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Clear Separation (clear + separation)
Selected AbstractsDiffering body size between the autumn and the winter,spring cohorts of neon flying squid (Ommastrephes bartramii) related to the oceanographic regime in the North Pacific: a hypothesisFISHERIES OCEANOGRAPHY, Issue 5 2004Taro Ichii Abstract The neon flying squid (Ommastrephes bartramii), which is the target of an important North Pacific fishery, is comprised of an autumn and winter,spring cohort. During summer, there is a clear separation of mantle length (ML) between the autumn (ML range: 38,46 cm) and the winter,spring cohorts (ML range: 16,28 cm) despite their apparently contiguous hatching periods. We examined oceanic conditions associated with spawning/nursery and northward migration habitats of the two different-sized cohorts. The seasonal meridional movement of the sea surface temperature (SST) range at which spawning is thought to occur (21,25°C) indicates that the spawning ground occurs farther north during autumn (28,34°N) than winter,spring (20,28°N). The autumn spawning ground coincides with the Subtropical Frontal Zone (STFZ), characterized by enhanced productivity in winter because of its close proximity to the Transition Zone Chlorophyll Front (TZCF), which move south to the STFZ from the Subarctic Boundary. Hence this area is thought to become a food-rich nursery ground in winter. The winter,spring spawning ground, on the other hand, coincides with the Subtropical Domain, which is less productive throughout the year. Furthermore, as the TZCF and SST front migrate northward in spring and summer, the autumn cohort has the advantage of being in the SST front and productive area north of the chlorophyll front, whereas the winter,spring cohort remains to the south in a less productive area. Thus, the autumn cohort can utilize a food-rich habitat from winter through summer, which, we hypothesize, causes its members to grow larger than those in the winter,spring cohort in summer. [source] Tracing energy flow in stream food webs using stable isotopes of hydrogenFRESHWATER BIOLOGY, Issue 5 2010JACQUES C. FINLAY Summary 1. Use of the natural ratios of carbon and nitrogen stable isotopes as tracers of trophic interactions has some clear advantages over alternative methods for food web analyses, yet is limited to situations where organic materials of interest have adequate isotopic separation between potential sources. This constrains the use of natural abundance stable isotope approaches to a subset of ecosystems with biogeochemical conditions favourable to source separation. 2. Recent studies suggest that stable hydrogen isotopes (,D) could provide a robust tracer to distinguish contributions of aquatic and terrestrial production in food webs, but variation in ,D of consumers and their organic food sources are poorly known. To explore the utility of the stable hydrogen isotope approach, we examined variation in ,D in stream food webs in a forested catchment where variation in ,13C has been described previously. 3. Although algal ,D varied by taxa and, to a small degree, between sites, we found consistent and clear separation (by an average of 67,) from terrestrial carbon sources. Environmental conditions known to affect algal ,13C, such as water velocity and stream productivity did not greatly influence algal ,D, and there was no evidence of seasonal variation. In contrast, algal ,13C was strongly affected by environmental factors both within and across sites, was seasonally variable at all sites, and partially overlapped with terrestrial ,13C in all streams with catchment areas larger than 10 km2. 4. While knowledge of isotopic exchange with water and trophic fractionation of ,D for aquatic consumers is limited, consistent source separation in streams suggests that ,D may provide a complementary food web tracer to ,13C in aquatic food webs. Lack of significant seasonal or spatial variation in ,D is a distinct advantage over ,13C for applications in many aquatic ecosystems. [source] CFD analysis of an oscillating wing at various reduced frequenciesINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN FLUIDS, Issue 2 2009Farooq Umar Abstract The effect of various reduced frequencies has been examined for an oscillating aspect ratio 10 NACA 0015 wing. An unsteady, compressible three-dimensional (3D) Navier,Stokes code based on Beam and Warming algorithm with the Baldwin,Lomax turbulence model has been used. The code is validated for the study against published experimental data. The 3D unsteady flow field is simulated for reduced frequency values of 0.1, 0.2 and 0.3 for a fixed mean angle of attack position and fixed amplitude. The type of motion is sinusoidal harmonic. The force coefficients, pressure distributions and flow visualization show that at the given conditions the flow remains attached to the wing surface even at high angles of attack with no clear separation or typical light-to-deep category of dynamic stall. Increased magnitude of hysteresis and higher gradients are seen at higher reduced frequencies. The 3D effects are even found at midspan locations. In addition, the rate of decrease in lift near the wing tips compared with the wing root is not much like in the static cases. Copyright © 2008 John Wiley & Sons, Ltd. [source] Osteoprotegerin (OPG),a potential new role in the regulation of endothelialcell phenotype and tumour angiogenesis?INTERNATIONAL JOURNAL OF CANCER, Issue 8 2006Simon S. Cross Abstract The progression of cancer depends on the establishment of a tumour blood supply, and therefore tumour angiogenesis has been identified as a major target for new anticancer agents. Recent reports have suggested that osteoprotegerin (OPG) is involved in the control of endothelial cell survival through the inhibition of the activity of tumour necrosis factor- (TNF) related apoptosis-inducing ligand (TRAIL). The role of OPG in human tumour development and angiogenesis is currently unknown. In the present study we demonstrate the ability of OPG to support endothelial cell survival, as well as the formation of cord-like structures in vitro using a matrigel tubule formation assay. Investigation of various human cancers demonstrated endothelial OPG expression in 59% of malignant tumours (n = 512), but in contrast, OPG was absent in endothelial cells associated with benign tumours and normal tissues (n = 178). In a series of 400 breast tumours, endothelial OPG expression was associated with high tumour grade and certain histological types. Our data show a clear separation in endothelial OPG expression between malignant tumours and nonmalignant tissues, supporting a potential biological role for this molecule in the development and/or maintenance of the tumour vasculature. This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours. © 2005 Wiley-Liss, Inc. [source] The Institutional Requirements Of Apprenticeship: Evidence From Smaller EU CountriesINTERNATIONAL JOURNAL OF TRAINING AND DEVELOPMENT, Issue 1 2000Paul Ryan To what extent does the experience of other European econom-ies in which apprenticeship has proved successful suggest scope for reviving apprenticeship in the UK without requiring institutional regulation along German lines? The institutional attributes of apprenticeship in four smaller European economies (Austria, Denmark, Ireland and the Netherlands) are shown to be closer to Germany's social partnership than to the UK's deregulated market, in terms of: statutory governance; formal educational requirements; administration at sec-toral and local levels through social partnership; and funding based upon a clear separation of responsibilities between government and employers, though not between employers and apprentices. At the same time, the introduction of statu-tory apprenticeship into Irish industry in recent years, in an institutional environment that has traditionally had much in common with that of the UK, suggests that the scope for institutional development in support of apprenticeship has been obscured by the widespread tendency to limit the choice of international comparisons to the Anglo-Germanic. [source] Utilisation of morphological features in life table studies of Liriomyza huidobrensis (Dipt., Agromyzidae) developing in lettuceJOURNAL OF APPLIED ENTOMOLOGY, Issue 7-8 2002J. Head The growth ratios of cephalopharyngeal skeletons between first and second and second and third instar larvae were 1.80 and 1.47, respectively, enabling clear separation to be achieved for experimental work. Using this method the development rates of the immature stages of L. huidobrensis feeding on Lactuca sativa were determined under constant temperatures of 11, 16, 19, 26 and 28 ± 1°C and were shown to increase linearly with temperature over the range investigated. The theoretical lower threshold temperatures for development from oviposition to the end of each larval instar or pupal stage were 5.35, 6.30, 6.20 and 5.70°C, respectively. The overall threshold temperature for development from oviposition to 50% adult emergence (5.70°C) was used to calculate degree-day (DD) requirements for development from oviposition to each larval instar or pupal eclosion, which were 84.3, 30.1, 58.9, 143.7 DD, respectively. The use of these data for optimizing the timing of application of control agents which are effective against specific developmental stages is discussed. [source] Characterisation of user-defined health status in older adults with intellectual disabilitiesJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 6 2008J. M. Starr Abstract Background Older adults with Intellectual Disabilities (ID) have an excess disease burden that standard health assessments are designed to detect. Older adults with ID have a broader concept of health with dimensions of well being in addition to absence of disease in line with the World Health Organization's health definition. We sought to characterise user-defined health status in a sample of older adults with ID. Methods We administered a user-led health assessment to 57 adults with ID aged 40 years and over. Cluster analysis on user-defined health themes of participation, nutrition and hygiene/self-care identified clear separation of participants into a healthier and a less healthy group. Results Disease burden (P = 0.002) and medication use (P = 0.003) were greater in the less healthy group. The healthier group were taller (P = 0.005), stronger (P = 0.005) and had better vision (P < 0.001) than the less healthy group. Constipation (P = 0.014), urinary incontinence (P < 0.001) and faecal incontinence (P < 0.001) were commoner in the less healthy group. There were few significant differences between health groups on the majority of standard physical-examination items. Conclusions There is considerable overlap between user-defined health and that assessed by standard instruments. In addition, user-defined health encompasses aspects of physical fitness not captured by traditional disease-based health models. [source] Lawyers for Conservative Causes: Clients, Ideology, and Social DistanceLAW & SOCIETY REVIEW, Issue 1 2003John P. Heinz Scholars have devoted attention to "cause lawyers" on the political left, but lawyers who work on the conservative side of the American political spectrum have received relatively little academic consideration. This article presents systematic data on the characteristics of and relationships among lawyers affiliated with organizations active on a selected set of 17 conservative issues. We find that the lawyers serve several separate and distinct constituencies,business conservatives, Christian conservatives, libertarians, abortion opponents,and that the credentials of the lawyers serving these varying constituencies differ significantly. The greatest degree of social separation occurs between the business constituency and the abortion opponents, with another clear separation between libertarians and the interest groups devoted to traditional family values and order maintenance. The divisions among these constituencies appear to reflect the difference between "insider politics" and "populism," which is manifested in part in actual geographic separation between lawyers located in the District of Columbia and those in the South, West, and Midwest. In the center of the network, however, we find some potential "mediators",prominent lawyers who may facilitate communication and coordination among the several constituencies. These lawyers and the organizations they serve attempt to merge morality, market freedom, and individual liberty concerns, and they convene meetings of diverse sets of lawyers and organizational leaders to seek consensus on policy goals. Nonetheless, the findings indicate that most organizations are seldom active on issues that lie beyond the relatively narrow boundaries of their own interests. [source] Sustained effect of SQ-standardized grass allergy immunotherapy tablet on rhinoconjunctivitis quality of lifeALLERGY, Issue 6 2010L. Frølund To cite this article: Frølund L, Durham SR, Calderon M, Emminger W, Andersen JS, Rask P, Dahl R. Sustained effect of SQ-standardized grass allergy immunotherapy tablet on rhinoconjunctivitis quality of life. Allergy 2010; 65: 753,757. Abstract Background:, The prevalence of allergic rhinoconjunctivitis has increased significantly over the past decades with grass pollen being a common trigger. The impact of allergy on patient's quality of life is substantial. Aim:, To investigate the sustained effect on quality of life during the grass pollen season 1 year after 3 years of treatment with the SQ-standardized grass allergy immunotherapy tablet (AIT), Grazax® (Phleum pratense 75,000 SQ-T/2800 BAU; ALK, Denmark). Methods:, The trial was a randomized, parallel-group, double-blind, placebo-controlled trial in adult subjects with a history of moderate-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications. Subjects received 3 years of grass AIT (n = 157) or placebo (n = 126), followed by 1 year of follow-up. Quality of life assessments were based on the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ(S)); completed weekly during the entire grass pollen season. Results:, During follow-up, the overall RQLQ(S) score for the entire grass pollen season was significantly improved in the active group (relative difference to placebo: 23%, P = 0.004). The improvement was higher during the peak pollen season (28%, P = 0.001). The treatment effect of grass AIT during the follow-up year and the previous three treatment years was similar. Improvements were found in all seven RQLQ(S) domains. The RQLQ(S) as a function of the weekly average pollen counts showed a clear separation between the treatment groups (P < 0.001). Conclusion:, In subjects inadequately controlled by symptomatic medications, grass AIT provided sustained and clinically relevant improvements in rhinoconjunctivitis quality of life compared to placebo. The effect increased with increasing grass pollen exposure. [source] Eastern and Western Poor Cod (Trisopterus minutus capelanus) Populations in the Mediterranean Sea: Evidence from Allozyme and Minisatellite LociMARINE ECOLOGY, Issue 4 2003Valeria Mattiangeli Abstract., Nine allozyme and two minisatellite loci were used to investigate potential genetic differentiation among three samples of Mediterranean poor cod, Trisopterus minutus capelanus, from the Gulf of Lion, the Tuscan Archipelago and the Aegean Sea. Both types of markers showed consistent results, with FST values of 0.0262 and 0.0296 (P < 0.0015, after Bonferroni correction for multiple tests) for allozymes and minisatellites, respectively. Allele frequency heterogeneity tests between pairs of samples showed a clear separation between the two western Mediterranean samples (Gulf of Lion, Tuscan Archipelago) and the eastern one (Aegean Sea). The results indicate that at least two reproductively isolated populations of poor cod occur in the Mediterranean. [source] Enhanced star formation in narrow-line Seyfert 1 active galactic nuclei revealed by SpitzerMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 3 2010E. Sani ABSTRACT We present new low-resolution Spitzer mid-infrared spectroscopy of a sample of 20 ROSAT -selected local narrow-line Seyfert 1 galaxies (NLS1s). We detect strong active galactic nucleus (AGN) continuum in all and clear polycyclic aromatic hydrocarbon (PAH) emission in 70 per cent of the sources. The 6.2 ,m PAH luminosity spans three orders of magnitude, from ,1039 to ,1042 erg s,1, providing strong evidence for intense ongoing star formation in the circumnuclear regions of these sources. Using the Infrared Spectrograph/Spitzer archive, we gathered a large number of additional NLS1s and their broad-line counterparts (BLS1s) and constructed NLS1 and BLS1 subsamples to compare them in various ways. The comparison shows a clear separation according to full width at half-maximum (H,) [FWHM(H,)] such that objects with narrower broad H, lines are the strongest PAH emitters. We test this division in various ways trying to remove biases due to luminosity and aperture size. Specifically, we find that star formation activity around NLS1 AGN is larger than around BLS1 of the same AGN luminosity. The above result seems to hold over the entire range of distance and luminosity. Moreover, the star formation rate is higher in low black hole mass and high L/LEdd systems indicating that black hole growth and star formation are occurring simultaneously. [source] The phylogenetic affinities of the Pondaung taliAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 2 2010Marian Dagosto Abstract The phylogenetic affinities of the primates of the late middle Eocene Pondaung Formation of Myanmar have long been disputed. The discovery of the NMMP 39 talus (Marivaux et al.: Proc Natl Acad Sci USA 100 (2003) 13173,13178) provided the first clear evidence from the postcranium that a relatively large-bodied haplorhine primate is represented in the Pondaung fauna. Another talus (NMMP 82; Marivaux et al., 2010). Talar morphology, phylogenetic affinities and locomotor adaptation of a large-bodied amphipithecid primate from the late middle Eocene of Myanmar, Am J Phys Anthropol DOI: 10.1002/ajpa.21307) has been recently recovered which also pertains to Haplorhini. The metric and nonmetric features supporting the hypothesis of anthropoid affinities for NMMP 39 have been criticized by Gunnell and Ciochon (Gunnell GF, Ciochon RL. 2008. Revisiting primate postcrania from the Pondaung Formation of Myanmar. In: Fleagle JG, Gilbert CC, editors. Elwyn Simons: a search for origins. New York: Springer. p 211,228). Their analysis, however, was based on a very limited choice of variables, taxa, and individuals. Based on an extended sample, we are able to produce both principal components and discriminant functions that yield a rather clear separation of extant haplorhine and strepsirhine tali. Both principal components and discriminant function scores of the Pondaung tali fall with those of haplorhine primates. In addition, the Pondaung tali lack all the derived nonmetric features characteristic of strepsirhine primates, but exhibit all the features characteristic of haplorhine primates. We dispute the features Gunnell and Ciochon (2008) claim are uniquely shared by the Pondaung tali and adapiforms. Their rejection of the phylogenetic significance of the features shared by these tali and haplorhines is unwarranted by the evidence. Based on both metric and nonmetric features, the Pondaung tali are structurally most similar to the tali of haplorhines, particularly anthropoids. Am J Phys Anthropol 143:223,234, 2010. © 2010 Wiley-Liss, Inc. [source] Y-chromosomal variation confirms independent domestications of swamp and river buffaloANIMAL GENETICS, Issue 4 2010M. Yindee Summary Y-chromosomal variation in the water buffalo was analysed by sequencing of DBY, ZFY and SRY gene segments. A clear separation of the paternal lineages of the river and swamp types parallels the differences between their maternal lineages and nuclear DNA. Sequence divergence was found to be comparable to the divergence of taurine cattle and zebu, and this divergence predated domestication, confirming that river and swamp buffalo originated from different wild populations. Within a sample of 23 Thai swamp buffaloes, we identified four haplotypes with different geographical distributions, two of which were shared by Thai wild buffaloes. [source] Genetic diversity of Hungarian indigenous chicken breeds based on microsatellite markersANIMAL GENETICS, Issue 4 2009N. Bodzsar Summary Six local chicken breeds are registered in Hungary and are regarded as Hungarian national treasures: Hungarian White, Yellow and Speckled, and Transylvanian Naked Neck White, Black and Speckled. Three Hungarian academic institutes have maintained these genetic resources for more than 30 years. The Hungarian Yellow, the Hungarian Speckled and the Transylvanian Naked Neck Speckled breeds were kept as duplicates in two separate subpopulations since time of formation of conservation flocks at different institutes. In this study, we investigated genetic diversity of these nine Hungarian chicken populations using 29 microsatellite markers. We assessed degree of polymorphism and relationships within and between Hungarian breeds on the basis of molecular markers, and compared the Hungarian chicken populations with commercial lines and European local breeds. In total, 168 alleles were observed in the nine Hungarian populations. The FST estimate indicated that about 22% of the total variation originated from variation between the Hungarian breeds. Clustering using structure software showed clear separation between the Hungarian populations. The most frequent solutions were found at K = 5 and K = 6, respectively, classifying the Transylvanian Naked Neck breeds as a separate group of populations. To identify genetic resources unique to Hungary, marker estimated kinships were estimated and a safe set analysis was performed. We show that the contribution of all Hungarian breeds together to the total diversity of a given set of populations was lower when added to the commercial lines than when added to the European set of breeds. [source] The effect of protein,precipitant interfaces and applied shear on the nucleation and growth of lysozyme crystalsACTA CRYSTALLOGRAPHICA SECTION D, Issue 11 2009Nuno M. Reis This paper is concerned with the effect of protein,precipitant interfaces and externally applied shear on the nucleation and growth kinetics of hen egg-white lysozyme crystals. The early stages of microbatch crystallization of lysozyme were explored using both optical and confocal fluorescence microscopy imaging. Initially, an antisolvent (precipitant) was added to a protein drop and the optical development of the protein,precipitant interface was followed with time. In the presence of the water-soluble polymer poly(ethylene glycol) (PEG) a sharp interface was observed to form immediately within the drop, giving an initial clear separation between the lighter protein solution and the heavier precipitant. This interface subsequently became unstable and quickly developed within a few seconds into several unstable `fingers' that represented regions of high concentration-gradient interfaces. Confocal microscopy demonstrated that the subsequent nucleation of protein crystals occurred preferentially in the region of these interfaces. Additional experiments using an optical shearing system demonstrated that oscillatory shear significantly decreased nucleation rates whilst extending the growth period of the lysozyme crystals. The experimental observations relating to both nucleation and growth have relevance in developing efficient and reliable protocols for general crystallization procedures and the controlled crystallization of single large high-quality protein crystals for use in X-ray crystallography. [source] Patterns and gradients of diversity in South Patagonian ombrotrophic peat bogsAUSTRAL ECOLOGY, Issue 1 2010TILL KLEINEBECKER Abstract Many north-hemispherical mires seemingly untouched by drainage and cultivation are influenced by a diffuse sum of man-made environmental changes, such as atmospherical nitrogen deposition that mask general patterns in species richness and functional group responses along resource gradients. To obtain insights into natural diversity-environment relationships, we studied the vegetation and the peat chemistry of pristine bog ecosystems in southern Patagonia along a west,east transect across the Andes. The studied bog ecosystems covered a floristic gradient from hyperoceanic blanket bogs dominated by cushion building vascular plants via a transitional mixed type to Sphagnum -dominated raised bogs east of the mountain range. To test the influence of resource availability on diversity patterns, species richness and functional groups were related to environmental variables by calculating general regression models and generalized additive models. Species richness showed strong linear correlations to peat chemical features and the general regression model resulted in three major environmental variables (water level, total nitrogen, NH4Cl soluble calcium), altogether explaining 76% of variance. Functional group response illustrated a clear separation along environmental gradients. Mosses dominated at the low end of a nitrogen gradient, whereas cushion plants had their optimum at intermediate levels, and graminoids dominated at high nitrogen contents. Further shifts were related to NH4Cl soluble calcium and water level. The models documented partly non-linear relationships between functional group response and trophical peat properties. Within the three bog types, the calculated models differed remarkably illustrating the scale-dependency of the explanatory factors. Our findings confirmed several general patterns of species richness and functional shifts along resource gradients in a surprisingly clear way and underpin the significance of undisturbed peatlands as reference systems for testing of ecological theory and for conservation and ecological restoration in landscapes with strong human impact. [source] Development and validation of a simple thin layer chromatographic method for the analysis of artemisinin in Artemisia annua L. plant extractsBIOMEDICAL CHROMATOGRAPHY, Issue 5 2008Els Marchand Abstract Owing to the development of parasite resistance to standard antimalarial treatments like chloroquine and sulfadoxine,pyrimethamine, the demand for Artemisia annua, a key ingredient for new and highly effective antimalarial drugs, is huge. Therefore selective and precise methods to determine the content of artemisinin in dry plant material and in raw impure extracts are needed. In this work a method is described for the clear separation and extraction of artemisinin from other plant components in the Artemisia annua L. plant by thin-layer chromatography (TLC). To obtain optimal extraction and recovery efficiency, several parameters were evaluted, including choice of extraction solvent, TLC plate type and sensitivity between UV and visible light. Method validation was performed on both the dry plant material and non-purified plant extracts. Toluene presented the highest extraction efficiency compared with petroleum ether, hexane and methanol. Reversed-phase plates showed more concentrated spots than normal-phase plates, while the sensitivity of the analysis in UV was comparable to that in visible light but less precise. The impure plant extracts were analyzed by both TLC and HPLC-UV at 215 nm and both methods met the requirements for linearity, selectivity, precision and accuracy. Hence, the proposed TLC method can easily be used for both qualitative and quantitative control of the raw plant extract in areas where advanced methods are scarce. Copyright © 2007 John Wiley & Sons, Ltd. [source] Infraspecific variation and phylogeography of the high-polyploid Iberian endemic Anthoxanthum amarum Brot. (Poaceae; Pooideae) assessed by random amplified polymorphic DNA markers (RAPDs) and morphologyBOTANICAL JOURNAL OF THE LINNEAN SOCIETY, Issue 2 2007MANUEL PIMENTEL High morphological and ecological diversity has been observed in the north-west Iberian Peninsula endemic Anthoxanthum amarum Brot., for which two different morphotypes (northern and southern) have been described on the basis of qualitative traits and geographical origin. In the present study, a combined molecular and morphological method was applied to ten populations of this species with the following aims: (1) to assess whether the variation observed was taxonomically meaningful; (2) to assess the influence of the environment on the variation in the morphological characters; and (3) to track the potential phylogeographical information deduced from our random amplified polymorphic DNA marker (RAPD) data in order to draw inferences about the past history of this species in the north-west Iberian Peninsula. To achieve these aims, 26 macromorphological characters were recorded in 279 specimens, and 77 RAPD phenotypes were identified in the 79 plants studied. The association analyses performed using the morphological and molecular data showed that no clear separation existed between the morphs, and a strong correlation between qualitative characters and the environment was detected. Moreover, both the multivariate analyses and the assignment test based on RAPD data revealed that the genetic variation was hierarchically structured, and three genetically distinct groups could be identified. Two of these clusters might correspond to different expansion routes proposed in the literature for different plant species in the north-west Iberian Peninsula. © 2007 The Linnean Society of London, Botanical Journal of the Linnean Society, 2007, 155, 179,192. [source] Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibresBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2005Pascal Champeroux 1Torsade de Pointes (TdP) is a well-described major risk associated with various kinds of drugs. However, prediction of this risk is still uncertain both in preclinical and clinical trials. We tested 45 reference compounds on the model of isolated canine Purkinje fibres. Of them, 22 are clearly associated and/or labelled with a risk of TdP, and 13 others are drugs with published clinical evidence of QT prolongation, with only one or two exceptional cases of TdP. The 10 remaining drugs are without reports of TdP and QT prolongation. 2The relevance of different indicators such as APD90 increase, reverse use dependency, action potential triangulation or effect on Vmax was evaluated by comparison with available clinical data. Finally, a complex algorithm called TDPscreenÔ and based on two subalgorithms corresponding to particular electrophysiological patterns was defined. 3This latter algorithm enabled a clear separation of drugs into three groups: (A) drugs with numerous or several reports (>2 cases) of TdP, (B) drugs causing QT prolongation and/or TdP only, the latter at a very low frequency (2 cases), (C) drugs without reports of TdP or QT prolongation. 4The use of such an algorithm combined with a database accrued from reference compounds with available clinical data is suggested as a basis for testing new candidate drugs in the early stages of development for proarrhythmic risk prediction. British Journal of Pharmacology (2005) 144, 376,385. doi:10.1038/sj.bjp.0706070 [source] Functional Classification of Protein Kinase Binding Sites Using CavbaseCHEMMEDCHEM, Issue 10 2007Daniel Kuhn Dr. Abstract Increasingly, drug-discovery processes focus on complete gene families. Tools for analyzing similarities and differences across protein families are important for the understanding of key functional features of proteins. Herein we present a method for classifying protein families on the basis of the properties of their active sites. We have developed Cavbase, a method for describing and comparing protein binding pockets, and show its application to the functional classification of the binding pockets of the protein family of protein kinases. A diverse set of kinase cavities is mutually compared and analyzed in terms of recurring functional recognition patterns in the active sites. We are able to propose a relevant classification based on the binding motifs in the active sites. The obtained classification provides a novel perspective on functional properties across protein space. The classification of the MAP and the c-Abl kinases is analyzed in detail, showing a clear separation of the respective kinase subfamilies. Remarkable cross-relations among protein kinases are detected, in contrast to sequence-based classifications, which are not able to detect these relations. Furthermore, our classification is able to highlight features important in the optimization of protein kinase inhibitors. Using small-molecule inhibition data we could rationalize cross-reactivities between unrelated kinases which become apparent in the structural comparison of their binding sites. This procedure helps in the identification of other possible kinase targets that behave similarly in "binding pocket space" to the kinase under consideration. [source] | |||||||||||||||||||