全文获取类型
收费全文 | 106918篇 |
免费 | 5791篇 |
国内免费 | 2872篇 |
出版年
2023年 | 1102篇 |
2022年 | 1192篇 |
2021年 | 3188篇 |
2020年 | 2651篇 |
2019年 | 3460篇 |
2018年 | 2859篇 |
2017年 | 1976篇 |
2016年 | 2514篇 |
2015年 | 4617篇 |
2014年 | 8811篇 |
2013年 | 8764篇 |
2012年 | 6175篇 |
2011年 | 7425篇 |
2010年 | 5243篇 |
2009年 | 5134篇 |
2008年 | 5350篇 |
2007年 | 5562篇 |
2006年 | 4250篇 |
2005年 | 3718篇 |
2004年 | 2730篇 |
2003年 | 2239篇 |
2002年 | 2003篇 |
2001年 | 1345篇 |
2000年 | 1230篇 |
1999年 | 1055篇 |
1998年 | 967篇 |
1997年 | 871篇 |
1996年 | 976篇 |
1995年 | 1110篇 |
1994年 | 1027篇 |
1993年 | 1013篇 |
1992年 | 987篇 |
1991年 | 918篇 |
1990年 | 824篇 |
1989年 | 794篇 |
1988年 | 739篇 |
1987年 | 674篇 |
1986年 | 579篇 |
1985年 | 900篇 |
1984年 | 1261篇 |
1983年 | 790篇 |
1982年 | 1058篇 |
1981年 | 1006篇 |
1980年 | 778篇 |
1979年 | 752篇 |
1978年 | 496篇 |
1977年 | 510篇 |
1976年 | 447篇 |
1974年 | 306篇 |
1973年 | 340篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
81.
《Peptides》2014
The frog skin host-defense peptide tigerinin-1R (RVCSAIPLPICH.NH2) is insulinotropic both in vitro and in vivo. This study investigates the effects on insulin release and cytotoxicity of changes in cationicity and hydrophobicity produced by selected substitutions of amino acids by l-arginine, l-lysine and l-tryptophan. The [A5W], [L8W] and [I10W] analogs produced a significant (P < 0.01) increase in the rate of insulin release from BRIN-BD11 rat clonal β cells at concentration of 0.01 nM compared with 0.1 nM for tigerinin-1R. The increase in the rate of insulin release produced by a 3 μM concentration of the [S4R], [H12K], and [I10W] analogs from both BRIN-BD11 cells and mouse islets was significantly greater (P < 0.05) than that produced by tigerinin-1R. No peptide stimulated the release of lactate dehydrogenase at concentrations up to 3 μM indicating that plasma membrane integrity had been preserved. [A5W] tigerinin-1R was the only analog tested that showed cytotoxic activity against human erythrocytes (LC50 = 265 ± 16 μM) and inhibited growth of Escherichia coli (MIC = 500 μM) and Staphylococcus aureus (MIC = 250 μM). The circular dichroism spectra of tigerinin-1R and [A5W] tigerinin-1R indicate that the peptides adopt a mixture of β-sheet, random coil and reverse β-turn conformations in 50% trifluoroethanol/water and methanol/water. Administration of [S4R] tigerinin-1R (75 nmol/kg body weight) to high-fat fed mice with insulin resistance significantly (P < 0.05) enhanced insulin release and improved glucose tolerance over a 60 min period following an intraperitoneal glucose load. The study supports the claim that tigerinin-1R shows potential for development into novel therapeutic agents for treatment of type 2 diabetes mellitus. 相似文献
82.
Liver plasma membranes prepared from genetically diabetic (db/db) mice expressed levels of Gi α-2, Gi α-3 and G-protein β-subunits that were reduced by some 75, 63 and 73% compared with levels seen in membranes from lean animals. In contrast, there were no significant differences in the expression of the 42 and 45 kDa forms of Gs α-subunits. Pertussis toxin-catalysed ADP-ribosylation of membranes from lean animals identified a single 41 kDa band whose labelling was reduced by some 86% in membranes from diabetic animals. Cholera toxin-catalysed ADP-ribosylation identified two forms of Gs α-subunits whose labelling was about 4-fold greater in membranes from diabetic animals compared with those from lean animals. Maximal stimulations of adenylyl cyclase activity by forskolin (100 μM), GTP (100 μM), p[NH]ppG (100 μM), NaF (10 mM) and glucagon (10 μM) were similar in membranes from lean and diabetic animals, whereas stimulation by isoprenaline (100 μM) was lower by about 22%. Lower concentrations (EC50-60 nM) of p[NH]ppG were needed to activate adenylyl cyclase in membranes from diabetic animals compared to those from lean animals (EC50-158 nM). As well as causing activation, p[NH]ppG was capable of eliciting a pertussis toxin-sensitive inhibitory effect upon forskolin-stimulated adenylyl cyclase activity in membranes from both lean and diabetic animals. However, maximal inhibition of adenylyl cyclase activity in membranes from diabetic animals was reduced to around 60% of that found using membranes from lean animals. Pertussis toxin-treatment in vivo enhanced maximal stimulation of adenylyl cyclase by glucagon, isoprenaline and p[NH]ppG through a process suggested to be mediated by the abolition of functional Gi activity. The lower levels of expression of G-protein β-subunits, in membranes from diabetic compared with lean animals, is suggested to perturb the equilibria between holomeric and dissociated G-protein subunits. We suggest that this may explain both the enhanced sensitivity of adenylyl cyclase to stimulation by p[NH]ppG in membranes from diabetic animals and the altered ability of pertussis and cholera toxins to catalyse the ADP-ribosylation of G-proteins in membranes from these two animals. 相似文献
83.
P. Pellegrini Anna Maria Berghella T. Del Beato Sergio Cicia Domenico Adorno Carlo Umberto Casciani 《Cancer immunology, immunotherapy : CII》1996,42(1):1-8
Recent theories have established that, during an ongoing immune response, the lymphokines produced by TH1 and TH2 subsets
of CD4+ T cells are critical to the effectiveness of that response. In vivo and in vitro studies have demonstrated that the type
of environmental cytokines plays a determinant role in directing the development of naive T cells into TH1 or TH2 effector
cells. Disregulated expansion of one or other subset may contribute to the development of certain diseases. To establish whether
a similar situation might exist in the cells of the peripheral blood (PBMC) of colorectal cancer patients, we have performed
immunological studies on a group of patients and a group of healthy subjects. We examined the interleukin-2 (IL-2), interferon
γ (IFNγ), IL-4, IL-6 and tumour necrosis factor α levels in serum; the production of IL-4 and IL-2, with and without activating
agents, by PBMC, tumour-draining lymph node lymphocytes and tumour cells; and the proliferative response of PBMC to IL-2,
IL-4 and anti-CD3 monoclonal antibody (anti-CD3), which were variously combined. The data of the present study lead us to
hypothesize that, because of suppressive effects probably due to environmental IL-4, in the peripheral blood of patients there
seems to be a disregulation in the functionality of TH1 and TH2 subsets of CD4+ T cells, with an expansion in TH2 and a malfunction in TH1 cells. Moreover it seems that this disregulation increases with
as the disease progresses through the stages, suggesting that it can be directly implicated in the mechanisms that allow the
tumour to locate and progress in the host.
Received: 27 June 1995 / Accepted: 13 November 1995 相似文献
84.
Endophytic fungi, especially from mangrove plants, are rich source of secondary metabolites, which plays a major role in various pharmacological actions preferably in cancer and bacterial infections. To perceive its role in antidiabetic activity we isolated and tested the metabolites derived from a novel strain Alternaria longipes strain VITN14G obtained from mangrove plant Avicennia officinalis. The crude extract was analyzed for antidiabetic activity and subjected to column chromatography. The isolated fractions were screened in vitro for α-glucosidase and α-amylase inhibitory activities. The cytotoxicity of the isolated fractions was studied on L929 cell lines. Following which, the screened fraction 2 was allowed for structure elucidation using gas chromatography-mass spectrometry, one-dimensional, two-dimensional nuclear magnetic resonance spectroscopy, ultraviolet, and Fourier-transform infrared analysis. The binding energies of the isolated fraction 2 with glycolytic enzymes were calculated by molecular docking studies using AutoDock Vina. The isolated fraction 2 identified as 2,4,6-triphenylaniline, showed no significant difference in α-amylase inhibition rates and a significant difference of 10% in α-glucosidase inhibition rates than that of the standard drug acarbose. Further, the cytotoxicity assay of the isolated fraction 2 resulted in a cell viability of 73.96%. Supportingly, in silico studies showed 2,4,6-triphenylaniline to produce a stronger binding affinity toward the glycolytic enzyme targets. The compound 2,4,6-triphenylaniline isolated from A. longipes strain VITN14G exhibited satisfactory antidiabetic activity for type 2 diabetes in vitro, which will further be confirmed by in vivo studies. Successful outcome of the study will result in a natural substitute for existing synthetic antidiabetic drugs. 相似文献
85.
86.
87.
Second messengers are small rapidly diffusing molecules or ions that relay signals between receptors and effector proteins to produce a physiological effect. Lipid messengers constitute one of the four major classes of second messengers. The hydrolysis of two main classes of lipids, glycerophospholipids and sphingolipids, generate parallel profiles of lipid second messengers: phosphatidic acid (PA), diacylglycerol (DAG), and lysophosphatidic acid versus ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate, respectively. In this review, we examine the mechanisms by which these lipid second messengers modulate aldosterone production at multiple levels. Aldosterone is a mineralocorticoid hormone responsible for maintaining fluid volume, electrolyte balance, and blood pressure homeostasis. Primary aldosteronism is a frequent endocrine cause of secondary hypertension. A thorough understanding of the signaling events regulating aldosterone biosynthesis may lead to the identification of novel therapeutic targets. The cumulative evidence in this literature emphasizes the critical roles of PA, DAG, and sphingolipid metabolites in aldosterone synthesis and secretion. However, it also highlights the gaps in our knowledge, such as the preference for phospholipase D-generated PA or DAG, as well as the need for further investigation to elucidate the precise mechanisms by which these lipid second messengers regulate optimal aldosterone production. 相似文献
88.
The incidence of gallbladder cancer (GBC) is relatively rare but a high degree of malignancy. The migration and invasion potential of GBC severely affects the prognosis of patients with GBC. Glycochenodeoxycholate (GCDC) is one of the most important components in GBC-associated microenvironment. However, the role of GCDC in the metastatic feature of GBC cells is not fully understood. First, the results of this study found that GCDC could effectively enhance the metastasis of GBC cells. Furthermore, GCDC could lead to the enhancement of epithelial to mesenchymal transition (EMT) phenotype in GBC cells, which is concerned to be an important mechanism of tumor metastasis. Further studies showed that GCDC treatment induced the upregulation of matrix metalloproteinase-3 (MMP3), MMP9, and SOCS3/JAK2/p-STAT3 signal pathway in GBC cells, which could regulate the level of EMT. Beside that, we also found the positive expression of farnesoid X receptor (FXR) in GBC cells and inhibition of FXR could significantly block the effect of GCDC on the metastasis of GBC cells. These results indicated that GCDC promoted GBC cells metastasis by enhancing the level of EMT and inhibition of FXR could significantly block the effect of GCDC. On one hand, FXR might be an indicator for predicting the metastasis of patient with GBC. On the other hand, FXR might serve as a potential antimetastasis target in GBC therapy. 相似文献
89.
Abdominal aortic aneurysms (AAA) are progressive dilatations of infra-renal aorta causing structural weakening rendering the aorta prone to rupture. AAA can be potentially stabilized by inhibiting inflammatory enzymes such as matrix metalloproteinases (MMP); however, active regression of AAA is not possible without new elastic fiber regeneration. Here we report the elastogenic benefit of direct delivery of polyphenols such as pentagalloyl glucose (PGG), epigallocatechin gallate (EGCG), and catechin, to smooth muscle cells obtained either from healthy or from aneurysmal rat aorta. Addition of 10 μg/ml PGG and ECGC induce elastin synthesis, organization, and crosslinking while catechin does not. Our results indicate that polyphenols bind to monomeric tropoelastin and enhance coacervation, aid in crosslinking of elastin by increasing lysyl oxidase (LOX) synthesis, and by blocking MMP-2 activity. Thus, polyphenol treatments leads to increased mature elastin fibers synthesis without increasing the production of intracellular tropoelastin. 相似文献
90.
Matthew Glick Perry BiddleJosh Jantzi Samantha WeaverDoug Schirch 《Biochemical and biophysical research communications》2014
Clinical research is currently exploring the validity of the anti-tumor candidate 3-bromopyruvate (3-BP) as a novel treatment for several types of cancer. However, recent publications have overlooked rarely-cited earlier work about the instability of 3-BP and its decay to 3-hydroxypyruvate (3-HP) which have obvious implications for its mechanism of action against tumors, how it is administered, and for precautions when preparing solutions of 3-BP. This study found the first-order decay rate of 3-BP at physiological temperature and pH has a half-life of only 77 min. Lower buffer pH decreases the decay rate, while choice of buffer and concentration do not affect it. A method for preparing more stable solutions is also reported. 相似文献