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Miikka Pakkala Can Hekim Pasi Soininen Jari Leinonen Hannu Koistinen Janne Weisell Ulf‐HÅkan Stenman Jouko Vepsäläinen Ale Närvänen 《Journal of peptide science》2007,13(5):348-353
Human glandular kallikrein (KLK2) is a highly prostate-specific serine protease, which is mainly excreted into the seminal fluid, but part of which is also secreted into circulation from prostatic tumors. Since the expression level of KLK2 is elevated in aggressive tumors and it has been suggested to mediate the metastasis of prostate cancer, inhibition of the proteolytic activity of KLK2 is of potential therapeutic value. We have previously identified several KLK2-specific linear peptides by phage display technology. Two of its synthetic analogs, A R R P A P A P G (KLK2a) and G A A R F K V W W A A G (KLK2b), show specific inhibition of KLK2 but their sensitivity to proteolysis in vivo may restrict their potential use as therapeutic agents. In order to improve the stability of the linear peptides for in vivo use, we have prepared cyclic analogs and compared their biological activity and their structural stability. A series of cyclic variants with cysteine bridges were synthesized. Cyclization inactivated one peptide (KLK2a) and its derivatives, while the other peptide (KLK2b) and its derivatives remained active. Furthermore, backbone cyclization of KLK2b improved significantly the resistance against proteolysis by trypsin and human plasma. Nuclear magnetic resonance studies showed that cyclization of the KLK2b peptides does not make the structures more rigid. In conclusion, we have shown that backbone cyclization of KLK2 inhibitory peptides can be used to increase stability without losing biological activity. This should render the peptides more useful for in vivo applications, such as tumor imaging and prostate cancer targeting. 相似文献
23.
We studied experimentally how heterospecific attraction may affect habitat selection of migrant passerine birds in Finnish
Lapland. We manipulated the densities of resident tit species (Parus spp.). In four study plots residents were removed before the arrival of the migrants in the first study year, and in four
other plots their densities were increased by releasing caught individuals. In the second year the treatments of the areas
were reversed, allowing paired comparisons within each plot. We also investigated the relative abundance of arthropods in
the study plots by the sweep-net method. This allowed us to estimate the effect of food resources on the abundance of birds.
The heterospecific attraction hypothesis predicts that densities of migrant species (especially habitat generalists) would
be higher during increased resident density. Results supported this prediction. Densities and number of the most abundant
migrant species were significantly higher when resident density was increased than when they were removed. On the species
level the redwing (Turdus iliacus) showed the strongest positive response to the increased abundance of tits. Migrant bird abundances seemed not to vary in
parallel with relative arthropod abundance, with the exception of the pied flycatcher (Ficedula hypoleuca) which showed a strongly positive correlation with many arthropod groups. The results of the experiment indicate that migrants
can use resident tit species as a cue to a profitable breeding patch. The relationship between the abundance of the birds
and arthropods suggests that annual changes in food resources during the breeding season probably do not have a very important
effect on bird populations in these areas. The results stress the importance of positive interspecific interactions in structuring
northern breeding bird communities.
Received: 1 September 1997 / Accepted: 22 January 1998 相似文献
24.
Miroshnyk I Mirza S Zorky PM Heinämäki J Yli-Kauhaluoma J Yliruusi J 《Bioorganic & medicinal chemistry》2008,16(1):232-239
Quantitative analysis of the molecular conformations of the 14-membered macrolide antibiotics erythromycin A and B, clarithromycin, and roxithromycin in the solid state was performed. While the erythronolide macrocycle adopts a very similar folded-out conformation in all the macrolides studied, the proximity of the monosaccharide moieties, L-cladinose and D-desosamine, to each other is demonstrated to be the distinctive feature of their molecular conformations, based on atom-atom interaction energy analysis. More surprisingly, the common features in the relative orientation of the monosaccharide moieties (in terms of non-bonded atom-atom interactions) were revealed between the 14- and 15-membered (azithromycin) macrolide antibiotics. Herein we report on the details of the spatial arrangement of the monosaccharide moieties in these structurally related drug molecules and their influence on the biopharmaceutical properties of erythromycin derivatives. 相似文献
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Sanna Saarnio Sanna Järviö Timo Saarinen Harri Vasander Jouko Silvola 《Ecosystems》2003,6(1):0046-0060
Increasing concentrations of carbon dioxide (CO2) in the atmosphere or continuous nitrogen (N) deposition might alter the carbon (C) cycle in boreal mires and thus have significant
impacts on the development of climate change. The atmospheric impact of the C cycle in mires is twofold: C accumulation attenuates
and CH4 release strengthens the natural greenhouse effect. We studied the effects of an increased supply of CO2 or NH4NO3 on the vegetation and annual CO2 exchange in lawns of a boreal oligotrophic mire in eastern Finland over a 2-year period. Ten study plots were enclosed with
mini-FACE (Free Air Carbon Dioxide Enrichment) rings. Five plots were vented with CO2-enriched air (target 560 ppmv), while their controls were vented with ambient air; five plots were sprayed with NH4NO3, corresponding to a cumulative addition of 3 g N m−2 a−1, while their controls were sprayed with distilled water only. A raised NH4NO3 supply seemed to affect the composition of the moss layer. Raised CO2 did not affect the vegetation, but gross photosynthesis increased significantly. The change in net CO2 exchange depended on the annual weather conditions. Our results suggest that C accumulation may increase in wet years and
compensate for the warming effect caused by the increase in CH4 release from this mire. In contrast, a relatively dry and warm growing period favors decomposition and can even make the
CO2 balance negative. Along with the increased CH4 release under raised CO2, the decreased C accumulation then increases the radiative forcing of boreal mires.
Received 22 October 2001; accepted 13 May 2002. 相似文献
27.
In this study, a new concept for particle size prediction during the fluid bed granulation is presented. Using the process
measurements data obtained from a design of experimental study, predictive partial least squares models were developed for
spraying and drying phases. Measured and calculated process parameters from an instrumented fluid bed granulation environment
were used as explaining factors, whereas an in-line particle size data determined by spatial filtering technique were used
as response. Modeling was carried out by testing all possible combinations of two to six process parameters (factors) of the
total of 41 parameters. Eleven batches were used for model development and four batches for model testing. The selected models
predicted particle size (d
50) well, especially during the spraying phase (Q
2 = 0.86). While the measured in-line d
50 data were markedly influenced by different process failures, e.g., impaired fluidization activity, the predicted data remained
more consistent. This introduced concept can be applied in fluid bed granulation processes if the granulation environment
is soundly instrumented and if reliable real-time particle size data from the design of experiment batches are retrieved for
the model development. 相似文献
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30.
Tuomo A. Keinänen Mervi T. Hyvönen Leena Alhonen Jouko Vepsäläinen Alex R. Khomutov 《Amino acids》2014,46(3):605-620
Polyamine metabolism is intimately linked to the physiological state of the cell. Low polyamines levels promote growth cessation, while increased concentrations are often associated with rapid proliferation or cancer. Delicately balanced biosynthesis, catabolism, uptake and excretion are very important for maintaining the intracellular polyamine homeostasis, and deregulated polyamine metabolism is associated with imbalanced metabolic red/ox state. Although many cellular targets of polyamines have been described, the precise molecular mechanisms in these interactions are largely unknown. Polyamines are readily interconvertible which complicate studies on the functions of the individual polyamines. Thus, non-metabolizable polyamine analogues, like carbon-methylated analogues, are needed to circumvent that problem. This review focuses on methylated putrescine, spermidine and spermine analogues in which at least one hydrogen atom attached to polyamine carbon backbone has been replaced by a methyl group. These analogues allow the regulation of both metabolic and catabolic fates of the parent molecule. Substituting the natural polyamines with methylated analogue(s) offers means to study either the functions of an individual polyamine or the effects of altered polyamine metabolism on cell physiology. In general, gem-dimethylated analogues are considered to be non-metabolizable by polyamine catabolizing enzymes spermidine/spermine-N 1-acetyltransferase and acetylpolyamine oxidase and they support short-term cellular proliferation in many experimental models. Monomethylation renders the analogues chiral, offering some advantage over gem-dimethylated analogues in the specific regulation of polyamine metabolism. Thus, methylated polyamine analogues are practical tools to meet existing biological challenges in solving the physiological functions of polyamines. 相似文献