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951.
Juliano Alves Heiko Wurdak Jennifer L. Harris João M. Occhiucci Jun Li 《Biochemical and biophysical research communications》2009,384(4):495-500
Caspases are central players in proteolytic pathways that regulate cellular processes such as apoptosis and differentiation. To accelerate the discovery of novel caspase substrates we developed a method combining in silico screening and in vitro validation. With this approach, we identified TAF15 as a novel caspase substrate in a trial study. We find that TAF15 was specifically cleaved by caspases-3 and -7. Site-directed mutagenesis revealed the consensus sequence 106DQPD/Y110 as the only site recognized by these caspases. Surprisingly, TAF15 was cleaved at more than one site in staurosporine-treated Jurkat cells. In addition, we generated two oncogenic TAF15-CIZ/NMP4-fused proteins which have been found in acute myeloid leukemia and demonstrate that caspases-3 and -7 cleave the fusion proteins at one single site. Broad application of this combination approach should expedite identification of novel caspase-interacting proteins and provide new insights into the regulation of caspase pathways leading to cell death in normal and cancer cells. 相似文献
952.
A tetramer model for human immunodeficiency virus type 1 (HIV-1) integrase (IN) with DNA representing long terminal repeat (LTR) termini was previously assembled to predict the IN residues that interact with the LTR termini; these predictions were experimentally verified for nine amino acid residues [Chen, A., Weber, I. T., Harrison, R. W. & Leis, J. (2006). Identification of amino acids in HIV-1 and avian sarcoma virus integrase subsites required for specific recognition of the long terminal repeat ends. J. Biol. Chem., 281, 4173-4182]. In a similar strategy, the unique amino acids found in avian sarcoma virus IN, rather than HIV-1 or Mason-Pfizer monkey virus IN, were substituted into the structurally related positions of HIV-1 IN. Substitutions of six additional residues (Q44, L68, E69, D229, S230, and D253) showed changes in the 3′ processing specificity of the enzyme, verifying their predicted interaction with the LTR DNA. The newly identified residues extend interactions along a 16-bp length of the LTR termini and are consistent with known LTR DNA/HIV-1 IN cross-links. The tetramer model for HIV-1 IN with LTR termini was modified to include two IN binding domains for lens-epithelium-derived growth factor/p75. The target DNA was predicted to bind in a surface trench perpendicular to the plane of the LTR DNA binding sites of HIV-1 IN and extending alongside lens-epithelium-derived growth factor. This hypothesis is supported by the in vitro activity phenotype of HIV-1 IN mutant, with a K219S substitution showing loss in strand transfer activity while maintaining 3′ processing on an HIV-1 substrate. Mutations at seven other residues reported in the literature have the same phenotype, and all eight residues align along the length of the putative target DNA binding trench. 相似文献
953.
Mie Ø. Pedersen Agnete Larsen Milena Penkowa 《Progress in histochemistry and cytochemistry》2009,44(1):29-64
The antiapoptotic, antioxidant, proliferative, and angiogenic effects of metallothionein (MT)-I+II has resulted in increased focus on their role in oncogenesis, tumor progression, therapy response, and patient prognosis. Studies have reported increased expression of MT-I+II mRNA and protein in various human cancers; such as breast, kidney, lung, nasopharynx, ovary, prostate, salivary gland, testes, urinary bladder, cervical, endometrial, skin carcinoma, melanoma, acute lymphoblastic leukemia (ALL), and pancreatic cancers, where MT-I+II expression is sometimes correlated to higher tumor grade/stage, chemotherapy/radiation resistance, and poor prognosis. However, MT-I+II are downregulated in other types of tumors (e.g. hepatocellular, gastric, colorectal, central nervous system (CNS), and thyroid cancers) where MT-I+II is either inversely correlated or unrelated to mortality. Large discrepancies exist between different tumor types, and no distinct and reliable association exists between MT-I+II expression in tumor tissues and prognosis and therapy resistance. Furthermore, a parallel has been drawn between MT-I+II expression as a potential marker for prognosis, and MT-I+II's role as oncogenic factors, without any direct evidence supporting such a parallel. This review aims at discussing the role of MT-I+II both as a prognostic marker for survival and therapy response, as well as for the hypothesized role of MT-I+II as causal oncogenes. 相似文献
954.
An “Age” Structured Model of Hematopoietic Stem Cell Organization with Application to Chronic Myeloid Leukemia 总被引:1,自引:0,他引:1
Previously, we have modeled hematopoietic stem cell organization by a stochastic, single cell-based approach. Applications
to different experimental systems demonstrated that this model consistently explains a broad variety of in vivo and in vitro data. A major advantage of the agent-based model (ABM) is the representation of heterogeneity within the hematopoietic stem
cell population. However, this advantage comes at the price of time-consuming simulations if the systems become large. One
example in this respect is the modeling of disease and treatment dynamics in patients with chronic myeloid leukemia (CML),
where the realistic number of individual cells to be considered exceeds 106. To overcome this deficiency, without losing the representation of the inherent heterogeneity of the stem cell population,
we here propose to approximate the ABM by a system of partial differential equations (PDEs). The major benefit of such an
approach is its independence from the size of the system. Although this mean field approach includes a number of simplifying
assumptions compared to the ABM, it retains the key structure of the model including the “age”-structure of stem cells. We
show that the PDE model qualitatively and quantitatively reproduces the results of the agent-based approach. 相似文献
955.
O.H. Petersen A.V. Tepikin Julia V. Gerasimenko O.V. Gerasimenko R. Sutton D.N. Criddle 《Cell calcium》2009,45(6):634-642
Pancreatitis, a potentially fatal disease in which the pancreas digests itself as well as its surroundings, is a well recognized complication of hyperlipidemia. Fatty acids have toxic effects on pancreatic acinar cells and these are mediated by large sustained elevations of the cytosolic Ca2+ concentration. An important component of the effect of fatty acids is due to inhibition of mitochondrial function and subsequent ATP depletion, which reduces the operation of Ca2+-activated ATPases in both the endoplasmic reticulum and the plasma membrane. One of the main causes of pancreatitis is alcohol abuse. Whereas the effects of even high alcohol concentrations on isolated pancreatic acinar cells are variable and often small, fatty acid ethyl esters – synthesized by combination of alcohol and fatty acids – consistently evoke major Ca2+ release from intracellular stores, subsequently opening Ca2+ entry channels in the plasma membrane. The crucial trigger for pancreatic autodigestion is intracellular trypsin activation. Although there is still uncertainty about the exact molecular mechanism by which this Ca2+-dependent process occurs, progress has been made in identifying a subcellular compartment – namely acid post-exocytotic endocytic vacuoles – in which this activation takes place. 相似文献
956.
陈飞龙 《上海生物医学工程》2009,(4):220-223
目的探讨妊娠急性脂肪肝(acute fatty liver of pregnancy,AFLP)的有效治疗方法。方法回顾性分析36例AFIP的治疗方法,其中31例妊娠急性脂肪肝,首选剖宫产术终止妊娠,其次考虑阴道分娩。5例患者因为发生肝功能衰竭而采用MARS联合血浆置换治疗。结果31例的患者获得了良好的预后,尤其是5例AFLP肝功能衰竭患者均采用人工肝血浆置换疗法,均获痊愈。结论妊娠急性脂肪肝通过治疗,能获得良好的预后。 相似文献
957.
Kuan Zhang Tong Zhao Xin Huang Zhao-hui Liu Lei Xiong Ming-ming Li Li-ying Wu Yong-qi Zhao Ling-ling Zhu Ming Fan 《Cell stress & chaperones》2009,14(4):407-415
It has been shown that induction of HSP70 by administration of geranylgeranylacetone (GGA) leads to protection against ischemia/reperfusion
injury. The present study was performed to determine the effect of GGA on the survival of mice and on brain damage under acute
hypobaric hypoxia. The data showed that the mice injected with GGA survived significantly longer than control animals (survival
time of 9.55 ± 3.12 min, n = 16 vs. controls at 4.28 ± 4.29 min, n = 15, P < 0.005). Accordingly, the cellular necrosis or degeneration of the hippocampus and the cortex induced by sublethal hypoxia
for 6 h could be attenuated by preinjection with GGA, especially in the CA2 and CA3 regions of the hippocampus. In addition,
the activity of nitric oxide synthase (NOS) of the hippocampus and the cortex was increased after exposure to sublethal hypoxia
for 6 h but could be inhibited by the preinjection of GGA. Furthermore, the expression of HSP70 was significantly increased
at 1 h after GGA injection. These results suggest that administration of GGA improved survival rate and prevented acute hypoxic
damage to the brain and that the underlying mechanism involved induction of HSP70 and inhibition of NOS activity. 相似文献
958.
目的:在应用基因工程技术人工表达获得多表位BCR-ABL融合蛋白的基础上,对该融合抗原在体外诱导对自血病细胞的特异性杀伤效应进行检测,探索慢性髓性自血病(CML)免疫治疗的新途径。方法:从外周血单个核细胞培养树突细胞(DC),以BCR-ABL融合抗原脉冲刺激DC,诱导特异性细胞毒T淋巴细胞(CTL)产生;MTT法检测CTL对白血病靶细胞的特异性杀伤活性。结果:以BCR-ABL融合抗原刺激产生的CTL能特异性抑制b3a2+的靶细胞生长,包括K562细胞(P〈0.01)和HIJA-A2+/b3a2+的CML原代细胞(P〈0.05),而对HIA-A2-或b2a2+靶细胞无明显抑制作用。结论:设计表达的多表位BCR-ABL融合抗原能在体外诱导特异性抗CML免疫反应,抑制b3a2+自血病细胞生长,有望为进一步的体内实验奠定基础。 相似文献
959.
Xiaodan Su David M. Lucas Liwen Zhang Hua Xu Vlad Zabrouskov Melanie E. Davis Amy R. Knapp Donn C. Young Philip R. O. Payne Mark R. Parthun Guido Marcucci Michael R. Grever John C. Byrd Michael A. Freitas Dr. 《Proteomics》2009,9(5):1197-1206
The in vitro evaluation of histones and their PTMs has drawn substantial interest in the development of epigenetic therapies. The differential expression of histone isoforms may serve as a potential marker in the classification of diseases affected by chromatin abnormalities. In this study, protein profiling by LC and MS was used to explore differences in histone composition in primary chronic lymphocytic leukemia (CLL) cells. Extensive method validations were performed to determine the experimental variances that would impact histone relative abundance. The resulting data demonstrated that the proposed methodology was suitable for the analysis of histone profiles. In 4 normal individuals and 40 CLL patients, a significant decrease in the relative abundance of histone H2A variants (H2AFL and H2AFA/M*) was observed in primary CLL cells as compared to normal B cells. Protein identities were determined using high mass accuracy MS and shotgun proteomics. 相似文献
960.
R. Gerlai D. Chatterjee T. Pereira T. Sawashima and R. Krishnannair 《Genes, Brain & Behavior》2009,8(6):586-599
The zebrafish has been in the forefront of developmental genetics for decades and has also been gaining attention in neurobehavioral genetics. It has been proposed to model alcohol-induced changes in human brain function and behavior. Here, adult zebrafish populations, AB and SF (short-fin wild type), were exposed to chronic treatment (several days in 0.00% or 0.50% alcohol v/v) and a subsequent acute treatment (1 h in 0.00%, 0.25%, 0.50% or 1.00% alcohol). Behavioral responses of zebrafish to computer-animated images, including a zebrafish shoal and a predator, were quantified using videotracking. Neurochemical changes in the dopaminergic and serotoninergic systems in the brain of the fish were measured using high-precision liquid chromatography with electrochemical detection. The results showed genetic differences in numerous aspects of alcohol-induced changes, including, for the first time, the behavioral effects of withdrawal from alcohol and neurochemical responses to alcohol. For example, withdrawal from alcohol abolished shoaling and increased dopamine and 3,4-dihydroxyphenylacetic acid in AB but not in SF fish. The findings show that, first, acute and chronic alcohol induced changes are quantifiable with automated behavioral paradigms; second, robust neurochemical changes are also detectable; and third, genetic factors influence both alcohol-induced behavioral and neurotransmitter level changes. Although the causal relationship underlying the alcohol-induced changes in behavior and neurochemistry is speculative at this point, the results suggest that zebrafish will be a useful tool for the analysis of the biological mechanisms of alcohol-induced functional changes in the adult brain. 相似文献