全文获取类型
收费全文 | 202篇 |
免费 | 19篇 |
出版年
2022年 | 1篇 |
2021年 | 6篇 |
2020年 | 6篇 |
2019年 | 10篇 |
2018年 | 7篇 |
2017年 | 5篇 |
2016年 | 9篇 |
2015年 | 10篇 |
2014年 | 5篇 |
2013年 | 3篇 |
2012年 | 9篇 |
2011年 | 9篇 |
2010年 | 10篇 |
2009年 | 7篇 |
2008年 | 5篇 |
2007年 | 3篇 |
2006年 | 8篇 |
2005年 | 11篇 |
2004年 | 4篇 |
2003年 | 15篇 |
2002年 | 8篇 |
2001年 | 7篇 |
2000年 | 13篇 |
1999年 | 8篇 |
1998年 | 8篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1995年 | 6篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 5篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1975年 | 1篇 |
排序方式: 共有221条查询结果,搜索用时 15 毫秒
61.
Kajsa Sjöholm Björn Carlsson Lena MS Carlsson 《Central European Journal of Biology》2006,1(2):221-234
The leptin system regulates body fat mass through a feedback loop between adipose tissue and the hypothalamus. To test if
leptin responsiveness may be regulated we assayed hypothalamic response to leptin during the estrous cycle; when changes in
food intake are known to occur. Immature rats were treated with pregnant mare’s serum gonadotropin (PMSG) to induce synchronized
follicular development, ovulation and corpus luteum formation. Leptin response was estimated by measuring the in vitro induction of tis11, a primary response gene activated by STAT3-dependent cytokines in hypothalamic explants after leptin stimulation. In addition,
mRNA levels of the suppressor cytokine signaling-3 (SOCS-3), a possible mediator of leptin resistance, were analyzed. Serum
leptin levels did not change between days 2 and day 3 (corresponding to proestrus and estrus, respectively) but the response
to leptin was higher on day 2 than on day 3 (p=0.05). Food intake displayed a tendency towards downregulation between day
1 and day 2 (p=0.057), and a tendency towards upregulation between day 2 and day 3 (p=0.072), although the body weight increased
on day of the study (p<0.0001). There was no significant difference in hypothalamic expression of SOCS-3 between day 2 and
day 3. In conclusion, we have shown that leptin responsiveness changes during a hormonally induced estrous cycle in rats.
Our data suggest that a change in the hypothalamic response to leptin may cause the cyclic feeding behavior seen in rats. 相似文献
62.
Gotsman M Dusa C Nassar H Hasin Y Lotan C Rozenman Y 《International journal of cardiovascular interventions》1999,2(3):187-190
The Cutting Balloon consists of a standard balloon dilatation catheter with four microtome-sharp blades that incise the plaque and minimize arterial wall trauma. It was used in 31 patients; nine had calcified arteries, ten had non-compliant lesions, three had in-stent restenosis and nine had aorto-ostial lesions. Seventeen lesions were predilated, 28 were post-dilated and 18 required stent implantation. The procedure was very effective in aorto-ostial lesions, non-compliant lesions that were not responsive to high-pressure balloon dilatation, and was partially successful in calcified arteries. It has a very specific niche in selected lesions. 相似文献
63.
Marsilje TH Hedrick MP Desharnais J Capps K Tavassoli A Zhang Y Wilson IA Benkovic SJ Boger DL 《Bioorganic & medicinal chemistry》2003,11(20):4503-4509
The design and synthesis of 10-(2-benzoxazolcarbonyl)-DDACTHF (1) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. Ketone 1 and the corresponding alcohol 13 were evaluated for inhibition of GAR Tfase and AICAR Tfase and the former was found to be a potent inhibitor of recombinant human (rh) GAR Tfase (Ki=600 nM). 相似文献
64.
Parrish JP Kastrinsky DB Stauffer F Hedrick MP Hwang I Boger DL 《Bioorganic & medicinal chemistry》2003,11(17):3815-3838
An extensive series of CBI analogues of the duocarmycins and CC-1065 exploring substituent effects within the first indole DNA binding subunit is detailed. In general, substitution at the indole C5 position led to cytotoxic potency enhancements that can be >/=1000-fold providing simplified analogues containing a single DNA binding subunit that are more potent (IC(50)=2-3 pM) than CBI-TMI, duocarmycin SA, or CC-1065. 相似文献
65.
Lucotte GL;French MS Consortium 《Genetic counseling (Geneva, Switzerland)》2002,13(2):133-138
To identify the chromosomal localizations of the multiple sclerosis (MS) genes, we conducted a genomewide linkage analysis using eighteen affected families. A MS gene is linked to markers located in the 19q13.3 region (multipoint lod-score = 2.1). Apolipoprotein E (ApoE) gene, located in this region, is an excellent candidate gene for MS because the ApoEe4 allele is acting as a severity allele in the disease. 相似文献
66.
67.
Substitution bias, rapid saturation, and the use of mtDNA for nematode systematics 总被引:13,自引:0,他引:13
Only relatively recently have researchers turned to molecular methods for
nematode phylogeny reconstruction. Thus, we lack the extensive literature
on evolutionary patterns and phylogenetic usefulness of different DNA
regions for nematodes that exists for other taxa. Here, we examine the
usefulness of mtDNA for nematode phylogeny reconstruction and provide data
that can be used for a priori character weighting or for parameter
specification in models of sequence evolution. We estimated the
substitution pattern for the mitochondrial ND4 gene from intraspecific
comparisons in four species of parasitic nematodes from the family
Trichostrongylidae (38-50 sequences per species). The resulting pattern
suggests a strong mutational bias toward A and T, and a lower
transition/transversion ratio than is typically observed in other taxa. We
also present information on the relative rates of substitution at first,
second, and third codon positions and on relative rates of saturation of
different types of substitutions in comparisons ranging from intraspecific
to interordinal. Silent sites saturate extremely quickly, presumably owing
to the substitution bias and, perhaps, to an accelerated mutation rate.
Results emphasize the importance of using only the most closely related
sequences in order to infer patterns of substitution accurately for
nematodes or for other taxa having strongly composition-biased DNA. ND4
also shows high amino acid polymorphism at both the intra- and
interspecific levels, and in higher level comparisons, there is evidence of
saturation at variable amino acid sites. In general, we recommend using
mtDNA coding genes only for phylogenetics of relatively closely related
nematode species and, even then, using only nonsynonymous substitutions and
the more conserved mitochondrial genes (e.g., cytochrome oxidases). On the
other hand, the high substitution rate in genes such as ND4 should make
them excellent for population genetics studies, identifying cryptic
species, and resolving relationships among closely related congeners when
other markers show insufficient variation.
相似文献
68.
Differentiation-associated modulation of heparan sulfate structure and function in CaCo-2 colon carcinoma cells 总被引:3,自引:2,他引:1
Salmivirta M; Safaiyan F; Prydz K; Andresen MS; Aryan M; Kolset SO 《Glycobiology》1998,8(10):1029-1036
Heparan sulfate species expressed by different cell and tissue types differ
in their structural and functional properties. Limited information is
available on differences in regulation of heparan sulfate biosynthesis
within a single tissue or cell population under different conditions. We
have approached this question by studying the effect of cell
differentiation on the biosynthesis and function of heparan sulfate in
human colon carcinoma cells (CaCo-2). These cells undergo spontaneous
differentiation in culture when grown on semipermeable supports; the
differentiated cells show phenotypic similarity to small intestine
enterocytes. Metabolically labeled heparan sulfate was isolated from the
apical and basolateral media from cultures of differentiated and
undifferentiated cells. Compositional analysis of disaccharides, derived
from the contiguous N-sulfated regions of heparan sulfate, indicated a
greater proportion of 2-O- sulfated iduronic acid units and a smaller
amount of 6-O-sulfated glucosamine units in differentiated than in
undifferentiated cells. By contrast, the overall degree of sulfation, the
chain length and the size distribution of the N-acetylated regions were
similar regardless the differentiation status of the cells. The structural
changes were found to affect the binding of heparan sulfate to the long
isoform of platelet-derived growth factor A chain but not to fibroblast
growth factor 2. These findings show that heparan sulfate structures change
during cell differentiation and that heparan sulfate-growth factor
interactions may be affected by such changes.
相似文献
69.
Chong Y Hwang I Tavassoli A Zhang Y Wilson IA Benkovic SJ Boger DL 《Bioorganic & medicinal chemistry》2005,13(10):3587-3592
Structurally-related, but non-polyglutamylatable, derivatives of 10-CF3CO-DDACTHF (1), which incorporate L-glutamine (2) and L-isoglutamine (3) in place of L-glutamate, were prepared and evaluated as inhibitors of recombinant human (rh) GAR Tfase. While the L-glutamate alpha-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (K(i) = 4.8 microM) and inactive in cellular functional assays, the gamma-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (K(i) = 0.056 microM) being only 4-fold less potent than 1 (K(i) = 0.015 microM). Moreover, 2 was effective in cellular functional assays exhibiting purine sensitive cytotoxic activity (IC50 = 300 nM, CCRF-CEM) only 20-fold less potent than 1 (IC50 = 16 nM), consistent with inhibition of de novo purine biosynthesis via selective inhibition of GAR Tfase. Like 1, 2 is transported into the cell by the reduced folate carrier. Unlike 1, the functional activity of 2 is not dependent upon FPGS polyglutamylation. 相似文献
70.
Leung D Du W Hardouin C Cheng H Hwang I Cravatt BF Boger DL 《Bioorganic & medicinal chemistry letters》2005,15(5):1423-1428
The concurrent implementation of a proteome-wide serine hydrolase selectivity screen with traditional efforts to optimize fatty acid amide hydrolase (FAAH) inhibition potency led to the expedited discovery of a new class of exceptionally potent (Ki < 300 pM) and unusually selective (> 100-fold selective) inhibitors. The iterative inhibitor design and evaluation with assistance of the selectivity screen served to differentiate otherwise indistinguishable inhibitors permitting the simultaneous optimization of potency and selectivity. Significantly, the simultaneous assessment of all potential competitive enzymes with the selectivity screen does not require the use of expressed or purified enzymes or a competitive substrate, no modification of the inhibitors is required, and the relative potency for competitive enzymes can be quantified (IC50's) including those that lack known substrates or function. 相似文献