全文获取类型
收费全文 | 1479篇 |
免费 | 188篇 |
国内免费 | 2篇 |
专业分类
1669篇 |
出版年
2023年 | 8篇 |
2022年 | 16篇 |
2021年 | 35篇 |
2020年 | 15篇 |
2019年 | 22篇 |
2018年 | 31篇 |
2017年 | 32篇 |
2016年 | 42篇 |
2015年 | 80篇 |
2014年 | 86篇 |
2013年 | 105篇 |
2012年 | 121篇 |
2011年 | 116篇 |
2010年 | 68篇 |
2009年 | 52篇 |
2008年 | 69篇 |
2007年 | 66篇 |
2006年 | 73篇 |
2005年 | 68篇 |
2004年 | 61篇 |
2003年 | 57篇 |
2002年 | 46篇 |
2001年 | 25篇 |
2000年 | 40篇 |
1999年 | 22篇 |
1998年 | 13篇 |
1997年 | 15篇 |
1996年 | 13篇 |
1995年 | 11篇 |
1994年 | 11篇 |
1993年 | 13篇 |
1992年 | 17篇 |
1991年 | 23篇 |
1990年 | 9篇 |
1989年 | 23篇 |
1988年 | 19篇 |
1987年 | 14篇 |
1986年 | 10篇 |
1985年 | 16篇 |
1984年 | 10篇 |
1983年 | 12篇 |
1982年 | 9篇 |
1981年 | 10篇 |
1980年 | 6篇 |
1979年 | 10篇 |
1978年 | 12篇 |
1976年 | 5篇 |
1973年 | 6篇 |
1971年 | 4篇 |
1968年 | 4篇 |
排序方式: 共有1669条查询结果,搜索用时 0 毫秒
991.
Amiloride-sensitive and amiloride-insensitive components of 22Na+ uptake were examined in brush-border membrane vesicles prepared from rabbit renal cortex. Both components could be stimulated by interior-negative electrical potentials, demonstrating a sodium conductance pathway and an effect of electrical potential on the initial rate of Na+/H+ exchange. 相似文献
992.
Three human neuroblastoma cell lines were shown to have markedly different contents of catecholamines and serotonin. Two of the cell lines (CHP-134 and IMR-5) have higher levels of dopamine and its metabolites, while CHP-404 cells have higher levels of serotonin and its metabolites. Each cell line responded to the addition of D,L-2-amino-5-phosphonovalerate, an agent which increases plasma membrane permeability to Ca2+ (Pastuszko and Wilson, 1988; with striking changes in the metabolism of the neurotransmitters. These changes were dependent on the extracellular calcium concentration and include activation of dopamine synthesis (tyrosine hydroxylase), increased levels of dihydroxyphenylacetic acid and increased formation of N-methylated dopamine derivatives. Catabolism of serotonin to 5-hydroxyindole acetic acid was inhibited while that to 5-hydroxytryptophol was stimulated. These data clearly identify several important sites for regulation of neurotransmitter metabolism by calcium. The mechanisms, direct or indirect, by which the enzyme activities are modulated by calcium remain to be established. 相似文献
993.
Effect of temperature, pH, and oxygen level on the multiplication of naturally occurring Legionella pneumophila in potable water 总被引:4,自引:0,他引:4
R M Wadowsky R Wolford A M McNamara R B Yee 《Applied and environmental microbiology》1985,49(5):1197-1205
A water culture containing naturally occurring Legionella pneumophila and associated microbiota was maintained in the laboratory by serially transferring the culture in tap water which had been sterilized by membrane filtration. Successful maintenance of the water culture depended upon transferring the culture when the growth of L. pneumophila was in the late-exponential to early-stationary phase. The water culture was used as a source of naturally occurring bacteria to determine some of the parameters which affect the multiplication of L. pneumophila in tap water. Naturally occurring L. pneumophila multiplied at a temperature between 25 and 37 degrees C, at pH levels of 5.5 to 9.2, and at concentrations of dissolved oxygen of 6.0 to 6.7 mg/liter. Multiplication did not occur in tap water which contained less than 2.2 mg of dissolved oxygen per liter. An association was observed between the multiplication of L. pneumophila and the non-Legionellaceae bacteria which were also present in the water culture. The method of preserving naturally occurring L. pneumophila and associated microbiota may facilitate studies on the symbiosis of L. pneumophila with other microorganisms. 相似文献
994.
Hongfeng Yuan Zhiqiang Wang Chunggang Gao Wengang Chen Qin Huang Jiing-Kuan Yee Ravi Bhatia WenYong Chen 《The Journal of biological chemistry》2010,285(7):5085-5096
Acquired resistance through genetic mutations is a common phenomenon in several cancer therapies using molecularly targeted drugs, best exemplified by the BCR-ABL inhibitor imatinib in treating chronic myelogenous leukemia (CML). Overcoming acquired resistance is a daunting therapeutic challenge, and little is known about how these mutations evolve. To facilitate understanding the resistance mechanisms, we developed a novel culture model for CML acquired resistance in which the CML cell line KCL-22, following initial response to imatinib, develops resistant T315I BCR-ABL mutation. We demonstrate that the emergence of BCR-ABL mutations do not require pre-existing BCR-ABL mutations derived from the original patient as the subclones of KCL-22 cells can form various BCR-ABL mutations upon imatinib treatment. BCR-ABL mutation rates vary from cell clone to clone and passages, in contrast to the relatively stable mutation rate of the hypoxanthine-guanine phosphoribosyltransferase gene. Strikingly, development of BCR-ABL mutations depends on its gene expression because BCR-ABL knockdown completely blocks KCL-22 cell relapse on imatinib and acquisition of mutations. We further show that the endogenous BCR-ABL locus has significantly higher mutagenesis potential than the transduced randomly integrated BCR-ABL cDNA. Our study suggests important roles of BCR-ABL gene expression and its native chromosomal locus for acquisition of BCR-ABL mutations and provides a new tool for further studying resistance mechanisms. 相似文献
995.
Lewis NE Schramm G Bordbar A Schellenberger J Andersen MP Cheng JK Patel N Yee A Lewis RA Eils R König R Palsson BØ 《Nature biotechnology》2010,28(12):1279-1285
Metabolic interactions between multiple cell types are difficult to model using existing approaches. Here we present a workflow that integrates gene expression data, proteomics data and literature-based manual curation to model human metabolism within and between different types of cells. Transport reactions are used to account for the transfer of metabolites between models of different cell types via the interstitial fluid. We apply the method to create models of brain energy metabolism that recapitulate metabolic interactions between astrocytes and various neuron types relevant to Alzheimer's disease. Analysis of the models identifies genes and pathways that may explain observed experimental phenomena, including the differential effects of the disease on cell types and regions of the brain. Constraint-based modeling can thus contribute to the study and analysis of multicellular metabolic processes in the human tissue microenvironment and provide detailed mechanistic insight into high-throughput data analysis. 相似文献
996.
Ivan K.H. Poon Dean Y. Yee Allison L. Jones Robert J. Wood David S. Davis Craig Freeman Christopher R. Parish Mark D. Hulett 《The international journal of biochemistry & cell biology》2010,42(9):1507-1516
Heparanase, an endo-β-d-glucuronidase, is involved in numerous normal physiological and pathological processes, such as inflammation, wound healing and tumour metastasis/angiogenesis, through its ability to mediate the degradation of heparan sulfate, a key structural component of the extracellular matrix and on the surface of cells. Identifying endogenous molecules that can regulate heparanase activity will aid the understanding of its molecular function in health and disease and provide the potential for development of novel anti-cancer and anti-inflammatory therapeutics. The ability of the extracellular heparanase to tether onto cell surface heparan sulfate proteoglycans and other receptor(s), such as the cation-independent mannose-6-phosphate receptor, is key to its activation, function and uptake into intracellular compartments. Here we describe experiments demonstrating that a relatively abundant plasma glycoprotein, histidine-rich glycoprotein, directly interacts with platelet-derived heparanase and enhances its enzymatic activity. The findings in this study also show that histidine-rich glycoprotein interferes with heparanase binding to cell surface receptors, particularly heparan sulfate proteoglycans. Thus, the interaction between histidine-rich glycoprotein and heparanase can potentially regulate the role of heparanase in a variety of physiological and pathological conditions. 相似文献
997.
Chui‐Yee Fong Kalamegam Gauthaman Ariff Bongso 《Journal of cellular biochemistry》2010,111(4):769-781
Although basic research on human embryonic stem cells (hESCs) at the laboratory bench has progressed with enviable speed there has been little head way in terms of its clinical application. A look at the Internet however shows several stem cell clinics worldwide offering direct transplantation of undifferentiated hESCs to patients for the cure of a variety of diseases before bona fide evidence‐based results can be demonstrated from large controlled studies. This raises concern because reliable protocols have to be first developed to resolve the three major hurdles delaying clinical trials such as inadequate cell numbers, immunorejection and tumorigenesis. Cell expansion methods using bioreactors, rotary culture and mitotic agents have now been developed to generate stem cell derivatives in large numbers. The problem of immunorejection can now be overcome with the development of indirect and direct reprogramming protocols to personalize tissues to patients (human induced pluripotent stem cells, hiPSCs; nuclear transfer stem cells, NTSCs; induced neuronal cells, iN). However, hESC, hiPSC, and NTSCs being pluripotent have the disadvantage of teratoma formation in vivo which has to be carefully addressed so as to provide safe stem cell based therapies to the patient. This review addresses the issue of tumorigenesis and discusses approaches by which this concern may be overcome and at the same time emphasizes the need to concurrently explore alternative stem cell sources that do not confer the disadvantages of pluripotency but are widely multipotent so as to yield safe desirable tissues for clinical application as soon as possible. J. Cell. Biochem. 111: 769–781, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
998.
George Sharbeen Adam J. L. Cook K. K. Edwin Lau Joanna Raftery Christine W. Y. Yee Christopher J. Jolly 《Nucleic acids research》2010,38(22):8120-8130
Activation-induced cytidine deaminase (AID) protein initiates Ig gene mutation by deaminating cytosines, converting them into uracils. Excision of AID-induced uracils by uracil-N-glycosylase is responsible for most transversion mutations at G:C base pairs. On the other hand, processing of AID-induced G:U mismatches by mismatch repair factors is responsible for most mutation at Ig A:T base pairs. Why mismatch processing should be error prone is unknown. One theory proposes that long patch excision in G1-phase leads to dUTP-incorporation opposite adenines as a result of the higher G1-phase ratio of nuclear dUTP to dTTP. Subsequent base excision at the A:U base pairs produced could then create non-instructional templates leading to permanent mutations at A:T base pairs (1). This compelling theory has remained untested. We have developed a method to rapidly modify DNA repair pathways in mutating mouse B cells in vivo by transducing Ig knock-in splenic mouse B cells with GFP-tagged retroviruses, then adoptively transferring GFP+ cells, along with appropriate antigen, into primed congenic hosts. We have used this method to show that dUTP-incorporation is unlikely to be the cause of AID-induced mutation of A:T base pairs, and instead propose that A:T mutations might arise as an indirect consequence of nucleotide paucity during AID-induced DNA repair. 相似文献
999.
Avner Schlessinger Pär Matsson James E. Shima Ursula Pieper Sook Wah Yee Libusha Kelly Leonard Apeltsin Robert M. Stroud Thomas E. Ferrin Kathleen M. Giacomini Andrej Sali 《Protein science : a publication of the Protein Society》2010,19(3):412-428
Solute carriers are eukaryotic membrane proteins that control the uptake and efflux of solutes, including essential cellular compounds, environmental toxins, and therapeutic drugs. Solute carriers can share similar structural features despite weak sequence similarities. Identification of sequence relationships among solute carriers is needed to enhance our ability to model individual carriers and to elucidate the molecular mechanisms of their substrate specificity and transport. Here, we describe a comprehensive comparison of solute carriers. We link the proteins using sensitive profile–profile alignments and two classification approaches, including similarity networks. The clusters are analyzed in view of substrate type, transport mode, organism conservation, and tissue specificity. Solute carrier families with similar substrates generally cluster together, despite exhibiting relatively weak sequence similarities. In contrast, some families cluster together with no apparent reason, revealing unexplored relationships. We demonstrate computationally and experimentally the functional overlap between representative members of these families. Finally, we identify four putative solute carriers in the human genome. The solute carriers include a biomedically important group of membrane proteins that is diverse in sequence and structure. The proposed classification of solute carriers, combined with experiment, reveals new relationships among the individual families and identifies new solute carriers. The classification scheme will inform future attempts directed at modeling the structures of the solute carriers, a prerequisite for describing the substrate specificities of the individual families. 相似文献
1000.
Li-Fong Seet Roseline Su V. A. Barathi Wing Sum Lee Rebekah Poh Yee Meng Heng Ed Manser Eranga N. Vithana Tin Aung Matt Weaver E. Helene Sage Tina T. Wong 《PloS one》2010,5(2)
Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC-null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC-null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery. 相似文献