Biosynthesis of astromicin and related antibiotics. II. Biosynthetic studies with blocked mutants of Micromonospora olivasterospora

An inosamine-idiotrophic mutant, KY11559, which produced no astromicin unless scyllo-inosamine was added to the fermentation medium, was isolated from Micromonospora olivasterospora. Biotransformation studies were performed with resting cells of this mutant and compounds assumed to be precursors of 1,4-diaminocyclitol (fortamine). Scyllo-inosose, scyllo-inosamine and FU-10 were converted to astromicin. A number of mutants blocked in the biosynthesis of astromicin were developed from M. olivasterospora, and the intermediates accumulated by these mutants were isolated and identified. Twenty-five blocked mutants were classified into 10 groups, based on their complementation patterns by cosynthesis experiments. Further, utilizing these blocked mutants and the isolated compounds, biotransformation analyses were performed. The results showed that the amination at position 4 in fortamine occurred after formation of the pseudodisaccharide. Subsequently, the aminosugar and aminocyclitol moieties were aminated, methylated, dehydroxylated, epimerized and acylated to produce astromicin. Thus it was demonstrated that the astromicin biosynthetic pathway has a unique feature which is not found in the biosynthesis of other aminoglycoside antibiotics.     

Neural mechanisms of timing control in a coincident timing task

Many ball sports such as tennis or baseball require precise temporal anticipation of both sensory input and motor output (i.e., receptor anticipation and effector anticipation, respectively) and close performance monitoring. We investigated the neural mechanisms underlying timing control and performance monitoring in a coincident timing task involving both types of anticipations. Peak force for two time-to-peak force (TTP) conditions—recorded with a force-sensitive key—was required to coincide with a specific position of a stimulus rotating either slow or fast on a clock face while the contingent negative variation (CNV) and the motor-elicited negativity were recorded. Absolute timing error was generally smaller for short TTP (high velocity) conditions. CNV amplitudes increased with both faster stimulus velocity and longer TTPs possibly reflecting increased motor programming efforts. In addition, the motor-elicited negativity was largest in the slow stimulus/short TTP condition, probably representing some forms of performance monitoring as well as shorter response duration. Our findings indicate that the coincident timing task is a good model for real-life situations of tool use.     

Relation of coronary plaque composition determined by 64-slice multidetector computed tomography in patients with suspected coronary heart disease

Sixty-four-slice multidetector row computed tomography is a noninvasive method of assessing coronary artery stenosis and plaque composition. The aim of this study was to clarify the relation between plaque composition and coronary heart disease. Three hundred sixty consecutive patients and 1,085 plaques were evaluated using 64-slice multidetector row computed tomography. On axial or cross-sectional multiplanar reconstruction images, 3 regions of interest were randomly selected within each plaque. Soft plaques and calcified plaques were defined as having computed tomographic densities <50 and >130 Hounsfield units, respectively. The association between coronary risk factors and plaque composition was analyzed. The number of plaques and the mean computed tomographic density of plaques were significantly higher in men than in women (p = 0.002 and p = 0.04, respectively). Coronary plaques were more frequent in patients with stroke, diabetes, hypertension, and dyslipidemia than in patients without these conditions (all p values <0.001). Calcified plaques were more frequent in patients with hypertension (p = 0.02), and patients with calcified plaques also had significantly lower low-density lipoprotein cholesterol levels (p <0.001). Soft plaques were more frequent in patients with dyslipidemia (p <0.001). Patients with soft plaques had significantly higher low-density lipoprotein cholesterol levels (p = 0.02) and lower high-density lipoprotein cholesterol levels (p <0.001) than those without soft plaques. In conclusion, 64-slice multidetector row computed tomography is a useful noninvasive method for quantifying coronary plaques.     

Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy

Neurofibrillary tangles (NFTs) have been implicated in mediating neuronal death and disease progression in human tauopathies; however, mounting in vivo data suggest that NFTs may not be the primary initiators of neurotoxicity. Caspase activity has been implicated in processes associated with the development of tauopathy, but the position that caspase activation holds in neurodegenerative cascades remains uncertain. Using multiphoton real-time imaging microscopy, de Calignon et al recently demonstrated that caspase activation precedes and leads to tangle formation within 24 hours in the rTg4510 mouse model of tauopathy. Here, we used immunoelectron microscopy to determine whether caspase-cleaved tau was present in NFTs of rTg4510 mice. Using a caspase-cleaved tau-specific antibody (TauC3), we found very little immunogold labeling in NFTs in the brains of rTg4510 mice. By immunohistochemistry, the number of TauC3-positive neurons was far less than the numbers of neurons stained with the MC1 antibody, which recognizes abnormal conformations of tau. Biochemically, caspase-cleaved tau was barely detectable in fractions of rTg4510 mouse brain extracts. Our data suggest that caspase activation might be one of multiple routes through which NFT formation occurs, rather than an obligatory initiation step in pathologic tau production in rTg4510 mice.     

Endoscopic biliary drainage for patients with unresectable pancreatic cancer with obstructive jaundice who are to undergo gemcitabine chemotherapy

INTRODUCTION Pancreatic cancer is one of the most intractable mali- gnancies of the digestive tract and has a dismal prognosis. Such cancer in most patients is in an advanced stage when they first visit medical facilities, and management of obstructive ja…