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131.
Kallio P Patrikainen P Suomela JP Mäntsälä P Metsä-Ketelä M Niemi J 《Biochemistry》2011,50(24):5535-5543
A simplified model system composed of a NADPH-dependent flavoprotein hydroxylase PgaE and a short-chain alcohol dehydrogenase/reductase (SDR) CabV was used to dissect a multistep angucycline modification redox cascade into several subreactions in vitro. We demonstrate that the two enzymes are sufficient for the conversion of angucycline substrate 2,3-dehydro-UWM6 to gaudimycin C. The flavoenzyme PgaE is shown to be responsible for two consecutive NADPH- and O(2)-dependent reactions, consistent with the enzyme-catalyzed incorporation of oxygen atoms at C-12 and C-12b in gaudimycin C. The two reactions do not significantly overlap, and the second catalytic cycle is initiated only after the original substrate 2,3-dehydro-UWM6 is nearly depleted. This allowed us to isolate the product of the first reaction at limiting NADPH concentrations and allowed the study of the qualitative and kinetic properties of the separated reactions. Dissection of the reaction cascade also allowed us to establish that the SDR reductase CabV catalyzes the final biosynthetic step, which is closely coupled to the second PgaE reaction. In the absence of CabV, the complete PgaE reaction leads invariably to product degradation, whereas in its presence, the reaction yields the final product, gaudimycin C. The result implies that the C-6 ketoreduction step catalyzed by CabV is required for stabilization of a reactive intermediate. The close relationship between PgaE and CabV would explain previous in vivo observations: why the absence of a reductase gene may result in the lack of C-12b-oxygenated species and, vice versa, why all C-12b-oxygenated angucyclines appear to have undergone reduction at position C-6. 相似文献
132.
Measurements of the kinetics of hyperpolarized (13)C label exchange between [1-(13)C]pyruvate and lactate in suspensions of intact and lysed murine lymphoma cells, and in cells in which lactate dehydrogenase expression had been modulated by inhibition of the PI3K pathway, were used to determine quantitatively the role of enzyme activity and membrane transport in controlling isotope flux. Both steps were shown to share in the control of isotope flux in these cells. The kinetics of label exchange were well described by a kinetic model that employed rate constants for the lactate dehydrogenase reaction that had been determined previously from steady state kinetic studies. The enzyme showed pyruvate inhibition in steady state kinetic measurements, which the kinetic model predicted should also be observed in the isotope exchange measurements. However, no such pyruvate inhibition was observed in either intact cells or cell lysates and this could be explained by the much higher enzyme concentrations present in the isotope exchange experiments. The kinetic analysis presented here shows how lactate dehydrogenase activity can be determined from the isotope exchange measurements. The kinetic model should be useful for modeling the exchange reaction in vivo, particularly as this technique progresses to the clinic. 相似文献
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Habitat fragmentation is one of the most studied topics in ecology but our knowledge is still limited particularly concerning matrix effects on species distribution in a human-dominated landscape. We tested the ability of random sampling hypothesis, colonization–extinction dynamics and matrix-related concepts to explain the variation in species richness, total bird density and community composition in old-forest bird assemblages in two contrasting landscapes. We collected data on breeding bird abundances from 66 old-growth forest reserves in NE Finland and six larger areas in adjacent Russian Karelia using the line transect method. In Finland, protected old-forest patches are embedded in a matrix dominated by young regeneration stands. In Russia, study areas were situated in continuous, old forest dominated landscapes. Bird assemblages in old-forest patches embedded in human-modified matrix in Finland were not random samples from Russian bird assemblages. In the Finnish assemblages, species richness was lower and total bird density higher. Species richness declined with increasing distance (isolation) to Russia. Bird assemblages in large forest reserves in Finland close to Russia were structurally more similar to assemblages in the continuous reference landscape than those in small and more distant reserves. The results support the idea that several mechanisms related to colonisation–extinction dynamics and to matrix resource availability influence species distribution in fragmented landscapes but in species-specific ways. We conclude that even though small and isolated protected areas may foster high relative bird species density their ecological integrity is compromised, and therefore, improving matrix quality around reserves may lead to considerable conservation benefits. 相似文献
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137.
Reza Karimi G?ran Tornling Helena Forsslund Mikael Mikko ?sa M Wheelock Sven Nyrén Carl Magnus Sk?ld 《Respiratory research》2014,15(1):23
Background
Smokers have increased cell concentration in the lower respiratory tract indicating a chronic inflammatory state, which in some individuals may lead to development of chronic obstructive pulmonary disease (COPD). Computer tomography (CT) imaging provides means of quantifying pulmonary structure and early signs of disease. We investigated whether lung density on high resolution CT differs between smokers and never-smokers and if this were associated to intensity of inflammation.Methods
Forty smoking volunteers with normal pulmonary function, 40 healthy never-smokers and 40 patients with COPD of GOLD stage I-II, were included. Mean lung attenuation and percentage of pixels in the lung with attenuation between −750 and −900 HU (percentage higher density spectrum (%HDS)) were calculated on inspiratory CT-scans. Markers of systemic inflammation in blood and cell counts in bronchoalveolar lavage (BAL) fluid were recorded.Results
Lung density expressed as %HDS was increased in smokers (44.0 ± 5.8%) compared to both never-smokers (38.3 ± 5.8%) and patients with COPD (39.1 ± 5.8%), (p < 0.001, for both). Females had denser lungs than males, which was dependent on body height. Cell concentration in BAL were correlated to lung density in smokers (r = 0.50, p < 0.001).Conclusions
Lung density on CT is associated with cell concentration in BAL in smokers and may mirror an inflammatory response in the lung. Gender difference in lung density is dependent on height. In COPD with emphysema, loss of lung tissue may counterbalance the expected increase in density due to inflammation. The findings may help to interpret high resolution CT in the context of smoking and gender and highlight the heterogeneity of structural changes in COPD. 相似文献138.
Mikko Taina Miika Korhonen Mika Haataja Antti Muuronen Otso Arponen Marja Hedman Pekka J?k?l? Petri Sipola Pirjo Mustonen Ritva Vanninen 《PloS one》2014,9(7)
Objectives
Left atrial appendage (LAA) dilatation and morphology may influence an individual''s risk for intracardiac thrombi and ischemic stroke. LAA size and morphology can be evaluated using cardiac computed tomography (cCT). The present study evaluated the reproducibility of LAA volume and morphology assessments.Methods
A total of 149 patients (47 females; mean age 60.9±10.6 years) with suspected cardioembolic stroke/transient ischemic attack underwent cCT. Image quality was rated based on four categories. Ten patients were selected from each image quality category (N = 40) for volumetric reproducibility analysis by two individual readers. LAA and left atrium (LA) volume were measured in both two-chamber (2CV) and transversal view (TV) orientation. Intertechnique reproducibility was assessed between 2CV and TV (200 measurement pairs). LAA morphology (A = Cactus, B = ChickenWing, C = WindSock, D = CauliFlower), LAA opening height, number of LAA lobes, trabeculation, and orientation of the LAA tip was analysed in all study subjects by three individual readers (447 interobserver measurement pairs). The reproducibility of volume measurements was assessed by intra-class correlation (ICC) and the reproducibility of LAA morphology assessments by Cohen''s kappa.Results
The intra-observer and interobserver reproducibility of LAA and LA volume measurements was excellent (ICCs>0.9). The LAA (ICC = 0.954) and LA (ICC = 0.945) volume measurements were comparable between 2CV and TV. Morphological classification (ĸ = 0.24) and assessments of LAA opening height (ĸ = 0.1), number of LAA lobes (ĸ = 0.16), trabeculation (ĸ = 0.15), and orientation of the LAA tip (ĸ = 0.37) was only slightly to fairly reproducible.Conclusions
LA and LAA volume measurements on cCT provide excellent reproducibility, whereas visual assessment of LAA morphological features is challenging and results in unsatisfactory agreement between readers. 相似文献139.
Matti Viluksela P?ivi Heikkinen Leo T. M. van der Ven Filip Rendel Robert Roos Javier Esteban Merja Korkalainen Sanna Lensu Hanna M. Miettinen Kari Savolainen Satu Sankari Hellmuth Lilienthal Annika Adamsson Jorma Toppari Maria Herlin Mikko Finnil? Juha Tuukkanen Heather A. Leslie Timo Hamers Gerd Hamscher Lauy Al-Anati Ulla Stenius Kine-Susann Dervola Inger-Lise Bogen Frode Fonnum Patrik L. Andersson Dieter Schrenk Krister Halldin Helen H?kansson 《PloS one》2014,9(8)
PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions. 相似文献
140.
Heidi Hintsala Tuomas V. Kentt? Mikko Tulppo Antti Kiviniemi Heikki V. Huikuri Matti M?ntysaari Sirkka Kein?nen-Kiukaannemi Risto Bloigu Karl-Heinz Herzig Riitta Antikainen Hannu Rintam?ki Jouni J. K. Jaakkola Tiina M. Ik?heimo 《PloS one》2014,9(7)