全文获取类型
收费全文 | 1797篇 |
免费 | 135篇 |
国内免费 | 1篇 |
专业分类
1933篇 |
出版年
2024年 | 3篇 |
2023年 | 20篇 |
2022年 | 38篇 |
2021年 | 86篇 |
2020年 | 34篇 |
2019年 | 58篇 |
2018年 | 47篇 |
2017年 | 53篇 |
2016年 | 72篇 |
2015年 | 108篇 |
2014年 | 107篇 |
2013年 | 132篇 |
2012年 | 159篇 |
2011年 | 148篇 |
2010年 | 93篇 |
2009年 | 96篇 |
2008年 | 115篇 |
2007年 | 105篇 |
2006年 | 89篇 |
2005年 | 75篇 |
2004年 | 58篇 |
2003年 | 62篇 |
2002年 | 44篇 |
2001年 | 16篇 |
2000年 | 13篇 |
1999年 | 9篇 |
1998年 | 4篇 |
1997年 | 8篇 |
1996年 | 6篇 |
1995年 | 6篇 |
1994年 | 4篇 |
1993年 | 8篇 |
1992年 | 8篇 |
1991年 | 5篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1970年 | 1篇 |
1969年 | 2篇 |
1966年 | 1篇 |
1965年 | 1篇 |
1964年 | 1篇 |
1960年 | 1篇 |
排序方式: 共有1933条查询结果,搜索用时 0 毫秒
91.
It is believed that pericentromeric heterochromatin may play a major role in the epigenetic regulation of gene expression. We have previously shown that centromeres in human peripheral blood cells aggregate into distinct "myeloid" and "lymphoid" spatial patterns, suggesting that the three-dimensional organization of centromeric heterochromatin in interphase may be ontogenically determined during hematopoietic differentiation. To investigate this possibility, the spatial patterns of association of different centromeres were analyzed in hematopoietic progenitors and compared with those in early-B and early-T cells, mature B and T lymphocytes, and, additionally, mature granulocytes and monocytes. We show that those patterns change during lymphoid differentiation, with major spatial arrangements taking place at different stages during T and B cell differentiation. Heritable patterns of centromere association are observed, which can occur either at the level of the common lymphoid progenitor, or in early-T or early-B committed cells. A correlation of the observed patterns of centromere association with the gene content of the respective chromosomes further suggests that the variation in the composition of these heterochromatic structures may contribute to the dynamic relocation of genes in different nuclear compartments during cell differentiation, which might have functional implications for cell-stage-specific gene expression. 相似文献
92.
Eriksson S Hurme R Rhen M 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2002,357(1423):887-893
Bacteria are ubiquitous colonizers of various environments and host organisms, and they are therefore often subjected to drastic temperature alterations. Temperature alterations set demands on these colonizers, in that the bacteria need to readjust their biochemical constitution and physiology in order to survive and resume growth at the new temperature. Furthermore, temperature alteration is also a main factor determining the expression or repression of bacterial virulence functions. To cope with temperature variation, bacteria have devices for sensing temperature alterations and a means of translating this sensory event into a pragmatic gene response. While such regulatory cascades may ultimately be complicated, it appears that they contain primary sensor machinery at the top of the cascade. The functional core of such machinery is usually that of a temperature-induced conformational or physico-chemical change in the central constituents of the cell. In a sense, a bacterium can use structural alterations in its biomolecules as the primary thermometers or thermostats. 相似文献
93.
Intestinal parasites and malnutrition cause high morbidity among children in developing countries. A study to establish the associations between intestinal parasitism and undernourishment was undertaken in a village in the Colombian Amazon region. Two hundred thirty seven children each provided four stool samples for parasitic analysis. Anthropometric indices were calculated based on height and weight (HAZ), weight and age (WAZ) and height and weight (WHZ) using the international growth standards recommended by the World Health Organization. Of the 237 children, 86.1% were carrying parasites, 54% had 2 or more parasites, 30% were stunted, 10% were underweight, and 2.5% were wasting. HAZ and WAZ indices were inversely related to age and number of parasites. Socioeconomic status was positively correlated with the number of parasites and inversely related to the HAZ index (p < 0.05). In conclusion, frequencies of undernourishment and intestinal parasites among the sample population were higher than the national average for Colombia. As previous studies have indicated, age, intestinal parasitism and socio-economic level are variables significantly related to nutritional state. 相似文献
94.
The neuropeptide Y (NPY) receptor subtypes Y1 and Y5 are involved in the regulation of feeding and several other physiological functions in mammals. To increase our understanding of the origin and mechanisms of the complex NPY system, we report here the cloning and pharmacological characterization of receptors Y1 and Y5 in the first non-mammal, chicken (Gallus gallus). The receptors display 80-83% and 64-72% amino acid sequence identity, respectively, with their mammalian orthologues. The three endogenous ligands NPY, peptide YY (PYY) and pancreatic polypeptide (PP) have similar affinities as in mammals, i.e. NPY and PYY have subnanomolar affinity for both receptors whereas chicken PP bound with nanomolar affinity to Y5 but not to Y1. A notable difference to mammalian receptor subtypes is that the Y1 antagonist SR120819A does not bind chicken Y1, whereas BIBP3226 does. The Y5 antagonist CGP71863A binds to the chicken Y5 receptor. Anatomically, both Y1 and Y5 have high mRNA expression levels in the infundibular nucleus which is the homologous structure of the hypothalamic arcuate nucleus in mammals. These results suggest that some of the selective Y1 and Y5 antagonists developed in mammals can be used to study appetite regulation in chicken. 相似文献
95.
Tobacco-smoke exposure indicators and urinary mutagenicity 总被引:2,自引:0,他引:2
The protective effect of calcium given orally by gavage with two doses (40 and 80mg/kg body weight) was evaluated against clastogenecity induced by lead acetate with two concentrations (200 and 400mg/kg diet) on bone marrow and spermatocyte cells of mice in vivo. The parameter screened was percentage of chromosomal aberrations with and without gaps and sperm abnormalities. Statistical analyses indicated the protection efficacy of calcium with the high dose rather than the other in both types of mouse cells.The observation from the laboratory tests, dealing that lead acetate can be considered as an environmental genotoxic material. We recommended that it must be administered of calcium (as calcium chloride) as a protective agent to reduce the genotoxic effect of lead in the somatic and germ cells. 相似文献
96.
Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Molecular biology of the cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Transforming growth factor-beta (TGF-beta) is a potent regulator of cell growth and differentiation in many cell types. The Smad signaling pathway constitutes a main signal transduction route downstream of TGF-beta receptors. We studied TGF-beta-induced rearrangements of the actin filament system and found that TGF-beta 1 treatment of PC-3U human prostate carcinoma cells resulted in a rapid formation of lamellipodia. Interestingly, this response was shown to be independent of the Smad signaling pathway; instead, it required the activity of the Rho GTPases Cdc42 and RhoA, because ectopic expression of dominant negative mutant Cdc42 and RhoA abrogated the response. Long-term stimulation with TGF-beta 1 resulted in an assembly of stress fibers; this response required both signaling via Cdc42 and RhoA, and Smad proteins. A known downstream effector of Cdc42 is p38(MAPK); treatment of the cells with the p38(MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), as well as ectopic expression of a kinase-inactive p38(MAPK), abrogated the TGF-beta-induced actin reorganization. Moreover, treatment of cells with the inhibitors of the RhoA target-protein Rho-associated coiled-coil kinase (+)-R-trans-4-(aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide (Y-27632) and 1-5(-isoquinolinesulfonyl)homopiperazine (HA-1077), as well as ectopic expression of kinase-inactive Rho coiled-coil kinase-1, abrogated the TGF-beta 1-induced formation of stress fibers. Collectively, these data indicate that TGF-beta-induced membrane ruffles occur via Rho GTPase-dependent pathways, whereas long-term effects require cooperation between Smad and Rho GTPase signaling pathways. 相似文献
97.
Tetrathiomolybdate (TM), a specific copper chelator, has been shown to be a potent antiangiogenic and antimetastatic compound possibly through suppression of the NFkappaB signaling cascade. To further delineate the molecular mechanism of the anticancer effect of TM, we investigated whether TM has antineoplastic activity in the setting of genetic NFkappaB inhibition. In this study, SUM149 inflammatory breast carcinoma cells were transfected with a dominant-negative IkappaBalpha (S32AS36A) expression vector. Similar to TM-treated SUM149 cells, SUM149-IkappaBalphaMut clones secreted lower amounts of proangiogenic mediators, vascular endothelial growth factor, interleukin-1alpha, and interleukin-8 and exhibited a less invasive and motile phenotype. The reduction in the angiogenic and metastatic potential of SUM149-IkappaBalphaMut clones was not further affected by TM in vitro. SUM149-IkappaBalphaMut xenografts grew substantially slower and had less lung metastasis than SUM149 and SUM149-empty vector xenografts. The growth and metastatic potential of SUM149 and SUM149-empty tumors was significantly inhibited with systemic TM treatment, whereas TM had no further antitumor effect on the SUM149-IkappaBalphaMut tumors. Additionally, nuclear proteins isolated from TM-treated SUM149 tumors had lower NFkappaB binding activity, while AP1 and SP1 binding activities were unchanged. Taken together, these results strongly support that suppression of NFkappaB is the major mechanism used by TM to inhibit angiogenesis and metastasis. 相似文献
98.
We previously reported the genetic engineering of the first soluble, bivalent major histocompatibility complex (MHC) class II-peptide ligand for T-cell receptor (TCR). This ligand binds stably and specifically to cognate T-cells and exhibits immunomodulatory effects in vitro and in vivo. The increase in valence of MHC class II-peptide ligands was shown to parallel their avidity for cognate TCRs and potency in stimulating cognate T-cells. We describe a new enzymatic method to increase the valence of MHC-peptide ligands by cross-linking the N-glycan moieties of dimeric MHC II-peptide units through a flexible, bifunctional polyethylene glycol linker. Using this method, we generated covalently stabilized tetravalent and octavalent MHC II-peptide ligands which bound stably and specifically to cognate TCR and preserved their structural integrity in blood and lymphoid organs for 72 h. Depending on the TCR/CD4 occupancy and degree of TCR/CD4 co-clustering, the multivalent MHC II-peptide ligands polarized efficiently the antigen-specific CD4(+) T-cells toward type 2 cell differentiation or induced T-cell anergy and apoptosis. The enzymatically mediated engineering of multivalent MHC-peptide ligands for cognate TCRs may provide rational grounds for the development of new therapeutic agents endowed with strong modulatory effects on antigen-specific T-cells. 相似文献
99.
In Drosophila the eye-antennal disc gives rise to most adult structures of the fly's head. Yet the molecular basis for its regionalization during development is poorly understood. Here we show that homothorax is required early during development for normal eye development and is necessary for the formation of the ventral head capsule. In the ventral region of the disc only, homothorax and wingless are involved in a positive feedback loop necessary to restrict eye formation. homothorax is able to prevent the initiation and progression of the morphogenetic furrow without inducing wingless, which points to homothorax as a key negative regulator of eye development. In addition, we show that the iroquois-complex genes are required for dorsal head development antagonizing the function of homothorax in this region of the disc. 相似文献
100.
The crystals of the soil-isolated Bacillus thuringiensis (Bt) strain A4 consist of two polypeptides with molecular mass of 140 kDa and 32 kDa that exhibit insecticidal activity against
adult flies of Bactrocera oleae (Diptera). Plasmid curing applied to this strain resulted in the isolation of several subclones exhibiting alterations in
their crystal polypeptides as well as two acrystalliferous subclones. The crystals of subclone 1.1 lacked the 32-kDa polypeptide
and consisted uniquely of a 140-kDa polypeptide antigenically related to the parental 140-kDa crystal polypeptide. Additionally,
the crystals of this subclone exhibited insecticidal activity against B. oleae equivalent to that of the parental strain. Therefore, the 32-kDa crystal polypeptide is dispensable for insecticidal activity,
which appears to be dependent on the presence of the 140-kDa crystal polypeptide.
Received: 5 April 2000 / Accepted 2 May 2000 相似文献