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alpha 1-Proteinase inhibitor (alpha 1-PI), a member of the serineproteinase inhibitor superfamily, has a primary role in controllingneutrophil elastase activity within the mammalian circulation. Severalstudies have indicated that the reactive center region of alpha 1-PI, theamino acid sequence of which is critical to recognition of and binding totarget proteinases, is highly divergent within and among species. Thisappears to be a consequence of accelerated rates of evolution that may havebeen driven by positive Darwinian selection. In order to examine this andother features of alpha 1-PI evolution in more detail, we have isolated andsequenced cDNAs representing alpha 1- PI mRNAs of the mouse species Mussaxicola and Mus minutoides and have compared these with a number of othermammalian alpha 1-PI mRNAs. Relative to other mammalian mRNAs, the extentof nonsynonymous substitution is generally high throughout the alpha 1-PImRNA molecule, indicating greater overall rates of amino acid substitution.Within and among mouse species, the 5'-half of the mRNA, but not the3'-half, has been homogenized by concerted evolution. Finally, the reactivecenter is under diversifying or positive Darwinian selection in muridrodents (rats, mice) and guinea pigs yet is under purifying selection inprimates and artiodactyls. The significance of these findings to alpha 1-PIfunction and the possible selective forces driving evolution of serpins ingeneral are discussed. 相似文献
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Several fundamental questions remain enigmatic concerning human olfactorysensitivity, including (i) whether detection threshold differences existbetween the two sides of the nose (and, if so, whether such differences areinfluenced by handedness) and (ii) whether bilateral (i.e. binasal)stimulation leads to lower thresholds than unilateral stimulation (and, ifso, whether the degree of facilitation is inversely related to generalolfactory ability). In this study, and well-validated single staircaseprocedure was used to establish bilateral and unilateral detectionthresholds for the cranial nerve I stimulant phenyl ethyl alcohol in 130right- and 33 left-handed subjects. No differences in sensitivity betweenthe left and right sides of the nose were observed in either group.Bilateral thresholds were lower, on average, than unilateral thresholdswhen the latter were categorized in terms of left and right nares. However,the bilateral thresholds did not differ significantly from those of theside of the nose with the lower threshold. Overall smell ability, asmeasured by the University of Pennsylvania Smell Identification Test, didnot interact with any of the test measures. These data imply that (i) theleft and right sides of the nose do not systematically differ in detectionthreshold sensitivity for either dextrals or sinistrals and (ii) if centralintegration of left:right olfactory threshold sensitivity occurs, itseffects do not exceed the function of the better side of the nose. 相似文献
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VLJ Whitehall TD Dumenil DM McKeone CE Bond ML Bettington RL Buttenshaw L Bowdler GW Montgomery LF Wockner BA Leggett 《Epigenetics》2014,9(11):1454-1460
The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features. 相似文献
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Jeff A Johnson Heather RL Lerner Pamela C Rasmussen David P Mindell 《BMC evolutionary biology》2006,6(1):65-12
Background
Populations of the Oriental White-backed Vulture (Gyps bengalensis) have declined by over 95% within the past decade. This decline is largely due to incidental consumption of the non-steroidal anti-inflammatory veterinary pharmaceutical diclofenac, commonly used to treat domestic livestock. The conservation status of other Gyps vultures in southern Asia is also of immediate concern, given the lack of knowledge regarding status of their populations and the continuing existence of taxonomic uncertainties. In this study, we assess phylogenetic relationships for all recognized species and the majority of subspecies within the genus Gyps. The continuing veterinary use of diclofenac is an unknown but potential risk to related species with similar feeding habits to Gyps bengalensis. Therefore, an accurate assessment of the phylogenetic relationships among Gyps vultures should aid in their conservation by clarifying taxonomic uncertainties, and enabling inference of their respective relatedness to susceptible G. bengalensis. 相似文献10.
Laurents DV Huyghues-Despointes BM Bruix M Thurlkill RL Schell D Newsom S Grimsley GR Shaw KL Treviño S Rico M Briggs JM Antosiewicz JM Scholtz JM Pace CN 《Journal of molecular biology》2003,325(5):1077-1092
The pK values of the titratable groups in ribonuclease Sa (RNase Sa) (pI=3.5), and a charge-reversed variant with five carboxyl to lysine substitutions, 5K RNase Sa (pI=10.2), have been determined by NMR at 20 degrees C in 0.1M NaCl. In RNase Sa, 18 pK values and in 5K, 11 pK values were measured. The carboxyl group of Asp33, which is buried and forms three intramolecular hydrogen bonds in RNase Sa, has the lowest pK (2.4), whereas Asp79, which is also buried but does not form hydrogen bonds, has the most elevated pK (7.4). These results highlight the importance of desolvation and charge-dipole interactions in perturbing pK values of buried groups. Alkaline titration revealed that the terminal amine of RNase Sa and all eight tyrosine residues have significantly increased pK values relative to model compounds.A primary objective in this study was to investigate the influence of charge-charge interactions on the pK values by comparing results from RNase Sa with those from the 5K variant. The solution structures of the two proteins are very similar as revealed by NMR and other spectroscopic data, with only small changes at the N terminus and in the alpha-helix. Consequently, the ionizable groups will have similar environments in the two variants and desolvation and charge-dipole interactions will have comparable effects on the pK values of both. Their pK differences, therefore, are expected to be chiefly due to the different charge-charge interactions. As anticipated from its higher net charge, all measured pK values in 5K RNase are lowered relative to wild-type RNase Sa, with the largest decrease being 2.2 pH units for Glu14. The pK differences (pK(Sa)-pK(5K)) calculated using a simple model based on Coulomb's Law and a dielectric constant of 45 agree well with the experimental values. This demonstrates that the pK differences between wild-type and 5K RNase Sa are mainly due to changes in the electrostatic interactions between the ionizable groups. pK values calculated using Coulomb's Law also showed a good correlation (R=0.83) with experimental values. The more complex model based on a finite-difference solution to the Poisson-Boltzmann equation, which considers desolvation and charge-dipole interactions in addition to charge-charge interactions, was also used to calculate pK values. Surprisingly, these values are more poorly correlated (R=0.65) with the values from experiment. Taken together, the results are evidence that charge-charge interactions are the chief perturbant of the pK values of ionizable groups on the protein surface, which is where the majority of the ionizable groups are positioned in proteins. 相似文献