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排序方式: 共有175条查询结果,搜索用时 15 毫秒
131.
Tianbao Lu Carsten Schubert Maxwell D. Cummings Gilles Bignan Peter J. Connolly Karine Smans Donald Ludovici Michael H. Parker Christophe Meyer Christian Rocaboy Richard Alexander Bruce Grasberger Sabine De Breucker Norbert Esser Erwin Fraiponts Ron Gilissen Boudewijn Janssens Danielle Peeters Lieven Meerpoel 《Bioorganic & medicinal chemistry letters》2018,28(12):2159-2164
We designed and synthesized a new series of fatty acid synthase (FASN) inhibitors with potential utility for the treatment of cancer. Extensive SAR studies led to highly active FASN inhibitors with good cellular activity and oral bioavailability, exemplified by compound 34. Compound 34 is a potent inhibitor of human FASN (IC50?=?28?nM) that effectively inhibits proliferation of A2780 ovarian cells (IC50?=?13?nM) in lipid-reduced serum (LRS). This cellular activity can be rescued by addition of palmitate, consistent with an on-target effect. Compound 34 is also active in many other cell types, including PC3M (IC50?=?25?nM) and LnCaP-Vancouver prostate cells (IC50?=?66?nM), and is highly bioavailable (F 61%) with good exposure after oral administration. In a pharmacodynamics study in H460 lung xenograft-bearing mice, oral treatment with compound 34 results in elevated tumor levels of malonyl-CoA and decreased tumor levels of palmitate, fully consistent with the desired target engagement. 相似文献
132.
Molecular evolution of chloroplast DNA sequences 总被引:13,自引:1,他引:12
Comparative data on the evolution of chloroplast genes are reviewed. The
chloroplast genome has maintained a similar structural organization over
most plant taxa so far examined. Comparisons of nucleotide sequence
divergence among chloroplast genes reveals marked similarity across the
plant kingdom and beyond to the cyanobacteria (blue-green algae). Estimates
of rates of nucleotide substitution indicate a synonymous rate of 1.1 x
10(-9) substitutions per site per year. Noncoding regions also appear to be
constrained in their evolution, although addition/deletion events are
common. There have also been evolutionary changes in the distribution of
introns in chloroplast encoded genes. Relative to mammalian mitochondrial
DNA, the chloroplast genome evolves at a conservative rate.
相似文献
133.
High nucleotide sequence variation in a region of low recombination in Drosophila simulans is consistent with the background selection model 总被引:2,自引:0,他引:2
We surveyed nucleotide sequence variation at glucose dehydrogenase (Gld),
in a region of low recombination on chromosome 3R, from a population sample
of Drosophila simulans. The levels of nucleotide variation were
surprisingly high. There was no departure from the expectation of a neutral
model for the level of polymorphism, indicating no evidence of a selective
sweep in this region. There was a significant deficiency of singleton
polymorphisms according to the Fu and Li test, although Tajima and Hudson,
Kreitman, and Aguade (HKA) tests do not provide evidence of a significant
elevation of variation due to balancing selection. Genetic map data for the
D. simulans third chromosome were used to calculate expected values of pi
for Gld under a current model of background selection, varying the values
for the parameter sh (selection coefficient against deleterious mutations).
We show that the recombinational landscape of D. simulans is sufficiently
different from that of D. melanogaster that we expect higher variation
under the background selection model, even when effective population sizes
are assumed to be equal. The data for Gld were tested against the
predictions using computer simulations of the distribution of the number of
segregating sites conditioned on pi. Background selection alone can explain
our observations as long as sh is larger than 0.005 and species-level
effective population size is assumed to be several- fold larger than in D.
melanogaster. Alternatively, the deleterious mutation rate may be smaller
in D. simulans, or balancing selection may be acting nearby, thereby
reducing the effect of background selection.
相似文献
134.
Comparative evolutionary analysis of rDNA ITS regions in Drosophila 总被引:17,自引:2,他引:15
Schlotterer C; Hauser MT; von Haeseler A; Tautz D 《Molecular biology and evolution》1994,11(3):513-522
The internal transcribed spacer (ITS) of the ribosomal DNA is generally
considered to be under low functional constraint, and it is therefore often
treated as a typical nonfunctional spacer sequence. We have analyzed the
ITS regions of five species from the Drosophila melanogaster subgroup, two
Drosophila species from outside this group (D. pseudoobscura and D.
virilis), as well as from the more distantly related dipteran fly Musca
domestica. The sequence comparisons show a distinctive
conservation/divergence pattern, indicating that some regions are more
conserved than others. Moreover, secondary-structure calculations indicate
several conserved structural elements within the ITS regions. On the other
hand, a statistical test that allows us to estimate the fraction of sites
that are not under selective constraint suggests that more than half of the
spacer is apparently free to diverge and evolves with a rate that is close
to the neutral rate of sequence evolution in Drosophila. The ITS sequences
can be used to derive a molecular phylogeny for the species under study. We
find that the ITS tree is largely in line with the so-far-known phylogeny
of this group of species, with one difference. The species most distant
within the D. melanogaster subgroup is D. yakuba, rather than D. orena, as
is normally assumed.
相似文献
135.
Summary Heteronuclear 2D (13C, 1H) and (15N, 1H) correlation spectra of (13C, 15N) fully enriched proteins can be acquired simultaneously with virtually no sensitivity loss or increase in artefact levels. Three pulse sequences are described, for 2D time-shared or TS-HSQC, 2D TS-HMQC and 2D TS-HSMQC spectra, respectively. Independent spectral widths can be sampled for both heteronuclei. The sequences can be greatly improved by combining them with field-gradient methods. By applying the sequences to 3D and 4D NMR spectroscopy, considerable time savings can be obtained. The method is demonstrated for the 18 kDa HU protein.Abbreviations HMQC
heteronuclear multiple-quantum coherence spectroscopy
- HSQC
heteronuclear single-quantum coherence spectroscopy
- HSMQC
heteronuclear single- and multiple-quantum coherence spectroscopy
- NOESY
nuclear Overhauser enhancement spectroscopy 相似文献
136.
137.
138.
Else Eising Sjoerd M. H. Huisman Ahmed Mahfouz Lisanne S. Vijfhuizen Verneri Anttila Bendik S. Winsvold Tobias Kurth M. Arfan Ikram Tobias Freilinger Jaakko Kaprio Dorret I. Boomsma Cornelia M. van Duijn Marjo-Riitta R. Järvelin John-Anker Zwart Lydia Quaye David P. Strachan Christian Kubisch Martin Dichgans George Davey Smith Kari Stefansson Aarno Palotie Daniel I. Chasman Michel D. Ferrari Gisela M. Terwindt Boukje de Vries Dale R. Nyholt Boudewijn P. F. Lelieveldt Arn M. J. M. van den Maagdenberg Marcel J. T. Reinders 《Human genetics》2016,135(4):425-439
139.
A 4-parameter model to represent the relationship between slowly changing arterial inflow and the resulting pressure change
was proposed. In order to determine values for the parameters and test the model in a wide range of pressure and flow, two
experimental procedures were used. Firstly, slow oscillations in aortic pressure (period, 4 sec) were produced by means of
an external pump connected to the aorta, and secondly, cardiac arrest was induced for about 2–3 sec by stimulating the right
vagus. It was shown mathematically that the pressure and pump displacement information obtained in these experiments could
be related to the model parameters. Values for the model parameters were obtained in 6 anesthetized dogs using a least squares
adjustment procedure. Using aX
2-test, it was concluded that the model represented the arterial system for each animal well. 相似文献
140.