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81.
Rohde LA Ahring PK Jensen ML Nielsen EØ Peters D Helgstrand C Krintel C Harpsøe K Gajhede M Kastrup JS Balle T 《The Journal of biological chemistry》2012,287(6):4248-4259
The α4β2 subtype of the nicotinic acetylcholine receptor has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of α4β2 agonists is lacking. Using binding experiments, electrophysiology and x-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at α4β2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for α4β2 receptors. Crystal structures of five agonists with efficacies at α4β2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong intersubunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong intersubunit anchoring. 相似文献
82.
83.
Breiting LB Henriksen TF Kalialis LV Gramkow C Høyer AP 《Plastic and reconstructive surgery》2012,130(2):273-281
84.
85.
Line Blander Reinhardt David Pisinger 《Flexible Services and Manufacturing Journal》2012,24(3):349-374
The network design problem in liner shipping is of increasing importance in a strongly competitive market where potential cost reductions can influence market share and profits significantly. In this paper the network design and fleet assignment problems are combined into a mixed integer linear programming model minimizing the overall cost. To better reflect the real-life situation we take into account the cost of transhipment, a heterogeneous fleet, route dependent capacities, and butterfly routes. To the best of our knowledge it is the first time an exact solution method to the problem considers transhipment cost. The problem is solved with branch-and-cut using clover and transhipment inequalities. Computational results are reported for instances with up to 15 ports. 相似文献
86.
87.
The Revised Classification of Eukaryotes 总被引:1,自引:0,他引:1
Sina M. Adl Alastair G. B. Simpson Christopher E. Lane Julius Lukeš David Bass Samuel S. Bowser Matthew W. Brown Fabien Burki Micah Dunthorn Vladimir Hampl Aaron Heiss Mona Hoppenrath Enrique Lara Line le Gall Denis H. Lynn Hilary McManus Edward A. D. Mitchell Sharon E. Mozley‐Stanridge Laura W. Parfrey Jan Pawlowski Sonja Rueckert Laura Shadwick Conrad L. Schoch Alexey Smirnov Frederick W. Spiegel 《The Journal of eukaryotic microbiology》2012,59(5):429-514
This revision of the classification of eukaryotes, which updates that of Adl et al. [J. Eukaryot. Microbiol. 52 (2005) 399], retains an emphasis on the protists and incorporates changes since 2005 that have resolved nodes and branches in phylogenetic trees. Whereas the previous revision was successful in re‐introducing name stability to the classification, this revision provides a classification for lineages that were then still unresolved. The supergroups have withstood phylogenetic hypothesis testing with some modifications, but despite some progress, problematic nodes at the base of the eukaryotic tree still remain to be statistically resolved. Looking forward, subsequent transformations to our understanding of the diversity of life will be from the discovery of novel lineages in previously under‐sampled areas and from environmental genomic information. 相似文献
88.
Kristensen LH Nielsen AL Helgstrand C Lees M Cloos P Kastrup JS Helin K Olsen L Gajhede M 《The FEBS journal》2012,279(11):1905-1914
Dynamic methylations and demethylations of histone lysine residues are important for gene regulation and are facilitated by histone methyltransferases and histone demethylases (HDMs). KDM5B/Jarid1B/PLU1 is an H3K4me3/me2-specific lysine demethylase belonging to the JmjC domain-containing family of histone demethylases (JHDMs). Several studies have linked KDM5B to breast, prostate and skin cancer, highlighting its potential as a drug target. However, most inhibitor studies have focused on other JHDMs, and inhibitors for KDM5B remain to be explored. Here, we report the expression, purification and characterization of the catalytic core of recombinant KDM5B (ccKDM5B, residues 1-769). We show that ccKDM5B, recombinantly expressed in insect cells, demethylates H3K4me3 and H3K4me2 in vitro. The kinetic characterization showed that ccKDM5B has an apparent Michaelis constant (K(m) (app) ) value of 0.5 μm for its trimethylated substrate H3(1-15)K4me3, a considerably increased apparent substrate affinity than reported for related HDMs. Despite the presence of a PHD domain, the catalytic activity was not affected by additional methylation at the H3K9 position, suggesting that in vitro chromatin cross-talk between H3K4 and H3K9 does not occur for ccKDM5B. Inhibition studies of ccKDM5B showed both in vitro and in cell inhibition of ccKDM5B by 2,4-pyridinedicarboxylic acid (2,4-PDCA) with a potency similar to that reported for the HDM KDM4C. Structure-guided sequence alignment indicated that the binding mode of 2,4-PDCA is conserved between KDM4A/C and KDM5B. 相似文献
89.
Christian S Meyhoff Jørn Wetterslev Lars N Jorgensen Steen W Henneberg Inger Simonsen Therese Pulawska Line R Walker Nina Skovgaard Kim Heltø Peter Gocht-Jensen Palle S Carlsson Henrik Rask Sharaf Karim Charlotte G Carlsen Frank S Jensen Lars S Rasmussen 《Trials》2008,9(1):1-13
Background
Infants born at extreme prematurity (below 28 weeks' gestation) are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone which is recognised to be a frequent phenomenon in these infants. At present it is unclear whether low levels of thyroid hormone are a cause of disability, or a consequence of concurrent adversity.Methods
We propose an explanatory multi-centre double blind randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks' corrected gestational age. The primary outcome will be brain growth. This will be assessed by the width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks' corrected gestational. The secondary outcomes will be (a) thyroid hormone concentrations measured at increasing postnatal age, (b) status of the hypothalamic pituitary axis, (c) auxological data between birth and 36 weeks' corrected gestational age, (d) thyroid gland volume, (e) volumes of brain structures (measured by magnetic resonance imaging), (f) determination of the extent of myelination and white matter integrity (measured by diffusion weighted MRI) and brain vessel morphology (measured by magnetic resonance angiography) at expected date of delivery and (g) markers of morbidity including duration of mechanical ventilation and chronic lung disease. We will also examine how activity of the hypothalamic-pituitary-adrenal axis modulates the effects of thyroid supplementation. This will contribute to decisions about which confounding variables to assess in large-scale studies.Trial registration
Current Controlled Trials ISRCTN89493983 相似文献90.
The relatively long pelagic larval duration of Pomacentrus amboinensis, a tropical fish, suggests the potential for long-distance dispersal; however, several nongenetic studies have found substantial self-recruitment at one location. To analyse patterns of connectivity of this species, primers for nine independent microsatellite loci were developed for P. amboinensis using a magnetic bead enrichment protocol. Twenty individuals from one location were analysed and observed heterozygosities ranged from 0.7 to 0.95. Eight of nine loci were in Hardy-Weinberg equilibrium and no evidence of linkage or null alleles were found. 相似文献