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131.
132.
Nilantha Sirisoma Azra Pervin Hong Zhang Songchun Jiang J. Adam Willardsen Mark B. Anderson Gary Mather Christopher M. Pleiman Shailaja Kasibhatla Ben Tseng John Drewe Sui Xiong Cai 《Bioorganic & medicinal chemistry letters》2010,20(7):2330-2334
As a continuation of our efforts to discover and develop apoptosis inducing N-methyl-4-(4-methoxyanilino)quinazolines as novel anticancer agents, we explored substitution at the 5-, 6-, 7-positions of the quinazoline and replacement of the quinazoline by other nitrogen-containing heterocycles. A small group at the 5-position was found to be well tolerated. At the 6-position a small group like an amino was preferred. Substitution at the 7-position was tolerated much less than at the 6-position. Replacing the carbon at the 8-position or both the 5- and 8-positions with nitrogen led to about 10-fold reductions in potency. Replacement of the quinazoline ring with a quinoline, a benzo[d][1,2,3]triazine, or an isoquinoline ring showed that the nitrogen at the 1-position is important for activity, while the carbon at the 2-position can be replaced by a nitrogen and the nitrogen at the 3-position can be replaced by a carbon. Through the SAR study, several 5- or 6-substituted analogs, such as 2a and 2c, were found to have potencies approaching that of lead compound N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (1g, EP128495, MPC-6827, Azixa®). 相似文献
133.
Stuart Sullivan Eirini Kaiserli Tong-Seung Tseng John M Christie 《Plant signaling & behavior》2010,5(2):184-186
We reported recently that internalization of the plant blue light receptor phototropin 1 (phot1) from the plasma membrane in response to irradiation is reliant on receptor autophosphorylation. Pharmacological interference and co-immunoprecipitation analyses also indicated that light-induced internalization of phot1 involves clathrin-dependent processes. Here, we describe additional pharmacological studies that impact the subcellular localization and trafficking of Arabidopsis phot1. Alterations in the microtububle cytoskeleton led to dramatic differences in phot1 localization and function. Likewise, inhibition of phosphatidic acid (PA) signaling was found to impair phot1 localization and function. However, action of PA inhibition on phot1 function may be attributed to pleiotropic effects on cell growth. While phot1 kinase activation is necessary to stimulate its internalization, autophosphorylation is not required for phot1 turnover in response to prolonged blue light irradiation. The implications of these findings in regard to phot1 localization and function are discussed.Key words: phototropin 1 (phot1), phototropism, subcellular trafficking, autophosphorylation, protein turnover 相似文献
134.
Tzu-Ling Tseng Ting Jian Hsiao-Fang Sunny Sun Jia-Ching Shieh 《Biochemical and biophysical research communications》2010,395(1):152-157
Candida albicans CDC4 is nonessential and plays a role in suppressing filamentous growth, in contrast to its evolutionary counterparts involved in the G1-S transition of the cell cycle. Genetic epistasis analysis has indicated that proteins besides Sol1 are targets of C. albicans Cdc4. Moreover, no formal evidence suggests that C. albicans Cdc4 functions through the ubiquitin E3 ligase of the Skp1-Cul1/Cdc53-F-box complex. To elucidate the role of C. albicans CDC4, C. albicans Cdc4-associated proteins were sought by affinity purification. A 6×His epitope-tagged C. albicans Cdc4 expressed from Escherichia coli was used in affinity purifications with the cell lysate of C. albicans cdc4 homozygous null mutant. Candida albicans Cdc4 and its associated proteins were resolved by SDS-PAGE and visualized by silver staining. The candidate proteins were recovered and trypsin-digested to generate MALDI-TOF spectra profiles, which were used to search against those of known proteins in the database to reveal their identities. Two out of four proteins encoded by GPH1 and THR1 genes were further verified to interact with C. albicans Cdc4 using a yeast two-hybrid assay. We conclude that in vitro affinity purification using C. albicans Cdc4 generated from E. coli as the bait and proteins from cell lysate of C. albicans cdc4 homozygous null mutant as a source of prey permit the identification of novel proteins that physically interact and functionally associate with C. albicans Cdc4. 相似文献
135.
Summary Nested case–control (NCC) design is a popular sampling method in large epidemiological studies for its cost effectiveness to investigate the temporal relationship of diseases with environmental exposures or biological precursors. Thomas' maximum partial likelihood estimator is commonly used to estimate the regression parameters in Cox's model for NCC data. In this article, we consider a situation in which failure/censoring information and some crude covariates are available for the entire cohort in addition to NCC data and propose an improved estimator that is asymptotically more efficient than Thomas' estimator. We adopt a projection approach that, heretofore, has only been employed in situations of random validation sampling and show that it can be well adapted to NCC designs where the sampling scheme is a dynamic process and is not independent for controls. Under certain conditions, consistency and asymptotic normality of the proposed estimator are established and a consistent variance estimator is also developed. Furthermore, a simplified approximate estimator is proposed when the disease is rare. Extensive simulations are conducted to evaluate the finite sample performance of our proposed estimators and to compare the efficiency with Thomas' estimator and other competing estimators. Moreover, sensitivity analyses are conducted to demonstrate the behavior of the proposed estimator when model assumptions are violated, and we find that the biases are reasonably small in realistic situations. We further demonstrate the proposed method with data from studies on Wilms' tumor. 相似文献
136.
Bro1 stimulates Vps4 to promote intralumenal vesicle formation during multivesicular body biogenesis
Chun-Che Tseng Shirley Dean Brian A. Davies Ishara F. Azmi Natalya Pashkova Johanna A. Payne Jennifer Staffenhagen Matt West Robert C. Piper Greg Odorizzi David J. Katzmann 《The Journal of cell biology》2021,220(8)
Endosomal sorting complexes required for transport (ESCRT-0, -I, -II, -III) execute cargo sorting and intralumenal vesicle (ILV) formation during conversion of endosomes to multivesicular bodies (MVBs). The AAA-ATPase Vps4 regulates the ESCRT-III polymer to facilitate membrane remodeling and ILV scission during MVB biogenesis. Here, we show that the conserved V domain of ESCRT-associated protein Bro1 (the yeast homologue of mammalian proteins ALIX and HD-PTP) directly stimulates Vps4. This activity is required for MVB cargo sorting. Furthermore, the Bro1 V domain alone supports Vps4/ESCRT–driven ILV formation in vivo without efficient MVB cargo sorting. These results reveal a novel activity of the V domains of Bro1 homologues in licensing ESCRT-III–dependent ILV formation and suggest a role in coordinating cargo sorting with membrane remodeling during MVB sorting. Moreover, ubiquitin binding enhances V domain stimulation of Vps4 to promote ILV formation via the Bro1–Vps4–ESCRT-III axis, uncovering a novel role for ubiquitin during MVB biogenesis in addition to facilitating cargo recognition. 相似文献
137.
Chern CG Fan MJ Yu SM Hour AL Lu PC Lin YC Wei FJ Huang SC Chen S Lai MH Tseng CS Yen HM Jwo WS Wu CC Yang TL Li LS Kuo YC Li SM Li CP Wey CK Trisiriroj A Lee HF Hsing YI 《Plant molecular biology》2007,65(4):427-438
With the completion of the rice genome sequencing project, the next major challenge is the large-scale determination of gene
function. As an important crop and a model organism, rice provides major insights into gene functions important for crop growth
or production. Phenomics with detailed information about tagged populations provides a good tool for functional genomics analysis.
By a T-DNA insertional mutagenesis approach, we have generated a rice mutant population containing 55,000 promoter trap and
gene activation or knockout lines. Approximately 20,000 of these lines have known integration sites. The T0 and T1 plants
were grown in net “houses” for two cropping seasons each year since 2003, with the mutant phenotypes recorded. Detailed data
describing growth and development of these plants, in 11 categories and 65 subcategories, over the entire four-month growing
season are available in a searchable database, along with the genetic segregation information and flanking sequence data.
With the detailed data from more than 20,000 T1 lines and 12 plants per line, we estimated the mutation rates of the T1 population,
as well the frequency of the dominant T0 mutants. The correlations among different mutation phenotypes are also calculated.
Together, the information about mutant lines, their integration sites, and the phenotypes make this collection, the Taiwan
Rice Insertion Mutants (TRIM), a good resource for rice phenomics study. Ten T2 seeds per line can be distributed to researchers
upon request.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Chyr-Guan Chern, Ming-Jen Fan, and Su-May Yu have contributed equally to this work. 相似文献
138.
A recent publication by Kim et al. on penetrating both human embryonic kidney cells and mouse embryonic stem cells with Si nanowires highlights the increasing interest in using proven semiconductor materials not only to detect specific biomolecules in solutions but also to deliver genetic material or potentially screen for the presence of particular molecules at the cell level. Many semiconductors are biocompatible and this recent work has shown that penetrating cells with large diameters compared with those of the semiconductor nanowire is not fatal to the cell and that the cells remain functional for a few days. 相似文献
139.
140.
Schubauer-Berigan MK Daniels RD Fleming DA Markey AM Couch JR Ahrenholz SH Burphy JS Anderson JL Tseng CY 《Radiation research》2007,167(2):222-232
A nested case-control study was conducted among workers at five U.S. nuclear facilities to evaluate leukemia mortality risk (excluding chronic lymphocytic) from ionizing radiation using worksite doses and adjusting for potential confounding. Conditional logistic regression was used to estimate the relative risk (RR) of exposed workers and the excess relative risk (ERR) per unit of radiation among 206 cases and 823 age-matched controls. Adjusting for sex and benzene, the RR of leukemia for workers receiving more than 10 mSv was higher compared to those receiving lower or no dose; however, the risk increase was attenuated in the highest dose group. The ERR per 10 mSv was 1.44% (95% CI: < -1.03%, 7.59%) but was higher for workers born after 1921 compared to workers born earlier or when excluding leukemias of uncertain type. Excluding the 7% who were high-dose workers (> 100 mSv), the sex- and benzene-adjusted ERR per 10 mSv was 6.82% (95% CI: -2.87%, 24.1%). The results suggest that risks among these nuclear workers are comparable to those observed in high-dose populations, although no evidence was observed of a positive quadratic dose-response term in this study. This large study is among the first to jointly evaluate benzene and ionizing radiation risk. 相似文献