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Keywords: Heparin-induced thrombocytopenia; obesity; argatroban, body mass index, thrombosis Journal of Clinical Pharmacology, 2007;47:1028-1034 © 2007 the American College of Clinical Pharmacology Heparin-induced thrombocytopenia (HIT) is a severe, antibody-mediated complication [...]

Kinases include a wide variety of valuable drug targets, but full therapeutic exploitation requires a high degree of selectivity. A promising avenue to engineer the desired kinase selectivity relies on allosteric sites. Here, we provide a focused minireview of recent progress in allosteric modulation of cyclic nucleotide-dependent kinases, including protein kinases A and G. We show how apparently diverse emerging concepts, such as allosteric pluripotency, allosteric nonadditive binding, and uncompetitive allosteric inhibition, are all manifestations of complex conformational ensembles. Such ensembles include not only the typical apo-inactive and effector-bound-active states, but also mixed intermediates that feature attributes of the former states within a single molecule. We also discuss how allosteric responses are amplified by aggregation processes, thus establishing a novel interface between the signaling and amyloid fields. Finally we critically evaluate the challenges and opportunities for clinical translation opened by these emerging allosteric concepts. Key words: allostery, allosteric inhibitor, cAMP, cGMP, cyclic nucleotide, HCN, kinase, PKA, PKG Les kinases englobent une grande variete de cibles medicamenteuses de grand interet, mais il faut etre en mesure d'atteindre un degre eleve de selectivite pour pouvoir les exploiter pleinement en therapeutique. Une voie prometteuse pour parvenir a une selectivite pour les kinases visees repose sur les sites allosteriques. Dans le present article, nous proposons une minisynthese ciblee des recentes avancees en modulation allosterique des kinases dependantes de nucleotides cycliques, notamment les proteines kinases A et G. Nous montrons comment des concepts emergents en apparence divers, tels que la pluripotence allosterique, la liaison allosterique non additive et l'inhibition allosterique non competitive, sont tous en realite des manifestations d'ensembles conformationnels complexes. Ces ensembles comprennent non seulement les formes apo (inactives) typiques et les formes liees a l'effecteur (actives), mais aussi des intermediaires mixtes qui presentent les attributs de ces dernieres formes au sein d'une seule molecule. Nous discutons egalement de I'amplification des reponses allosteriques par les processus d'agregation, etablissant ainsi une nouvelle interface entre les champs de la signalisation et de I'amyloi'de. Enfin, nous evaluons de maniere critique les difficultes et les possibilites de transposition en clinique revelees par ces concepts allosteriques emergents. [Traduit par la Redaction] Mots-cles : allosterie, inhibiteur allosterique, AMPc, GMPc, nucleotide cyclique, HCN, kinase, PKA, PKG, Introduction The kinase superfamily provides a multitude of drug targets for a variety of pathological conditions related to cancer, neurodegeneration, and infections, e.g., leukemia, Huntington's disease, as well as malaria [...]

Wind-farm development may be an important contributor to forest fragmentation, but how such developments impact bats is poorly understood. We hypothesized that bat activity at a wind farm would be explained, at least in part, by attraction and avoidance behaviours caused by deforestation. We tested predictions of this hypothesis via a landscape- level acoustic, capture, and radiotelemetry survey of little brown bats (Myotis lucifugus (Le Conte, 1831)) and northern long-eared myotis (Myotis septentrionalis (Trouessart, 1897)). Acoustic and capture data indicated no significant difference in magnitude of activity between the fragmented wind farm and the less-fragmented surrounding areas. However, only 2 of 19 radio-tracked bats were ever located inside the wind farm despite being captured adjacent to it. Bat locations were compared against randomly generated locations within the same area in a logistic regression framework to rank landscape variables in order of association with bats. A multicriteria evaluation of forest metrics showed that, over a 3-year period, there was an increase of suitable habitat inside the wind farm for M. lucifugus and a decrease for M. septentrionalis. These results support the contention that, at this level of disturbance, M. lucifugus may use the cleared areas, while M. septentrionalis is negatively impacted by increased deforestation caused by wind-farm development. Key words: little brown bat, Myotis lucifugus, northern long-eared myotis, Myotis septentrionalis, forest fragmentation, distribution, movement, multicriteria evaluation, radiotelemetry, logistic regression. Si l'amenagement de parcs eoliens pourrait etre une importante cause de morcellement forestier, ses effets sur les chauves-souris ne sont pas bien compris. Nous avons postule que l'activite des chauves-souris dans un parc eolien s'expliquerait, en partie du moins, par des comportements d'attraction ou d'evitement causes par la deforestation. Nous avons verifie des predictions decoulant de cette hypothese en menant une etude acoustique, de capture et de radiotelemetrie a l'echelle du paysage des vespertilions brun (Myotis lucifugus (Le Conte, 1831)) et nordique (Myotis septentrionalis (Trouessart, 1897)). Les donnees acoustiques et de capture n'indiquaient aucune difference significative de la magnitude de l'activite entre le parc eolien morcele et des zones voisines moins morcelees. Seulement 2 des 19 chauves-souris suivies par radiotelemetrie ont toutefois ete decelees dans le parc eolien, malgre qu'elles aient ete capturees juste a cote. Les emplacements des chauves-souris ont ete compares a des emplacements generes aleatoirement dans la meme zone dans un cadre de regression logistique afin de classer les variables du paysage en ordre d'association avec les chauves-souris. Une evaluation multicriteres de parametres forestiers a demontre que, sur une periode de 3 ans, il y avait une augmentation des habitats convenables a l'interieur du parc eolien pour M. lucifugus et une diminution de ces habitats pour M. septentrionalis. Ces resultats appuient la these voulant que, a ce degre de perturbation, M. lucifugus pourrait utiliser les zones defrichees, alors qu'une deforestation accrue causee par l'amenagement de parcs eoliens a une incidence negative sur M. septentrionalis. [Traduit par la Redaction] Mots-cles : vespertilion brun, Myotis lucifugus, vespertilion nordique, Myotis septentrionalis, morcellement forestier, repartition, deplacement, evaluation multicriteres, radiotelemetrie, regression logistique., Introduction Anthropogenic alteration of natural environments can have major impacts on populations of local species (Tilman et al. 1994). The specific impacts may vary by species life-history traits, where some [...]

Pigs are considered the 'mixing vessel' in which avian, human, and swine influenza genetic material can be exchanged and result in new influenza viruses (1). Zoonotic influenza A infections in [...]

Understanding the tradeoff between exploitation and conservation is difficult in data-poor situations, which are typical for most recreational fisheries, even in developed countries. In a developing country where the target species is endangered, the stakes are higher and the management resources are fewer. We combined a mark-recapture experiment, life history invariants, and meta-analysis to parameterize a delay-difference model for a population of the endangered giant Eurasian trout (taimen, Hucho taimen) in northern Mongolia. The model allowed us to evaluate the impacts of a recreational fishery for taimen based on a suite of population characteristics including equilibrium abundance, biomass, and mean weight. The Bayesian framework and Monte Carlo simulations combine disparate sources of information while keeping track of uncertainty as it propagates through the model. In the case of taimen in the Eg-Uur watershed, the existing catch-release recreational fishery has likely reduced taimen abundance, biomass, and mean weight by less than 10% compared with levels predicted in the absence of recreational fishing. In comparison, if all taimen caught in this fishery were retained (as they are elsewhere in Mongolia), there is a 57% chance that such harvest levels, if maintained, would lead to the eventual extirpation of the population. Il est difficile de comprendre le compromis entre l'exploitation et la conservation dans les peches sportives lorsqu'il y a peu de donnees, ce qui est tres souvent le cas, meme dans les pays developpes. Dans un pays en voie de developpement lorsque l'espece cible est menacee, les enjeux sont plus importants et les ressources de gestion moindres. Nous combinons une experience de marquage-recapture, des invariants du cycle biologique et une meta-analyse afin de parame trer un modele de difference avec delais pour une population du huchon geant d'Eurasie (le taimen, Hucho taimen), une espece menacee, dans le nord de la Mongolie. Le modele nous permet d'evaluer l'impact d'une peche sportive du taimen a partir d'une serie de caracteristiques demographiques, dont l'abondance a l'equilibre, la biomasse et la masse moyenne. Le cadre bayesien et la methode de Monte Carlo combinent des sources disparates de renseignements, tout en tenant compte de l'incertitude a mesure qu'elle se propage dans le modele. Dans le cas du taimen de l'Eg-Uur, la peche sportive actuelle avec remise a l'eau des prises a vraisemblablement reduit l'abondance, la biomasse et la masse moyenne du taimen par moins de 10 %, par comparaison aux valeurs predites en l'absence de peche sportive. D'un autre cote, si tous les taimens captures dans cette peche etaient gardes (comme ils le sont ailleurs en Mongolie), il y a une probabilite de 57 % qu'une telle intensite de capture, si elle devait se maintenir, aboutirait a une extirpation eventuelle de la population. [Traduit par la Redaction], Introduction There is a growing realization that recreational fisheries have the capacity to severely reduce the abundance of fished species (Post et al. 2002; Coleman et al. 2004; Cooke and [...]

Author(s): Kimberly L. Dodge-Kafka [1, 3]; Joseph Soughayer [1]; Genevieve C. Pare [2]; Jennifer J. Carlisle Michel [1]; Lorene K. Langeberg [1]; Michael S. Kapiloff [2]; John D. Scott (corresponding [...]

Author(s): Gary Felsenfeld [1]; Mark Groudine [2] Genes were first shown to be made of DNA only nine years before the structure of DNA was discovered (ref. 1; and see [...]

Mutations in anc-1 (nuclear anchorage defective) disrupt the positioning of nuclei and mitochondria in Caenorhabditis elegans. ANC-1 is shown to consist of mostly coiled regions with a nuclear envelope localization domain (called the KASH domain) and an actin-binding domain; this structure was conserved with the Drosophila protein Msp-300 and the mammalian Syne proteins. Antibodies against ANC-1 localized cytoplasmically and were enriched at the nuclear periphery in an UNC-84-dependent manner. Overexpression of the KASH domain or the actin-binding domain caused a dominant negative anchorage defect. Thus, ANC-1 may connect nuclei to the cytoskeleton by interacting with UNC-84 at the nuclear envelope and with actin in the cytoplasm., A wide variety of organisms have syncytia, formed either when multiple nuclear divisions occur without cell divisions or when cells fuse together. Normally, syncytial nuclei are located in specific regions [...]

An everyday example of a distortion of memory is reported. Subjects were presented with a standard clock with numbers represented by Roman numerals. Of the subjects asked to draw the clock from memory, the majority mistakenly represented the four as 'IV' rather than as 'IIII'. The latter represents the standard form of Roman numeral representation upon clocks, but not elsewhere. It made no difference to performance whether or not subjects were warned in advance that they would have to draw the clock from memory. Subjects asked simply to copy the clock in full view did not make the error. The findings are interpreted in terms of schema theory., The last 20 years of memory research have differed from most of the previous 80 in that the study of everyday memory has been recognized as being of great importance [...]

Author(s): Chioma M. Okeoma [1]; Nika Lovsin [2]; B. Matija Peterlin [3]; Susan R. Ross (corresponding author) [1] Genomes of all mammals encode apobec3 genes, which are thought to have [...]

Generic drugs are lower-cost versions of patent-expired, original brand name medications. The approval of a generic drug requires the manufacturer to show that their product contains the same quantity of [...]