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31.
Divya Pathania Mario Sechi Michele Palomba Vanna Sanna Francesco Berrettini Angela Sias Laleh Taheri Nouri Neamati 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most cancers including pancreatic cancer. Elevated levels of intrinsic reactive oxygen species (ROS) in tumors make them more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm their adaptive antioxidant capacity and trigger ROS-mediated cell death. Recently, we have discovered a novel class of quinazolinediones that exert their cytotoxic effects by modulating ROS-mediated signaling.Methods
Cytotoxic potential was determined by colorimetric and colony formation assays. An XF24 Extracellular Flux Analyzer, and colorimetric and fluorescent techniques were used to assess the bioenergetics and oxidative stress effects, respectively. Mechanism was determined by Western blots.Results
Compound 3a (6-[(2-acetylphenyl)amino]quinazoline-5,8-dione) was identified through a medium throughput screen of ~ 1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics. Further structural optimizations led to the discovery of a more potent analog, 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) that displayed anti-proliferative activities in low micromolar range in both drug-sensitive and drug-resistant cancer cells. Treatment with 3b causes Akt activation resulting in increased cellular oxygen consumption and oxidative stress in pancreatic cancer cells. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) resulting in cancer cell death. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity.Conclusion
In conclusion, our novel quinazolinediones are promising lead compounds that selectively induce ROS-mediated cell death in cancer cells and warrant further preclinical studies.General significance
Since 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) exerts Akt-dependent ROS-mediated cell death, it might provide potential therapeutic options for chemoresistant and Akt-overexpressing cancers. 相似文献32.
J Steinbuch AC van Dijk FHBM Schreuder MTB Truijman J Hendrikse PJ Nederkoorn A van der Lugt E Hermeling APG Hoeks WH Mess 《Cardiovascular ultrasound》2017,15(1):9
Background
Mean or maximal intima-media thickness (IMT) is commonly used as surrogate endpoint in intervention studies. However, the effect of normalization by surrounding or median IMT or by diameter is unknown. In addition, it is unclear whether IMT inhomogeneity is a useful predictor beyond common wall parameters like maximal wall thickness, either absolute or normalized to IMT or lumen size. We investigated the interrelationship of common carotid artery (CCA) thickness parameters and their association with the ipsilateral internal carotid artery (ICA) stenosis degree.Methods
CCA thickness parameters were extracted by edge detection applied to ultrasound B-mode recordings of 240 patients. Degree of ICA stenosis was determined from CT angiography.Results
Normalization of maximal CCA wall thickness to median IMT leads to large variations. Higher CCA thickness parameter values are associated with a higher degree of ipsilateral ICA stenosis (p?<?0.001), though IMT inhomogeneity does not provide extra information. When the ratio of wall thickness and diameter instead of absolute maximal wall thickness is used as risk marker for having moderate ipsilateral ICA stenosis (>50%), 55 arteries (15%) are reclassified to another risk category.Conclusions
It is more reasonable to normalize maximal wall thickness to end-diastolic diameter rather than to IMT, affecting risk classification and suggesting modification of the Mannheim criteria.Trial registration
Clinical trials.gov NCT01208025.33.
Human platelet vasopressin receptors 总被引:1,自引:0,他引:1
Specific saturable binding of 125I-arginine-vasopressin to human platelets is described. For ten normal volunteers the mean (+/- S.D.) KD is 5.6 nM (+/- 2.1) and the mean (+/- S.D.) Bmax is 115 fmoles/mg protein (+/- 30). Association studies indicate that equilibrium is reached after 90 minutes on ice. Pharmacological inhibition studies with analogues indicate that the platelet receptor is very similar to the kidney medulla receptor. The function of the receptor may involve serotonin release and platelet aggregation. Vasopressin binding to platelets should provide a readily means of assessing vasopressin receptor function in man. 相似文献
34.
Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative
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Dick DM Foroud T Flury L Bowman ES Miller MJ Rau NL Moe PR Samavedy N El-Mallakh R Manji H Glitz DA Meyer ET Smiley C Hahn R Widmark C McKinney R Sutton L Ballas C Grice D Berrettini W Byerley W Coryell W DePaulo R MacKinnon DF Gershon ES Kelsoe JR McMahon FJ McInnis M Murphy DL Reich T Scheftner W Nurnberger JI 《American journal of human genetics》2003,73(1):107-114
We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder. 相似文献
35.
A mouse genomic clone containing a lactate dehydrogenase-A (LDH-A)
processed pseudogene and a B1 repetitive element was isolated, and a
nucleotide sequence of approximately 3 kb was determined. The pseudogene
and B1 element are flanked by perfect 13-bp repeats, and the B1 sequence
starts at 14 nucleotides 3' to the presumptive polyadenylation signal of
the pseudogene. The nucleotide sequences of the LDH-A genes and processed
pseudogenes from mouse, rat, and human were compared, and a phylogenetic
tree was constructed. The rate and pattern of nucleotide substitutions in
the LDH-A pseudogenes are similar to previously reported results (Li et al.
1984). The average rate of nucleotide substitutions in the LDH-A
pseudogenes is 4.3 X 10(- 9)/site/year. The substitutions of C----T and
G----A are most frequent, and A----G substitutions are relatively high. The
rate of synonymous substitutions in the LDH-A genes is 5.3 X 10(-9), which
is not significantly higher than the average rate of 4.7 X 10(-9) for 35
mammalian genes. The rate of nonsynonymous substitutions in the LDH-A genes
is 0.20 X 10(-9), which is considerably lower than the average rate of 0.88
X 10(-9) for 35 mammalian genes. Thus, the mammalian LDH-A gene appears to
be highly conserved in evolution.
相似文献
36.
Maximum likelihood estimation of the heterogeneity of substitution rate among nucleotide sites 总被引:23,自引:9,他引:14
This paper presents a maximum likelihood approach to estimating the
variation of substitution rate among nucleotide sites. We assume that the
rate varies among sites according to an invariant+gamma distribution, which
has two parameters: the gamma parameter alpha and the proportion of
invariable sites theta. Theoretical treatments on three, four, and five
sequences have been conducted, and computer program have been developed. It
is shown that rho = (1 + theta alpha)/(1 + alpha) is a good measure for the
rate heterogeneity among sites. Extensive simulations show that (1) if the
proportion of invariable sites is negligible, i.e., theta = 0, the gamma
parameter alpha can be satisfactorily estimated, even with three sequences;
(2) if the proportion of invariable sites is not negligible, the
heterogeneity rho can still be suitably estimated with four or more
sequences; and (3) the distances estimated by the proposed method are
almost unbiased and are robust against violation of the assumption of the
invariant + gamma distribution.
相似文献
37.
38.
The cDNA cloning and molecular evolution of reptile and pigeon lactate dehydrogenase isozymes 总被引:1,自引:0,他引:1
The cDNAs encoding lactate dehydrogenase isozymes LDH-A (muscle) and LDH-B
(heart) from alligator and turtle and LDH-A, LDH-B, and LDH-C (testis) from
pigeon were cloned and sequenced. The evolutionary relationships among
vertebrate LDH isozymes were analyzed. Contrary to the traditional belief
that the turtle lineage branched off before the divergence between the
lizard/alligator and bird lineages, the turtle lineage was found to be
clustered with either the alligator lineage or the alligator-bird clade,
while the lizard lineage was found to have branched off before the
divergence between the alligator/turtle and bird lineages. The pigeon
testicular LDH-C isozyme was evidently duplicated from LDH-B (heart), so it
is not orthologous to the mammalian testicular LDH-C isozymes.
相似文献
39.
Bias-corrected paralinear and LogDet distances and tests of molecular clocks and phylogenies under nonstationary nucleotide frequencies 总被引:10,自引:9,他引:1
The statistical properties of the paralinear and LogDet distances under
nonstationary nucleotide frequencies were studied. First, we developed
formulas for correcting the estimation biases of the paralinear and LogDet
distances, i.e., the bias-corrected distance is estimated by dc = d -
2var(d), where d and var(d) are the estimated distance and sampling
variance, respectively. The performances of these formulas and the formulas
for sampling variances were examined by computer simulation. Second, we
developed a method for estimating the variance- covariance matrix of
paralinear distances, so that statistical tests of DNA phylogenies can be
conducted in the nonstationary case. Third, a new LogDet-based method for
testing the molecular clock hypothesis was developed under nonstationary
nucleotide frequencies.
相似文献
40.
Caffeoyl-coenzyme A (CoA) O-methyltransferase (CCoAOMT) has been proposed to be involved in an alternative methylation pathway of lignin biosynthesis. However, no direct evidence has been available to confirm that CCoAOMT is essential for lignin biosynthesis. To understand further the methylation steps in lignin biosynthesis, we used an antisense approach to alter O-methyltransferase (OMT) gene expression and investigated the consequences of this alteration. We generated transgenic tobacco plants with a substantial reduction in CCoAOMT as well as plants with a simultaneous reduction in both CCoAOMT and caffeic acid O-methyltransferase (CAOMT). Lignin analysis showed that the reduction in CCoAOMT alone resulted in a dramatic decrease in lignin content. The reduction in CCoAOMT also led to a dramatic alteration in lignin composition. Both guaiacyl lignin and syringyl lignin were reduced in the transgenic plants. However, guaiacyl lignin was preferentially reduced, which resulted in an increase in the S/G (syringl/guaiacyl) ratio. We have also analyzed lignin content and composition in transgenic plants having a simultaneous reduction in both CCoAOMT and CAOMT. The reduction in both OMTs resulted in a further decrease in total lignin content. This is in sharp contrast to the effect that resulted from the reduction in CAOMT alone, which only decreased the syringl lignin unit without a reduction in overall lignin content. These results unequivocally demonstrate that methylation reactions in lignin biosynthesis are catalyzed by both CCoAOMT and CAOMT. 相似文献