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Efficient new ribozyme mimics: direct mapping of molecular design principles from small molecules to macromolecular, biomimetic catalysts 总被引:1,自引:1,他引:0 下载免费PDF全文
Dramatic improvements in ribozyme mimics have been achieved by employing the principles of small molecule catalysis to the design of macromolecular, biomimetic reagents. Ribozyme mimics derived from the ligand 2,9-dimethylphenanthroline (neocuproine) show at least 30-fold improvements in efficiency at sequence-specific RNA cleavage when compared with analogous o-phenanthroline- and terpyridine-derived reagents. The suppression of hydroxide-bridged dimers and the greater activation of coordinated water by Cu(II) neocuproine (compared with the o-phananthroline and terpyridine complexes) better allow Cu(II) to reach its catalytic potential as a biomimetic RNA cleavage agent. This work demonstrates the direct mapping of molecular design principles from small-molecule cleavage to macromolecular cleavage events, generating enhanced biomimetic, sequence-specific RNA cleavage agents. 相似文献
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We sampled populations of forest-floor dwelling cave and ground wētā using footprint tracking tunnels and spotlight transect counts in southern beech forest, New Zealand. Samples were compared to estimates of wētā density based on mark–recapture estimates from 25?m2 enclosures. Both activity indices captured variability in cave wētā in time and space, were strongly correlated with each other, and have the potential for monitoring cave wētā activity levels. Comparisons between indices and cave wētā density estimates were equivocal, as recapture rates were too low to calculate high-resolution density estimates. We also found that cave wētā counts had a curved relationship increasing with temperature, and a negative relationship with increasing shrub and woody debris cover. Based on these preliminary results, tracking tunnels could be a viable method of monitoring cave wētā as they appear more efficient than transect counts and are relatively inexpensive. However, further calibration trials are needed to determine if indices mirror robust population density estimates. 相似文献
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Inès J Goossens-Beumer Jan Oosting Wim E Corver Marjolein JFW Janssen Bart Janssen Wilbert van Workum Eliane CM Zeestraten Cornelis JH van de Velde Hans Morreau Peter JK Kuppen Tom van Wezel 《BMC genomics》2015,16(1)
Background
In rectal cancer, total mesorectal excision surgery combined with preoperative (chemo)radiotherapy reduces local recurrence rates but does not improve overall patient survival, a result that may be due to the harmful side effects and/or co-morbidity of preoperative treatment. New biomarkers are needed to facilitate identification of rectal cancer patients at high risk for local recurrent disease. This would allow for preoperative (chemo)radiotherapy to be restricted to high-risk patients, thereby reducing overtreatment and allowing personalized treatment protocols. We analyzed genome-wide DNA copy number (CN) and allelic alterations in 112 tumors from preoperatively untreated rectal cancer patients. Sixty-six patients with local and/or distant recurrent disease were compared to matched controls without recurrence. Results were validated in a second cohort of tumors from 95 matched rectal cancer patients. Additionally, we performed a meta-analysis that included 42 studies reporting on CN alterations in colorectal cancer and compared results to our own data.Results
The genomic profiles in our study were comparable to other rectal cancer studies. Results of the meta-analysis supported the hypothesis that colon cancer and rectal cancer may be distinct disease entities. In our discovery patient study cohort, allelic retention of chromosome 7 was significantly associated with local recurrent disease. Data from the validation cohort were supportive, albeit not statistically significant, of this finding.Conclusions
We showed that retention of heterozygosity on chromosome 7 may be associated with local recurrence in rectal cancer. Further research is warranted to elucidate the mechanisms and effect of retention of chromosome 7 on the development of local recurrent disease in rectal cancer.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1550-0) contains supplementary material, which is available to authorized users. 相似文献45.
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Studies of the hyaluronan (HA) tetrasaccharides are important for
understanding hydrogen-bonding in the HA polymer, as they are probably the
smallest oligomers in which characteristics of the constituent
monosaccharides and the polymer are simultaneously exhibited. Here we
present extensive molecular dynamics simulations of the two
tetrasaccharides of HA in dilute aqueous solution. These simulations have
confirmed the existence of intramolecular hydrogen-bonds between the
neighboring sugar residues of HA in solution, as proposed by Scott (1989).
However, our simulations predict that these intramolecular hydrogen-bonds
are not static as previously proposed, but are in constant dynamic exchange
on the sub-nanosecond time-scale. This process results in discrete internal
motion of the HA tetrasaccharides where they rapidly move between low
energy conformations. Specific interactions between water and
intramolecular hydrogen-bonds involving the hydroxymethyl group were found
to result in differing conformations and dynamics for the two alternative
tetrasaccharides of HA. This new observation suggests that this residue may
play a key role in the entropy and stability of HA in solution, allowing it
to stay soluble up to high concentration. The vicinal coupling constants3 J
NHCH of the acetamido groups have been calculated from our aqueous
simulations of HA. We found that high values of 3J NHCH approximately 8 Hz,
as experimentally measured for HA, are consistent with mixtures of both
trans and cis conformations, and thus3 J NHCH cannot be used to imply a
purely trans conformation of the acetamido. The rapid exchange of
intramolecular hydrogen-bonds indicates that although the structure is at
any moment stabilized by these hydrogen-bonds, no one hydrogen-bond exists
for an extended period of time. This could explain why NMR often fails to
provide evidence for intramolecular hydrogen-bonds in HA and other aqueous
carbohydrate structures.
相似文献
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Isolation of a basophilic membrane protein binding the anti-allergic drug cromolyn. 总被引:2,自引:1,他引:1 下载免费PDF全文
The membrane protein component in basophils, responsible for the specific, Ca2+-dependent, binding of the anti-allergic drug cromolyn [disodium cromoglycate, DSCG; the disodium salt of 1,2 bis(2- carboxychromon -5- yloxy )-2-hydroxy propane] was isolated by two procedures based on affinity for the drug. In the first procedure, involving immunoprecipitation, rat basophilic leukemia cells (RBL-2H3), surface labeled by 125I were reacted with a polyvalent conjugate of DSCG and bovine serum albumin and then subjected to solubilization by the non-ionic detergent Nonidet P-40 (NP-40). From these lysates, precipitation was specifically attained by subsequent addition of rabbit anti-DSCG antibodies. In an SDS-polyacrylamide gel electrophoresis (SDS-PAGE), a single radioactive band was observed, having an apparent mol. wt. of 60 000 daltons. Competitive inhibition of the immunoprecipitation in the presence of free drug or excess of EDTA demonstrated the specificity of the isolation. Furthermore, this particular membrane component could not be isolated from several other cell types examined. The second isolation from several other cell types examined. The second isolation procedure employed affinity chromatography on DSCG immobilized on polyacryl- hydrazido agarose beads. The DSCG-binding protein was eluted from the affinity column with either DSCG or with EDTA and also migrated on SDS-PAGE as a single band of 60 000 mol. wt., similar to that obtained by the immunoprecipitation procedure. These and other results suggest that this newly isolated protein is the one responsible for the Ca2+-dependent binding of the drug to the basophil membrane. 相似文献
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