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排序方式: 共有347条查询结果,搜索用时 15 毫秒
81.
Ihor E. Kopka Linus S. Lin James P. Jewell Thomas J. Lanza Tung M. Fong Chun-Pyn Shen Zhege J. Lao Sookhee Ha Laurie G. Castonguay Lex Van der Ploeg Mark T. Goulet William K. Hagmann 《Bioorganic & medicinal chemistry letters》2010,20(16):4757-4761
The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant 1 are described. The initial inspiration for these taranabant derivatives was its conformation 1a, determined by 1H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure. The results obtained are discussed in the context of a predicted binding of 1 to a homology model of CB1R. 相似文献
82.
Most researchers confidently assume that transformation of recombinant plasmid libraries into microbial hosts followed by outgrowth of isolated colonies results in a "one cell-one mutant gene-one protein variant" paradigm. Indeed, this assumption is supported by the overwhelming majority of published studies employing bacterial expression hosts. In stark contrast, we recently reported on Saccharomyces cerevisiae libraries containing unexpectedly high frequencies of cells harboring heterogeneous mixtures of plasmids, so called Multiple Vector Transformants (MVT). Intriguingly, we observed that yeast MVT persist as a significant proportion of populations for multiple generations. MVT can lead to misidentification of isolated mutants loss of functionally enhanced clones, and unwitting propagation of false positives derived from contaminating control sequences. Such experimental complications can have devastating outcomes in the context of protein engineering by combinatorial library screening. Herein, we demonstrate that the phenomenon of MVT is not restricted to vectors bearing the CEN/ARSH origin of replication, but may be an even greater concern when using high copy 2 μm plasmids. To mitigate the risks associated with MVT, we have developed an optimized sequencing procedure that facilitates rapid and reliable identification of MVT among clones of interest. In our experience, MVT and their associated risks can be virtually eliminated by employing extended liquid outgrowths of transformed populations and archiving sequence-verified, monoclonal, mutant genes from cell-templated PCR amplicons. 相似文献
83.
84.
A. Pernet D. Hoisington J. Dintinger D. Jewell C. Jiang M. Khairallah P. Letourmy J.-L. Marchand J.-C. Glaszmann D. González de León 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1999,99(3-4):540-553
The streak disease has a major effect on maize in sub-Saharan Africa. Various genetic factors for resistance to the virus
have been identified and mapped in several populations; these factors derive from different sources of resistance. We have
focused on the Réunion island source and have recently identified several factors in the D211 line. A second very resistant
line, CIRAD390, was crossed to the same susceptible parent, B73. The linkage map comprised 124 RFLP markers, of which 79 were
common with the D211×B73 map. A row-column design was used to evaluate the resistance to maize streak virus (MSV) of 191 F2:3 families under artificial infestation at two locations: Harare (Zimbabwe) and in Réunion island. Weekly ratings of resistance
were taken and disease incidence and severity calculated. QTL analyses were conducted for each scoring date and for the integration
over time of the disease scores, of incidence, and of severity. Heritability estimates (71–98%) were as high as for the D211×B73
population. Eight QTLs were detected on chromosomes 1, 2, 3, 5 (two QTLs), 6, 8, and 10. The chr1-QTL explained the highest
proportion of phenotypic variation, about 45%. The QTLs on chromosomes 1, 2, and 10 were located in the same chromosomal bin
as QTLs for MSV resistance in the D211×B73 population. In a simultaneous fit, QTLs explained together 43–67% of the phenotypic
variation. The QTLs on chromosomes 3, 5, and 6 appeared to be specific for one or the other component of the resistance. For
the chr3-QTL, resistance was contributed by the susceptible parent. There were significant QTL × environment interactions
for some of the variables studied, but QTLs were stable in the two environments. They also appeared to be stable over time.
Global gene action ranged from partial dominance to overdominance, except for disease severity. Some additional putative QTLs
were also detected. The major QTL on chromosome 1 seemed to be common to the other sources of resistance, namely Tzi4, a tolerant
line from IITA, and CML202 from CIMMYT. However, the distribution of the other QTLs within the genome revealed differences
in Réunion germplasm and across these other resistance sources. This diversity is of great importance when considering the
durability of the resistance.
Received: 15 June 1998 / Accepted: 30 January 1999 相似文献
85.
Shihai Zhang Huanyu Wang Chase H. Melick Mi-Hyeon Jeong Adna Curukovic Shweta Tiwary Tshering D. Lama-Sherpa Delong Meng Kelly A. Servage Nicholas G. James Jenna L. Jewell 《PLoS genetics》2021,17(10)
The mammalian target of rapamycin complex 1 (mTORC1) senses multiple stimuli to regulate anabolic and catabolic processes. mTORC1 is typically hyperactivated in multiple human diseases such as cancer and type 2 diabetes. Extensive research has focused on signaling pathways that can activate mTORC1 such as growth factors and amino acids. However, less is known about signaling cues that can directly inhibit mTORC1 activity. Here, we identify A-kinase anchoring protein 13 (AKAP13) as an mTORC1 binding protein, and a crucial regulator of mTORC1 inhibition by G-protein coupled receptor (GPCR) signaling. GPCRs paired to Gαs proteins increase cyclic adenosine 3’5’ monophosphate (cAMP) to activate protein kinase A (PKA). Mechanistically, AKAP13 acts as a scaffold for PKA and mTORC1, where PKA inhibits mTORC1 through the phosphorylation of Raptor on Ser 791. Importantly, AKAP13 mediates mTORC1-induced cell proliferation, cell size, and colony formation. AKAP13 expression correlates with mTORC1 activation and overall lung adenocarcinoma patient survival, as well as lung cancer tumor growth in vivo. Our study identifies AKAP13 as an important player in mTORC1 inhibition by GPCRs, and targeting this pathway may be beneficial for human diseases with hyperactivated mTORC1. 相似文献
86.
Schwartz CE May MM Carpenter NJ Rogers RC Martin J Bialer MG Ward J Sanabria J Marsa S Lewis JA Echeverri R Lubs HA Voeller K Simensen RJ Stevenson RE 《American journal of human genetics》2005,77(1):41-53
Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations. 相似文献
87.
Bivariate current status data with univariate monitoring times 总被引:2,自引:0,他引:2
88.
Ferrario CM Trask AJ Jessup JA 《American journal of physiology. Heart and circulatory physiology》2005,289(6):H2281-H2290
Angiotensin-converting enzyme 2 (ACE2) is the first human homologue of ACE to be described. ACE2 is a type I integral membrane protein that functions as a carboxypeptidase, cleaving a single hydrophobic/basic residue from the COOH-terminus of its substrates. Because ACE2 efficiently hydrolyzes the potent vasoconstrictor angiotensin II to angiotensin (1-7), this has changed our overall perspective about the classical view of the renin angiotensin system in the regulation of hypertension and heart and renal function, because it represents the first example of a feedforward mechanism directed toward mitigation of the actions of angiotensin II. This paper reviews the new data regarding the biochemistry of angiotensin-(1-7)-forming enzymes and discusses key findings such as the elucidation of the regulatory mechanisms participating in the expression of ACE2 and angiotensin-(1-7) in the control of the circulation. 相似文献
89.
Jewell C Cusack S Cashman KD 《Prostaglandins, leukotrienes, and essential fatty acids》2005,72(3):163-171
Conjugated linoleic acid (CLA) increases paracellular permeability across human intestinal-like Caco-2 cell monolayers, which transport Ca predominantly by the transcellular route. In vivo, however, paracellular Ca transport is the predominant route of Ca transport. Therefore, the objective of this study was to investigate the effect of CLA on transepithelial Ca transport in Caco-2 cells transporting Ca predominantly by the paracellular route. Cells were seeded onto permeable transport membranes and allowed to differentiate, over 14 d, into intestinal-like cell monolayers. Monolayers (n=9/treatment) were exposed to 0 (control) or 80 microM- 18:2, -cis-9, trans-11 CLA or -trans-10, cis-12 CLA for 14 d prior to Ca transport studies. Overall transepithelial Ca transport as well as transcellular and parcellular Ca transport was significantly increased (P<0.001) by exposure of Caco-2 cells to both isomers of CLA, an effect which appeared to be related to altered localization of zona occludens 1 (a tight junction protein). 相似文献
90.
BACKGROUND: The control of proliferation, differentiation and survival of normal and malignant cells in the tumour microenvironment is under the control of a wide range of different factors, including cell:cell interactions, cytokines, growth factors and hormonal influences. However, the ways in which these factors interact are poorly understood. In order to compare the effects of multiple variables, experimental design becomes complex and difficult to manage. We have therefore evaluated the use of a novel approach to multifactorial experimental design, the Taguchi methods, to approach this problem. METHOD: The Taguchi methods are widely used by quality engineering scientists to compare the effects of multiple variables, together with their interactions, with a simple and manageable experimental design. In order to evaluate these methods, we have used a simple and robust system to compare a traditional experimental design with the Taguchi Methods. The effect of G-CSF, GM-CSF, IL3 and M-CSF on daunorubicin mediated cytotoxicity in K562 cells was measured using the MTT assay. RESULTS: Both methods demonstrated that the same combination of growth factors at the same concentrations minimised daunorubicin cytotoxicity in this assay. CONCLUSIONS: These findings demonstrate that Taguchi methods may be a valuable tool for the investigation of the interactions of multiple variables in the tumour microenvironment. 相似文献