, ~4 keV) which could be reprocessed X-rays by higher energy (> 11 keV) photons from an emission region near the stellar surface.Comment: 50 pages, 14 figures, accepted for publication in PAS

Destruxin E Decreases Beta-Amyloid Generation by Reducing Colocalization of Beta-Amyloid-Cleaving Enzyme 1 and Beta-Amyloid Protein Precursor

Alzheimer-disease-associated beta-amyloid (A beta) is produced by sequential endoproteolysis of beta-amyloid protein precursor (beta APP): the extracellular portion is shed by cleavage in the juxtamembrane region by beta-amyloid-cleaving enzyme (BACE)/beta-secretase, after which it is cleaved by presenilin (PS)/gamma-secretase near the middle of the transmembrane domain. Thus, inhibition of either of the secretases reduces A beta generation and is a fundamental strategy for the development of drugs to prevent Alzheimer disease. However, it is not clear how small compounds reduce A beta production without inhibition of the secretases. Such compounds are expected to avoid some of the side effects of secretase inhibitors. Here, we report that destruxin E (Dx-E), a natural cyclic hexadepsipeptide, reduces A beta generation without affecting BACE or PS/gamma-secretase activity. In agreement with this, Dx-E did not inhibit Notch signaling. We found that Dx-E decreases colocalization of BACE1 and beta APP, which reduces beta-cleavage of beta APP. Therefore, the data demonstrate that Dx-E represents a novel A beta-reducing process which could have fewer side effects than secretase inhibitors. Copyright (C) 2009 S. Karger AG, Base

Therapy for CKD-associated muscle dysfunction

Background Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS-targeted intervention using AST-120, which inhibits IS accumulation, or mitochondria-targeted intervention using L-carnitine or teneligliptin, a dipeptidyl peptidase-4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice. Methods The in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6-nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non-treatment group and AST-120, L-carnitine, or teneligliptin treatment groups. Results In C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC-1α and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co-incubation with an anti-oxidant, ascorbic acid, L-carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin-6 and atrophy-related factors such as myostatin and atrogin-1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG-1α and increased muscular autophagy, as reflected by decreased mitochondria-rich type I fibres. An AST-120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L-carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level. Conclusions Our results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS-targeted and mitochondria-targeted interventions for treating CKD-induced muscle atrophy and decreased exercise endurance

An Optically Dark GRB Observed by HETE-2: GRB 051022

GRB 051022 was detected at 13:07:58 on 22 October 2005 by HETE-2. The location of GRB 051022 was determined immediately by the flight localization system. This burst contains multiple pulses and has a rather long duration of about 190 seconds. The detections of candidate X-ray and radio afterglows were reported, whereas no optical afterglow was found. The optical spectroscopic observations of the host galaxy revealed the redshift z = 0.8. Using the data derived by HETE-2 observation of the prompt emission, we found the absorption N_H = 8.8 -2.9/+3.1 x 10^22 cm^-2 and the visual extinction A_V = 49 -16/+17 mag in the host galaxy. If this is the case, no detection of any optical transient would be quite reasonable. The absorption derived by the Swift XRT observations of the afterglow is fully consistent with those obtained from the early HETE-2 observation of the prompt emission. Our analysis implies an interpretation that the absorbing medium could be outside external shock at R ~ 10^16 cm, which may be a dusty molecular cloud.Comment: 6 pages, 2 figures, accepted for publication in PASJ lette

Analysis of the Evidence-practice Gap to Facilitate Proper Medical Care for the Elderly: Investigation, using Databases, of Utilization Measures for National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB)

As Japan becomes a super-aging society, presentation of the best ways to provide medical care for the elderly, and the direction of that care, are important national issues. Elderly people have multi-morbidity with numerous medical conditions and use many medical resources for complex treatment patterns. This increases the likelihood of inappropriate medical practices and an evidence-practice gap. The present study aimed to: derive findings that are applicable to policy from an elucidation of the actual state of medical care for the elderly; establish a foundation for the utilization of National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), and present measures for the utilization of existing databases in parallel with NDB validation. Cross-sectional and retrospective cohort studies were conducted using the NDB built by the Ministry of Health, Labor and Welfare of Japan, private health insurance claims databases, and the Kyoto University Hospital database (including related hospitals). Medical practices (drug prescription, interventional procedures, testing) related to four issues—potential inappropriate medication, cancer therapy, chronic kidney disease treatment, and end-of-life care—will be described. The relationships between these issues and clinical outcomes (death, initiation of dialysis and other adverse events) will be evaluated, if possible

Extracellular Electron Transfer via Outer Membrane Cytochromes in a Methanotrophic Bacterium Methylococcus capsulatus (Bath)

Electron exchange reactions between microbial cells and solid materials, referred to as extracellular electron transfer (EET), have attracted attention in the fields of microbial physiology, microbial ecology, and biotechnology. Studies of model species of iron-reducing, or equivalently, current-generating bacteria such as Geobacter spp. and Shewanella spp. have revealed that redox-active proteins, especially outer membrane c-type cytochromes (OMCs), play a pivotal role in the EET process. Recent (meta)genomic analyses have revealed that diverse microorganisms that have not been demonstrated to have EET ability also harbor OMC-like proteins, indicating that EET via OMCs could be more widely preserved in microorganisms than originally thought. A methanotrophic bacterium Methylococcus capsulatus (Bath) was reported to harbor multiple OMC genes whose expression is elevated by Cu starvation. However, the physiological role of these genes is unknown. Therefore, in this study, we explored whether M. capsulatus (Bath) displays EET abilities via OMCs. In electrochemical analysis, M. capsulatus (Bath) generated anodic current only when electron donors such as formate were available, and could reduce insoluble iron oxides in the presence of electron donor compounds. Furthermore, the current-generating and iron-reducing activities of M. capsulatus (Bath) cells that were cultured in a Cu-deficient medium, which promotes high levels of OMC expression, were higher than those cultured in a Cu-supplemented medium. Anodic current production by the Cu-deficient cells was significantly suppressed by disruption of MCA0421, a highly expressed OMC gene, and by treatment with carbon monoxide (CO) gas (an inhibitor of c-type cytochromes). Our results provide evidence of EET in M. capsulatus (Bath) and demonstrate the pivotal role of OMCs in this process. This study raises the possibility that EET to solid compounds is a novel survival strategy of methanotrophic bacteria