全文获取类型
收费全文 | 38851篇 |
免费 | 3501篇 |
国内免费 | 20篇 |
专业分类
42372篇 |
出版年
2023年 | 235篇 |
2022年 | 494篇 |
2021年 | 1061篇 |
2020年 | 610篇 |
2019年 | 772篇 |
2018年 | 917篇 |
2017年 | 770篇 |
2016年 | 1195篇 |
2015年 | 1988篇 |
2014年 | 2211篇 |
2013年 | 2346篇 |
2012年 | 3317篇 |
2011年 | 3026篇 |
2010年 | 1941篇 |
2009年 | 1666篇 |
2008年 | 2398篇 |
2007年 | 2350篇 |
2006年 | 2125篇 |
2005年 | 2007篇 |
2004年 | 1845篇 |
2003年 | 1737篇 |
2002年 | 1615篇 |
2001年 | 340篇 |
2000年 | 237篇 |
1999年 | 343篇 |
1998年 | 413篇 |
1997年 | 274篇 |
1996年 | 245篇 |
1995年 | 209篇 |
1994年 | 214篇 |
1993年 | 220篇 |
1992年 | 216篇 |
1991年 | 204篇 |
1990年 | 191篇 |
1989年 | 165篇 |
1988年 | 174篇 |
1987年 | 162篇 |
1986年 | 129篇 |
1985年 | 129篇 |
1984年 | 167篇 |
1983年 | 124篇 |
1982年 | 153篇 |
1981年 | 145篇 |
1980年 | 133篇 |
1979年 | 104篇 |
1978年 | 107篇 |
1977年 | 100篇 |
1976年 | 83篇 |
1974年 | 71篇 |
1973年 | 84篇 |
排序方式: 共有10000条查询结果,搜索用时 10 毫秒
971.
Daniel C. B. Jeffery Brandon A. Wyse Muhammad Attiq Rehman Geoffrey W. Brown Zhiying You Roxanne Oshidari Hisao Masai Krassimir Y. Yankulov 《Nucleic acids research》2013,41(18):8475-8488
Position-effect variegation (PEV) phenotypes are characterized by the robust multigenerational repression of a gene located at a certain locus (often called gene silencing) and occasional conversions to fully active state. Consequently, the active state then persists with occasional conversions to the repressed state. These effects are mediated by the establishment and maintenance of heterochromatin or euchromatin structures, respectively. In this study, we have addressed an important but often neglected aspect of PEV: the frequency of conversions at such loci. We have developed a model and have projected various PEV scenarios based on various rates of conversions. We have also enhanced two existing assays for gene silencing in Saccharomyces cerevisiae to measure the rate of switches from repressed to active state and vice versa. We tested the validity of our methodology in Δsir1 cells and in several mutants with defects in gene silencing. The assays have revealed that the histone chaperone Chromatin Assembly Factor I is involved in the control of epigenetic conversions. Together, our model and assays provide a comprehensive methodology for further investigation of epigenetic stability and position effects. 相似文献
972.
The Sm-like protein Hfq is required for gene regulation by small RNAs (sRNAs) in bacteria and facilitates base pairing between sRNAs and their mRNA targets. The proximal and distal faces of the Hfq hexamer specifically bind sRNA and mRNA targets, but they do not explain how Hfq accelerates the formation and exchange of RNA base pairs. Here, we show that conserved arginines on the outer rim of the hexamer that are known to interact with sRNA bodies are required for Hfq’s chaperone activity. Mutations in the arginine patch lower the ability of Hfq to act in sRNA regulation of rpoS translation and eliminate annealing of natural sRNAs or unstructured oligonucleotides, without preventing binding to either the proximal or distal face. Stopped-flow FRET and fluorescence anisotropy show that complementary RNAs transiently form a ternary complex with Hfq, but the RNAs are not released as a double helix in the absence of rim arginines. RNAs bound to either face of Hfq quench the fluorescence of a tryptophan adjacent to the arginine patch, demonstrating that the rim can simultaneously engage two RNA strands. We propose that the arginine patch overcomes entropic and electrostatic barriers to helix nucleation and constitutes the active site for Hfq’s chaperone function. 相似文献
973.
Erica S. Rinella Yongzhao Shao Lauren Yackowski Sreemanta Pramanik Ruth Oratz Freya Schnabel Saurav Guha Charles LeDuc Christopher L. Campbell Susan D. Klugman Mary Beth Terry Ruby T. Senie Irene L. Andrulis Mary Daly Esther M. John Daniel Roses Wendy K. Chung Harry Ostrer 《Human genetics》2013,132(5):523-536
The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations. 相似文献
974.
Henry M. Smilowitz Daniel Sasso Edward W. Lee Gyuhyeong Goh Peggy L. Micca F. Avraham Dilmanian 《Cancer immunology, immunotherapy : CII》2013,62(7):1187-1197
A reproducible therapy model for advanced intracerebral B16 melanoma is reported. Implanted tumors (D0), suppressed by a single 15 Gy radiosurgical dose of 100 kVp X-rays (D8), were further suppressed by a single ip injection of a Treg-depleting mAb given 2 days prior to the initiation (D9) of four weekly then eight bi-monthly sc injections of GMCSF-transfected, mitotically disabled B16 cells. The trends of seven independent experiments were similar to the combined result: The median (days) [SD/total N] of survival went from 15[1.09/62] (no treatment control) to 35.8[8.8/58] (radiation therapy only) to 52.5[13.5/57] (radiation therapy plus immunotherapy). Within 2 weeks after immunization, tumors in mice receiving radiation therapy plus immunotherapy were significantly smaller than tumors in mice treated only with radiosurgery. Splenocytes and lymph node cells from immunized mice showed increased interferon γ production when cultured with syngeneic tumor cells. We suggest that our model will be useful for the development and testing of novel combination therapies for brain tumors. 相似文献
975.
Interference between male and female functions within a monoecious plant may hinder crossing and decrease seed set. We assessed the probability of self-pollination and the effect of self-pollination on cross-pollination for two self-incompatible species: Nothofagus obliqua and N. nervosa. The probability of self-pollination was studied by tracking the phenologies of staminate and pistillate flowers, including an analysis of stigmatic receptivity. Pure and mixed pollinations were performed in order to evaluate the effect of self-pollination upon cross-pollination. Phenological observations suggest that self-pollination is highly likely in both species. Compared to pure cross-pollination, the application of self-pollination prior to cross-pollination resulted in lower numbers of germinated pollen grains for both species, and also in a lower production of viable seeds in N. nervosa. The low proportion of viable seeds often observed in natural populations of N. obliqua and N. nervosa may be related to self-pollination. 相似文献
976.
Daniel J. G. Lahr 《BioEssays : news and reviews in molecular, cellular and developmental biology》2013,35(4):339-347
The cellular slime mold Dictyostelium has cell‐cell connections similar in structure, function, and underlying molecular mechanisms to animal epithelial cells. These similarities form the basis for the proposal that multicellularity is ancestral to the clade containing animals, fungi, and Amoebozoa (including Dictyostelium): Amorphea (formerly “unikonts”). This hypothesis is intriguing and if true could precipitate a paradigm shift. However, phylogenetic analyses of two key genes reveal patterns inconsistent with a single origin of multicellularity. A single origin in Amorphea would also require loss of multicellularity in each of the many unicellular lineages within this clade. Further, there are numerous other origins of multicellularity within eukaryotes, including three within Amorphea, that are not characterized by these structural and mechanistic similarities. Instead, convergent evolution resulting from similar selective pressures for forming multicellular structures with motile and differentiated cells is the most likely explanation for the observed similarities between animal and dictyostelid cell‐cell connections. 相似文献
977.
Parents, predators, parasites, and the evolution of eggshell colour in open nesting birds 总被引:1,自引:0,他引:1
The colourful surface of birds’ eggshells varies dramatically between species, but the selective pressures driving this variation remain poorly understood. We used a large comparative dataset to test several hypotheses proposed to explain the evolution of eggshell colouration. We tested the hypothesis that predation pressure might select for cryptic eggshells by examining the relationship between predation rate and egg colouration. We found that predation rates were positively related to eggshell brightness. The blackmail hypothesis suggests that females lay colourful eggshells to coerce males into providing additional care during incubation to keep colourful eggs covered. According to this hypothesis, conspicuous eggs should be found in situations with high risk of visual detection from predators or brood parasites. In support of this hypothesis, proportional blue-green chroma was positively related to parasitism risk, and eggs with higher proportional blue-green chroma or higher ultraviolet chroma received higher combined parental nest attendance during the incubation period. The sexual signalling hypothesis states that blue-green colour indicates female quality; however, we did not find that blue-green eggshell colour was greater in species where males participate in any form of parental care, and relative male provisioning was unrelated to blue-green eggshell chroma. We found some support for the hypothesis that brood parasitism may select for high inter-clutch variation in eggshell colour to facilitate egg recognition. In our dataset, parasitism risk was negatively related to inter-clutch repeatability of blue-green chroma. Our study highlights the diversity of selection pressures acting on the evolution of eggshell colour in birds and provides suggestions for novel areas of future key research direction. 相似文献
978.
Amaia Artal-Martinez de Narvajas Timothy S. Gomez Jin-San Zhang Alexander O. Mann Yoshiyuki Taoda Jacquelyn A. Gorman Marta Herreros-Villanueva Thomas M. Gress Volker Ellenrieder Luis Bujanda Do-Hyung Kim Alan P. Kozikowski Alexander Koenig Daniel D. Billadeau 《Molecular and cellular biology》2013,33(20):3983-3993
979.
980.
Mauro Leonelli Daniel O. Martins Luiz R. G. Britto 《Cellular and molecular neurobiology》2013,33(3):379-392
The activation of the transient receptor potential vanilloid type 1 channel (TRPV1) has been correlated with oxidative and nitrosative stress and cell death in the nervous system. Our previous results indicate that TRPV1 activation in the adult retina can lead to constitutive and inducible nitric oxide synthase-dependent protein nitration and apoptosis. In this report, we have investigated the potential effects of TRPV1 channel activation on nitric oxide synthase (NOS) expression and function, and the putative participation of ionotropic glutamate receptors in retinal TRPV1-induced protein nitration, lipid peroxidation, and DNA fragmentation. Intravitreal injections of the classical TRPV1 agonist capsaicin up-regulated the protein expression of the inducible and endothelial NOS isoforms. Using 4,5-diaminofluorescein diacetate for nitric oxide (NO) imaging, we found that capsaicin also increased the production of NO in retinal blood vessels. Processes and perikarya of TRPV1-expressing neurons in the inner nuclear layer of the retina were found in the vicinity of nNOS-positive neurons, but those two proteins did not colocalize. Retinal explants exposed to capsaicin presented high protein nitration, lipid peroxidation, and cell death, which were observed in the inner nuclear and plexiform layers and in ganglion cells. This effect was partially blocked by AP-5, a NMDA glutamate receptor antagonist, but not by CNQX, an AMPA/kainate receptor antagonist. These data support a potential role for TRPV1 channels in physiopathological retinal processes mediated by NO, which at least in part involve glutamate release. 相似文献