全文获取类型
收费全文 | 723篇 |
免费 | 77篇 |
出版年
2023年 | 5篇 |
2022年 | 7篇 |
2021年 | 7篇 |
2020年 | 8篇 |
2019年 | 9篇 |
2018年 | 14篇 |
2017年 | 8篇 |
2016年 | 11篇 |
2015年 | 22篇 |
2014年 | 32篇 |
2013年 | 42篇 |
2012年 | 55篇 |
2011年 | 57篇 |
2010年 | 39篇 |
2009年 | 27篇 |
2008年 | 40篇 |
2007年 | 43篇 |
2006年 | 36篇 |
2005年 | 46篇 |
2004年 | 30篇 |
2003年 | 26篇 |
2002年 | 34篇 |
2001年 | 10篇 |
2000年 | 19篇 |
1999年 | 16篇 |
1998年 | 5篇 |
1996年 | 12篇 |
1995年 | 11篇 |
1994年 | 3篇 |
1993年 | 6篇 |
1992年 | 7篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 5篇 |
1988年 | 5篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1976年 | 6篇 |
1975年 | 5篇 |
1974年 | 4篇 |
1973年 | 6篇 |
1972年 | 4篇 |
1970年 | 3篇 |
1960年 | 3篇 |
1925年 | 5篇 |
排序方式: 共有800条查询结果,搜索用时 15 毫秒
61.
A wide variety of approaches, ranging from Petri nets to systems of partial differential equations, have been used to model very specific aspects of cellular or biochemical functions. Here we describe how an agent-based or dynamic cellular automata (DCA) approach can be used as a very simple, yet very general method to model many different kinds of cellular or biochemical processes. Specifically, using simple pairwise interaction rules coupled with random object moves to simulate Brownian motion, we show how the DCA approach can be used to easily and accurately model diffusion, viscous drag, enzyme rate processes, metabolism (the Kreb's cycle), and complex genetic circuits (the repressilator). We also demonstrate how DCA approaches are able to accurately capture the stochasticity of many biological processes. The success and simplicity of this technique suggests that many other physical properties and significantly more complicated aspects of cellular behavior could be modeled using DCA methods. An easy-to-use, graphically-based computer program, called SimCell, was developed to perform the DCA simulations described here. It is available at http://wishart.biology.ualberta.ca/SimCell/. 相似文献
62.
Dirk?GriesEmail author Andrea?Foetzki Stefan?K.?Arndt Helge?Bruelheide Frank?M.?Thomas Ximing?Zhang Michael?Runge 《Plant Ecology》2005,181(1):23-43
River oases at the southern fringe of the Taklamakan desert in NW China are surrounded by belts of spontaneous vegetation
that protect the oases from sand drift. As an important source of forage, fuel and construction wood, this foreland vegetation
is also a component part of the agricultural system of the oases but has been, and still is, destroyed through overuse. Within
a broader study that aimed to provide a basis for a sustainable management of this foreland vegetation, biomass and production
were studied in four vegetation types dominated either by Alhagi sparsifolia, Calligonum caput-medusae, Populus euphratica, or Tamarix ramosissima that were thought to occur under different regimes of natural flooding in the foreland of Qira (Cele) oasis, Xinjiang, NW
China. Shoot biomass components were closely correlated to basal area (Calligonum, Populus, Tamarix) or shrub volume and projection area (Alhagi), enabling non-destructive estimation of stand biomass from shoot diameters or shrub dimensions with sufficient precision
using allometric regression equations. Relationships between shoot basal area and biomass of the woody species (Calligonum, Populus and Tamarix) agreed with predictions by a theoretical model of plant vascular systems, suggesting that they are determined by hydraulic
and mechanical requirements for shoot architecture. Average aboveground biomass densities of typical stands in late summer
were 2.97 Mg/ha in Alhagi, 3.6 Mg/ha in a row plantation and 10.9 Mg/ha in homogenous stands of Calligonum, 22–29 Mg/ha in 22 year-old Populus forests and 1.9–3.1 Mg/ha in Tamarix-dominated vegetation. Annual aboveground production including wood and assimilation organs ranged from 2.11 to 11.3 Mg/ha
in plantations of Calligonum, 3.17 to 6.12 Mg/ha in Populus, and 1.55 to 1.74 Mg/ha (based on total ground area) or 3.10 to 7.15 Mg/ha (in homogenous stands) in Tamarix. Production of Alhagi is equal to peak biomass. A thinning treatment simulating use by the local population enhanced productivity of Calligonum, Populus and Tamarix. A complete harvest of Alhagi in late August decreased production in the following year. An artificial flood irrigation treatment did not sufficiently
increase soil water content except in the uppermost layer and had no clear beneficial effect on growth of the four species
and even a negative effect on Alhagi, which was due to increased competition from annual species. As biomass and production with or without artificial irrigation
were much higher than values expected for rain-fed desert vegetation at a mean annual precipitation of 35 mm, it is concluded
that the existence of all vegetation types studied is probably based on permanent access to groundwater and that natural floods
or precipitation do not contribute to their water supply. The effects of agricultural groundwater use in the oasis on groundwater
in the foreland of the oasis need further study. Sustainable use of this productive vegetation is possible but requires proper
management. 相似文献
63.
Denis FM Benecke A Di Gioia Y Touw IP Cayre YE Lutz PG 《The Journal of biological chemistry》2005,280(10):9043-9048
The promyelocytic leukemia RARalpha target gene encoding an adaptor molecule-1 (PRAM-1) is involved in a signaling pathway induced by retinoic acid in acute promyelocytic leukemia (APL) cells. To better understand the function of PRAM-1, we have undertaken the identification of its partners through a yeast two-hybrid screen. Here, we show that the proline-rich domain of PRAM-1 interacted with the Src homology 3 (SH3) domain of hematopoietic progenitor kinase 1 (HPK-1)-interacting protein of 55 kDa (HIP-55, also called SH3P7 and Abp1) known to stimulate the activity of HPK-1 and c-Jun N-terminal kinase (JNK). Overexpression of PRAM-1 in the NB4 APL cell line increased arsenic trioxide-induced JNK activation through a caspase 3-like-dependent activity. Dissociation of the SH3 domain from the rest of the HIP-55 protein was observed in the NB4 APL cell line treated with arsenic trioxide due to specific cleavage by caspase 3-like enzymes. The cleavage of HIP-55 correlated with the induction of PRAM-1 mRNA and protein expression. Taken together, our results suggest that the caspase 3-cleaved SH3 domain of HIP-55 is likely involved in PRAM-1-mediated JNK activation upon arsenic trioxide-induced differentiation of NB4 cells. 相似文献
64.
Mutation is the underlying force that provides the variation upon which evolutionary forces can act. It is important to understand how mutation rates vary within genomes and how the probabilities of fixation of new mutations vary as well. If substitutional processes across the genome are heterogeneous, then examining patterns of coding sequence evolution without taking these underlying variations into account may be misleading. Here we present the first rigorous test of substitution rate heterogeneity in the Drosophila melanogaster genome using almost 1500 nonfunctional fragments of the transposable element DNAREP1_DM. Not only do our analyses suggest that substitutional patterns in heterochromatic and euchromatic sequences are different, but also they provide support in favor of a recombination-associated substitutional bias toward G and C in this species. The magnitude of this bias is entirely sufficient to explain recombination-associated patterns of codon usage on the autosomes of the D. melanogaster genome. We also document a bias toward lower GC content in the pattern of small insertions and deletions (indels). In addition, the GC content of noncoding DNA in Drosophila is higher than would be predicted on the basis of the pattern of nucleotide substitutions and small indels. However, we argue that the fast turnover of noncoding sequences in Drosophila makes it difficult to assess the importance of the GC biases in nucleotide substitutions and small indels in shaping the base composition of noncoding sequences. 相似文献
65.
Madiraju C Edler MC Hamel E Raccor BS Balachandran R Zhu G Giuliano KA Vogt A Shin Y Fournier JH Fukui Y Brückner AM Curran DP Day BW 《Biochemistry》2005,44(45):15053-15063
(-)-Dictyostatin is a sponge-derived, 22-member macrolactone natural product shown to cause cells to accumulate in the G2/M phase of the cell cycle, with changes in intracellular microtubules analogous to those observed with paclitaxel treatment. Dictyostatin also induces assembly of purified tubulin more rapidly than does paclitaxel, and nearly as vigorously as does dictyostatin's close structural congener, (+)-discodermolide (Isbrucker et al. (2003), Biochem. Pharmacol. 65, 75-82). We used synthetic (-)-dictyostatin to study its biochemical and cytological activities in greater detail. The antiproliferative activity of dictyostatin did not differ greatly from that of paclitaxel or discodermolide. Like discodermolide, dictyostatin retained antiproliferative activity against human ovarian carcinoma cells resistant to paclitaxel due to beta-tubulin mutations and caused conversion of cellular soluble tubulin pools to microtubules. Detailed comparison of the abilities of dictyostatin and discodermolide to induce tubulin assembly demonstrated that the compounds had similar potencies. Dictyostatin inhibited the binding of radiolabeled discodermolide to microtubules more potently than any other compound examined, and dictyostatin and discodermolide had equivalent activity as inhibitors of the binding of both radiolabeled epothilone B and paclitaxel to microtubules. These results are consistent with the idea that the macrocyclic structure of dictyostatin represents the template for the bioactive conformation of discodermolide. 相似文献
66.
Pahnke J Mix E Knoblich R Müller J Zschiesche M Schubert B Koczan D Bauer P Böttcher T Thiesen HJ Lazarov L Wree A Rolfs A 《Experimental cell research》2004,297(2):484-494
The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. Mutations in components of its signaling pathway lead to severe migration deficits of neuronal crest stem cells, tumor formation, or ablation of the urinary system. In animal models of Parkinson's disease, GDNF has been recognized to be neuroprotective and to improve motor function when delivered into the cerebral ventricles or into the substantia nigra. Here, we characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and alpha-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. Axonal guidance depends on cell-surface molecules and extracellular matrix proteins. Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. Moreover, we found four key enzymes of the cholesterol-synthesis pathway to be down-regulated leading to decreased farnesyl-pyrophospate production. Many proteins are anchored by farnesyl-derivates at the cell membrane. The identification of these GDNF-regulated genes may open new opportunities for directly influencing differentiation and developmental processes of neurons. 相似文献
67.
By varying linker length and domain orientation three multivalent derivatives of a monovalent anti-CD22 single-chain fragment variable (scFv) antibody were generated. Shortening the linker of the V(H)-V(L) oriented scFv to 5 or 0 residues resulted in the formation of diabodies or a mixture of tetramers and trimers, respectively. Unexpectedly, a V(L)-0-V(H) scFv assembled to homogenous dimers, remained substantially more stable than the V(H)-5-V(L) diabody when incubated in human serum at 37 degrees C, and retained its dimeric state when concentrated up to 4 mg/ml. These properties suggest the V(L)-0-V(H) scFv could become an attractive vehicle for the selective delivery of multiple effector molecules to CD22(+) tumor cells. 相似文献
68.
Arndt PG Suzuki N Avdi NJ Malcolm KC Worthen GS 《The Journal of biological chemistry》2004,279(12):10883-10891
Polymorphonuclear leukocytes (neutrophils) respond to lipopolysaccharide (LPS) through the up-regulation of several pro-inflammatory mediators. We have recently shown that LPS-stimulated neutrophils express monocyte chemoattractant protein 1 (MCP-1), an AP-1-dependent gene, suggesting that LPS activates the c-Jun N-terminal kinase (JNK) pathway in neutrophils. Previously, we have shown the activation of p38 MAPK, but not JNK, in suspended neutrophils stimulated with LPS but have recently shown activation of JNK by TNF-alpha in an adherent neutrophil system. We show here that exposure to LPS activates JNK in non-suspended neutrophils and that LPS-induced MCP-1 expression, but not tumor necrosis factor-alpha (TNF-alpha) or interleukin-8 (IL-8), is dependent on JNK activation. In addition, LPS stimulation of non-suspended neutrophils activates Syk and phosphatidylinositol 3-kinase (PI3K). Inhibition of Syk with piceatannol or PI3K with wortmannin inhibited LPS-induced JNK activation and decreased MCP-1 expression after exposure to LPS, suggesting that both Syk and PI3K reside in a signaling pathway leading to LPS-induced JNK activation in neutrophils. This Syk- and PI3K-dependent pathway leading to JNK activation after LPS exposure in non-suspended neutrophils is specific for JNK, because inhibition of neither Syk nor PI3K decreased p38 activation after LPS stimulation. Furthermore we show that PI3K inhibition decreased LPS-induced Syk activation suggesting that PI3K resides upstream of Syk in this pathway. Finally, we show that Syk associates with Toll-like receptor 4 (TLR4) upon LPS stimulation further implicating Syk in the LPS-induced signaling pathway in neutrophils. Overall our data suggests that LPS induces JNK activation only in non-suspended neutrophils, which proceeds through Syk- and PI3K-dependent pathways, and that JNK activation is important for LPS-induced MCP-1 expression but not for TNF-alpha or IL-8 expression. 相似文献
69.
Fessler MB Arndt PG Frasch SC Lieber JG Johnson CA Murphy RC Nick JA Bratton DL Malcolm KC Worthen GS 《The Journal of biological chemistry》2004,279(38):39989-39998
Lipid rafts are cholesterol-rich membrane microdomains that are thought to act as coordinated signaling platforms by regulating dynamic, agonist-induced translocation of signaling proteins. They have been described to play a role in multiple prototypical cascades, among them the lipopolysaccharide pathway, and to host multiple signaling proteins, including kinases and low molecular weight G-proteins. Here we report lipopolysaccharide-induced activation of the Rho family GTPase Cdc42, and we show its activation in the human neutrophil to be mediated by a p38 mitogen-activated protein kinase-dependent mechanism. Subcellular fractionation reveals that lipopolysaccharide induces translocation of Cdc42 to lipid rafts, where it and p38 are both found to be activated. By contrast, lipopolysaccharide causes translocation of Rac from the polymorphonuclear leukocyte (PMN) rafts and does not induce its activation. With the use of methyl-beta-cyclodextrin, a cholesterol-depleting agent that reversibly disrupts rafts, we confirm an important regulatory role for rafts in the activation state of p38 and Cdc42 and in the Rho GTPase-dependent functions superoxide anion production and actin polymerization. Methyl-beta-cyclodextrin induces activation of p38 and Cdc42, but not Rac, in the nonstimulated PMN, yet inhibits subsequent lipopolysaccharide-induced activation of p38 and Cdc42. In parallel, methyl-beta-cyclodextrin primes the human PMN for subsequent superoxide release triggered by the formylated bacterial tripeptide formyl-Met-Leu-Phe, and induces actin polymerization in a subcellular distribution distinct from that induced by lipopolysaccharide. In sum, these findings provide evidence for an important regulatory role of cholesterol in both transmission of the lipopolysaccharide signal and the inflammatory phenotype of the human neutrophil. 相似文献
70.
Cdc37 is a molecular chaperone that is important for the stability and activity of several protein kinases, including Cdk4 and Raf1. We first determined, using in vitro assays, that Cdc37 binds to the amino-terminal lobe of Cdk4. Subsequent mutagenesis revealed that Gly-15 (G15A) and Gly-18 (G18A) were critical for Cdc37-Cdk4 complex formation. Gly-15 and Gly-18 of Cdk4 are within the conserved Gly-X-Gly-X-X-Gly motif that is required for ATP binding to the kinase. Mutation of either glycine at the equivalent positions of Raf1 (G358A and G361A) also inhibited Cdc37 binding to Raf1. Replacing another conserved residue critical for ATP binding and kinase activity, Lys-35 (K35A), reduced Cdc37-Cdk4 complex formation but to a lesser extent. The interaction of Cdk4 with Cdc37 in vitro was not sensitive to changes in ATP levels. Cell-based assays indicated that Cdk4(G15A) and Cdk4(G18A) were present at the same level as wild type Cdk4. Equivalent amounts of p16 bound to Cdk4(G15A) and Cdk4(G18A) relative to wild type Cdk4, suggesting that Cdk4(G15A) and Cdk4(G18A) adopt significant tertiary structure. However, in contrast to wild type Cdk4, Cdk4(G15A), and Cdk4(G18A) had greatly reduced binding of cyclin D1, Cdc37, and Hsp90. Importantly, overexpression of Cdc37 not only stimulated cyclin D1 binding to wild type Cdk4 but also restored its binding to Cdk4(G15A). Under the same conditions, p16 binding to wild type Cdk4 was suppressed. Our findings show that the interaction of Cdc37 with its client protein kinases requires amino acid residues within a motif that is present in many protein kinases. 相似文献