全文获取类型
收费全文 | 11220篇 |
免费 | 785篇 |
国内免费 | 7篇 |
出版年
2024年 | 13篇 |
2023年 | 46篇 |
2022年 | 169篇 |
2021年 | 223篇 |
2020年 | 166篇 |
2019年 | 219篇 |
2018年 | 336篇 |
2017年 | 280篇 |
2016年 | 430篇 |
2015年 | 700篇 |
2014年 | 727篇 |
2013年 | 830篇 |
2012年 | 1025篇 |
2011年 | 946篇 |
2010年 | 600篇 |
2009年 | 529篇 |
2008年 | 686篇 |
2007年 | 672篇 |
2006年 | 582篇 |
2005年 | 551篇 |
2004年 | 511篇 |
2003年 | 437篇 |
2002年 | 350篇 |
2001年 | 192篇 |
2000年 | 179篇 |
1999年 | 131篇 |
1998年 | 74篇 |
1997年 | 50篇 |
1996年 | 40篇 |
1995年 | 29篇 |
1994年 | 20篇 |
1993年 | 28篇 |
1992年 | 29篇 |
1991年 | 25篇 |
1990年 | 20篇 |
1989年 | 19篇 |
1988年 | 16篇 |
1987年 | 11篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 7篇 |
1983年 | 13篇 |
1982年 | 13篇 |
1981年 | 6篇 |
1980年 | 14篇 |
1979年 | 17篇 |
1977年 | 6篇 |
1975年 | 4篇 |
1974年 | 4篇 |
1971年 | 4篇 |
排序方式: 共有10000条查询结果,搜索用时 28 毫秒
941.
Ryu KY Maehr R Gilchrist CA Long MA Bouley DM Mueller B Ploegh HL Kopito RR 《The EMBO journal》2007,26(11):2693-2706
UbC is one of two stress-inducible polyubiquitin genes in mammals and is thought to supplement the constitutive UbA genes in maintaining cellular ubiquitin (Ub) levels during episodes of cellular stress. We have generated mice harboring a targeted disruption of the UbC gene. UbC(-/-) embryos die between embryonic days 12.5 and 14.5 in utero, most likely owing to a severe defect in liver cell proliferation. Mouse embryonic fibroblasts from UbC(-/-) embryos exhibit reduced growth rates, premature senescence, increased apoptosis and delayed cell-cycle progression, with slightly, but significantly, decreased steady-state Ub levels. UbC(-/-) fibroblasts are hypersensitive to proteasome inhibitors and heat shock, and unable to adequately increase Ub levels in response to these cellular stresses. Most, but not all of the UbC(-/-) phenotypes can be rescued by providing additional Ub from a poly hemagglutinin-tagged Ub minigene expressed from the Hprt locus. We propose that UbC is regulated by a process that senses Ub pool dynamics. These data establish that UbC constitutes an essential source of Ub during cell proliferation and stress that cannot be compensated by other Ub genes. 相似文献
942.
Role of Galpha12 and Galpha13 as novel switches for the activity of Nrf2, a key antioxidative transcription factor 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Cho MK Kim WD Ki SH Hwang JI Choi S Lee CH Kim SG 《Molecular and cellular biology》2007,27(17):6195-6208
Galpha12 and Galpha13 function as molecular regulators responding to extracellular stimuli. NF-E2-related factor 2 (Nrf2) is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by Galpha12 and Galpha13. A deficiency of Galpha12, but not of Galpha13, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, Galpha12 knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin and its glucuronosyl conjugations. An oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by Galpha12 gene knockout. Galpha12 deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did Galpha13 deficiency. The absence of Galpha12, but not of Galpha13, increased protein kinase C delta (PKC delta) activation and the PKC delta-mediated serine phosphorylation of Nrf2. Galpha13 gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by Galpha12 deficiency, suggesting that relief from Galpha12 repression leads to the Galpha13-mediated activation of Nrf2. Constitutive activation of Galpha13 promoted Nrf2 activity and target gene induction via Rho-mediated PKC delta activation, corroborating positive regulation by Galpha13. In summary, Galpha12 and Galpha13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas Galpha13 regulates Rho-PKC delta-mediated Nrf2 phosphorylation, which is negatively balanced by Galpha12. 相似文献
943.
Lee KY Jeong JW Wang J Ma L Martin JF Tsai SY Lydon JP DeMayo FJ 《Molecular and cellular biology》2007,27(15):5468-5478
The process of implantation, necessary for all viviparous birth, consists of tightly regulated events, including apposition of the blastocyst, attachment to the uterine lumen, and differentiation of the uterine stroma. In rodents and primates the uterine stroma undergoes a process called decidualization. Decidualization, the process by which the uterine endometrial stroma proliferates and differentiates into large epithelioid decidual cells, is critical to the establishment of fetal-maternal communication and the progression of implantation. The role of bone morphogenetic protein 2 (Bmp2) in regulating the transformation of the uterine stroma during embryo implantation in the mouse was investigated by the conditional ablation of Bmp2 in the uterus using the (PR-cre) mouse. Bmp2 gene ablation was confirmed by real-time PCR analysis in the PR-cre; Bmp2fl/fl (termed Bmp2d/d) uterus. While littermate controls average 0.9 litter of 6.2+/-0.7 pups per month, Bmp2d/d females are completely infertile. Analysis of the infertility indicates that whereas embryo attachment is normal in the Bmp2d/d as in control mice, the uterine stroma is incapable of undergoing the decidual reaction to support further embryonic development. Recombinant human BMP2 can partially rescue the decidual response, suggesting that the observed phenotypes are not due to a developmental consequence of Bmp2 ablation. Microarray analysis demonstrates that ablation of Bmp2 leads to specific gene changes, including disruption of the Wnt signaling pathway, Progesterone receptor (PR) signaling, and the induction of prostaglandin synthase 2 (Ptgs2). Taken together, these data demonstrate that Bmp2 is a critical regulator of gene expression and function in the murine uterus. 相似文献
944.
Choi IY Kim SJ Jeong HJ Park SH Song YS Lee JH Kang TH Park JH Hwang GS Lee EJ Hong SH Kim HM Um JY 《Molecular and cellular biochemistry》2007,305(1-2):153-161
The citrus unshiu peel has been used traditionally as a medicine to improve bronchial and asthmatic conditions or cardiac
and blood circulation in Korea, China, and Japan. Here, we report the effects of citrus unshiu peel water extract (CPWE) on
the phorbol myristate acetate (PMA) + calcium ionophore A23187-induced hypoxia-inducible factor-1α (HIF-1α) activation and
inflammatory cytokine production from the human mast cell line, HMC-1 cells. We compared CPWE with hesperidin, a common constituent
of citrus unshiu. CPWE and hesperidin inhibited the PMA + A23187-induced HIF-1α expression and the subsequent production of
vascular endothelial growth factor (VEGF). In addition, CPWE suppressed PMA + A23187-induced phosphorylation of the extracellular
signal-regulated kinase (ERK). We also show that the increased cytokines interleukin (IL)-1β, IL-8, and tumor necrosis factor
(TNF)-α level was significantly inhibited by treatment of CPWE or hesperidin. In the present study, we report that CPWE and
hesperidin are inhibitors of HIF-1α and cytokines on the mast cell-mediated inflammatory responses. 相似文献
945.
946.
947.
948.
Frequency of Secondary Symbiont Infection in an Invasive Psyllid Relates to Parasitism Pressure on a Geographic Scale in California 总被引:3,自引:2,他引:1
下载免费PDF全文
![点击此处可从《Applied microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Two endosymbionts, an obligate primary symbiont and a facultative secondary symbiont, are harbored within the invasive red gum (eucalyptus) lerp psyllid, Glycaspis brimblecombei, in California. An extensive survey of diversity and frequency of G. brimblecombei's secondary symbiont in multiple populations throughout the state of California was conducted using PCR detection, restriction enzymes, cloning, and sequencing. A total of 380 G. brimblecombei individuals in 19 populations were screened for secondary symbionts. Based on molecular screening results, only one type of secondary symbiont was present in G. brimblecombei populations in California. Overall, 40% of the 380 psyllids screened were infected with the secondary symbiont. Interestingly, secondary symbiont infection frequencies in G. brimblecombei populations varied dramatically from 0 to 75% and were significantly related to parasitism pressure by Psyllaphaegus bliteus, a solitary endoparasitoid of the psyllid. 相似文献
949.
Construction and Characterization of Shuttle Vectors for Succinic Acid-Producing Rumen Bacteria 总被引:2,自引:0,他引:2
下载免费PDF全文
![点击此处可从《Applied microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Yu-Sin Jang Young Ryul Jung Sang Yup Lee Ji Mahn Kim Jeong Wook Lee Doo-Byoung Oh Hyun Ah Kang Ohsuk Kwon Seh Hee Jang Hyohak Song Sang Jun Lee Kyu Young Kang 《Applied microbiology》2007,73(17):5411-5420
Shuttle vectors carrying the origins of replication that function in Escherichia coli and two capnophilic rumen bacteria, Mannheimia succiniciproducens and Actinobacillus succinogenes, were constructed. These vectors were found to be present at ca. 10 copies per cell. They were found to be stably maintained in rumen bacteria during the serial subcultures in the absence of antibiotic pressure for 216 generations. By optimizing the electroporation condition, the transformation efficiencies of 3.0 × 106 and 7.1 × 106 transformants/μg DNA were obtained with M. succiniciproducens and A. succinogenes, respectively. A 1.7-kb minimal replicon was identified that consists of the rep gene, four iterons, A+T-rich regions, and a dnaA box. It was found that the shuttle vector replicates via the theta mode, which was confirmed by sequence analysis and Southern hybridization. These shuttle vectors were found to be suitable as expression vectors as the homologous fumC gene encoding fumarase and the heterologous genes encoding green fluorescence protein and red fluorescence protein could be expressed successfully. Thus, the shuttle vectors developed in this study should be useful for genetic and metabolic engineering of succinic acid-producing rumen bacteria. 相似文献
950.
Characterization of DNA methylation change in stem cell marker genes during differentiation of human embryonic stem cells 总被引:5,自引:0,他引:5
Yeo S Jeong S Kim J Han JS Han YM Kang YK 《Biochemical and biophysical research communications》2007,359(3):536-542
Pluripotent human embryonic stem cells (hESCs) have the distinguishing feature of innate capacity to allow indefinite self-renewal. This attribute continues until specific constraints or restrictions, such as DNA methylation, are imposed on the genome, usually accompanied by differentiation. With the aim of utilizing DNA methylation as a sign of early differentiation, we probed the genomic regions of hESCs, particularly focusing on stem cell marker (SCM) genes to identify regulatory sequences that display differentiation-sensitive alterations in DNA methylation. We show that the promoter regions of OCT4 and NANOG, but not SOX2, REX1 and FOXD3, undergo significant methylation during hESCs differentiation in which SCM genes are substantially repressed. Thus, following exposure to differentiation stimuli, OCT4 and NANOG gene loci are modified relatively rapidly by DNA methylation. Accordingly, we propose that the DNA methylation states of OCT4 and NANOG sequences may be utilized as barometers to determine the extent of hESC differentiation. 相似文献