全文获取类型
收费全文 | 3393篇 |
免费 | 194篇 |
国内免费 | 5篇 |
专业分类
3592篇 |
出版年
2024年 | 9篇 |
2023年 | 11篇 |
2022年 | 49篇 |
2021年 | 66篇 |
2020年 | 46篇 |
2019年 | 68篇 |
2018年 | 111篇 |
2017年 | 71篇 |
2016年 | 137篇 |
2015年 | 192篇 |
2014年 | 218篇 |
2013年 | 243篇 |
2012年 | 304篇 |
2011年 | 275篇 |
2010年 | 191篇 |
2009年 | 182篇 |
2008年 | 219篇 |
2007年 | 189篇 |
2006年 | 139篇 |
2005年 | 142篇 |
2004年 | 112篇 |
2003年 | 111篇 |
2002年 | 82篇 |
2001年 | 72篇 |
2000年 | 82篇 |
1999年 | 53篇 |
1998年 | 17篇 |
1997年 | 17篇 |
1996年 | 11篇 |
1995年 | 14篇 |
1994年 | 5篇 |
1993年 | 9篇 |
1992年 | 13篇 |
1991年 | 15篇 |
1990年 | 17篇 |
1989年 | 14篇 |
1988年 | 7篇 |
1986年 | 5篇 |
1985年 | 8篇 |
1983年 | 7篇 |
1982年 | 3篇 |
1978年 | 3篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1972年 | 2篇 |
1969年 | 3篇 |
1954年 | 2篇 |
1952年 | 10篇 |
1951年 | 11篇 |
1950年 | 8篇 |
排序方式: 共有3592条查询结果,搜索用时 15 毫秒
991.
Saccharomyces cerevisiae Mph1 is a 3-5' DNA helicase, required for the maintenance of genome integrity. In order to understand the ATPase/helicase role of Mph1 in genome stability, we characterized its helicase activity with a variety of DNA substrates, focusing on its action on junction structures containing three or four DNA strands. Consistent with its 3' to 5' directionality, Mph1 displaced 3'-flap substrates in double-fixed or equilibrating flap substrates. Surprisingly, Mph1 displaced the 5'-flap strand more efficiently than the 3' flap strand from double-flap substrates, which is not expected for a 3-5' DNA helicase. For this to occur, Mph1 required a threshold size (>5 nt) of 5' single-stranded DNA flap. Based on the unique substrate requirements of Mph1 defined in this study, we propose that the helicase/ATPase activity of Mph1 play roles in converting multiple-stranded DNA structures into structures cleavable by processing enzymes such as Fen1. We also found that the helicase activity of Mph1 was used to cause structural alterations required for restoration of replication forks stalled due to damaged template. The helicase properties of Mph1 reported here could explain how it resolves D-loop structure, and are in keeping with a model proposed for the error-free damage avoidance pathway. 相似文献
992.
Seo JB Park SW Choe SS Jeong HW Park JY Choi EW Seen DS Jeong JY Lee TG 《Biochemical and biophysical research communications》2012,417(2):800-806
We have previously reported anti-obesity effects of Lysimachia foenum-graecum in high-fat diet (HFD)-induced obesity model. Here we isolated a triterpene saponin foenumoside B as an active component of L. foenum-graecum. Foenumoside B blocked the differentiation of 3T3-L1 preadipocytes in a dose-dependent manner with an IC50 of 0.2 μg/ml in adipogenesis assay and suppressed the induction of PPARγ, the master regulator of adipogenesis. Foenumoside B induced the activation of AMP-activated protein kinase (AMPK), and modulated the expression of genes involved in lipid metabolism towards lipid breakdown in differentiated adipocytes. In mouse model, oral administration of foenumoside B (10mg/kg/day for 6 weeks) reduced HFD-induced body weight gain significantly without affecting food intake. Treatment of foenumoside B suppressed lipid accumulation in white adipose tissues and the liver, and lowered blood levels of glucose, triglycerides, ALT, and AST in HFD-induced obese mice. Consistent with the in vitro results, foenumoside B activated AMPK signaling, suppressed the expression of lipogenic genes, and enhanced the expression of lipolytic genes in vivo. Foenumoside B also blocked HFD-induced proinflammatory cytokine production in adipose tissue, suggesting its protective role against insulin resistance. Taken together, these findings demonstrate that foenumoside B represents the anti-obesity effects of L. foenum-graecum, and suggest therapeutic potential of foenumoside B in obesity and obesity-related metabolic diseases. 相似文献
993.
Shin YC Yoon JH Jang TH Kim SY Do Heo W So I Jeon JH Park HH 《Biochemical and biophysical research communications》2012,424(2):269-273
The Ras small G protein-superfamily is a family of GTP hydrolases whose activity is regulated by GTP/GDP binding states. Rab6A, a member of the Ras superfamily, is involved in the regulation of vesicle trafficking, which is critical for endocytosis, biosynthesis, secretion, cell differentiation and cell growth. Rab6A exists in two isoforms, termed RabA and Rab6A′. Substitution of Gln72 to Leu72 (Q72L) at Rab6 family blocks GTP hydrolysis activity and this mutation usually causes the Rab6 protein to be constitutively in an active form. Here, we report the crystal structure of the human Rab6A′(Q72L) mutant form at 1.9 Å resolution. Unexpectedly, we found that Rab6A′(Q72L) possesses GDP/Mg2+ in the GTP binding pockets, which is formed by a flexible switch I and switch II. Large conformational changes were also detected in the switch I and switch II regions. Our structure revealed that the non-hydrolysable, constitutively active form of Rab6A′ can accommodate GDP/Mg2+ in the open conformation. 相似文献
994.
Biological systems designs require various dynamic controllers capable of modulating cellular phenotypes to adapt to changing environments. Cellular phenotypes are simultaneously affected by combinations of multiple genes that are controlled by global regulators. However, it is difficult to intentionally control the expression of these global regulators dynamically because they are essential for cell survival and are involved in regulatory networks clustered in operons. Here, we designed a platform that allows dynamic modulation of the expression of an essential gene. Using this system, comprising of on/off switches that respond to an extracellular stimulus, we successfully demonstrated the switching control of the expression of fusA encoding elongation factor G (EF-G). An additional control module in this system that responds to changed external signals was shown to provide the capacity to "switch gears" and reprogram cellular phenotypes with desired timing. 相似文献
995.
Background aimsNiemann–Pick disease type C1 (NPC) is an autosomal recessive cholesterol-storage disorder characterized by liver dysfunction, hepatosplenomegaly and progressive neurodegeneration. Thus far, studies of NPC mice have been performed mainly to study the brain and neurodegeneration, because degeneration in the brain was known as the primary cause of death in NPC mice. However, NPC is a systemic disease; therefore the purpose of this study was to find the possibility of a general therapeutic effect by applying and tracking transplanted human amniotic epithelial stem cells (hAESC) in NPC miceMethodshAESC were administered to NPC homozygous (NPC–/–) mice via intravenous injection from 5 weeks of age; each recipient received 5 × 105 cells every other week. The body weight of each of the mice was measured every week, and the survival and state of each mouse was evaluated every day. The weight of the organs was measured, and serum chemistry, histology and the intensity of Filipin staining were evaluatedResultsThe effect of cell transplantation was to extend the life span and reduce the rapid loss of weight. Moreover, alleviation of tissue damage was observed more in hAESC-treated NPC–/– mice than in non-treated NPC–/– mice. Cholesterol deposition was reduced after transplantation, and the relative weight of the liver was also decreasedConclusionsThese data show that hAESC could delay the degeneration caused by fatal genetic disorders such as NPC. This study presents the prospect of relief of precipitous disease progression and the therapeutic possibility of applying hAESC to fatal genetic disorders. 相似文献
996.
Kwon J Han E Bui CB Shin W Lee J Lee S Choi YB Lee AH Lee KH Park C Obin MS Park SK Seo YJ Oh GT Lee HW Shin J 《EMBO reports》2012,13(2):150-156
Sqstm1/p62 functions in the non-canonical activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, its physiological relevance is not certain. Here, we show that p62(-/-) mice exhibited an accelerated presentation of ageing phenotypes, and tissues from these mice created a pro-oxidative environment owing to compromised mitochondrial electron transport. Accordingly, mitochondrial function rapidly declined with age in p62(-/-) mice. In addition, p62 enhanced basal Nrf2 activity, conferring a higher steady-state expression of NAD(P)H dehydrogenase, quinone 1 (Nqo1) to maintain mitochondrial membrane potential and, thereby, restrict excess oxidant generation. Together, the p62-Nrf2-Nqo1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity. 相似文献
997.
998.
Kwang-Kuk Park Song-I Yang Kyung-Won Seo Young-Ok Kim Ki-Young Yoon 《World journal of surgical oncology》2012,10(1):1-3
Intramuscular myxoma is a rare benign soft tissue tumor which may be mistaken for other benign and low-grade malignant myxoid neoplasms. We present the case of a 63-year-old woman with an asymptomatic intramuscular myxoma discovered incidentally on a whole-body F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography. PET images showed a mild FDG uptake (maximum standardized uptake value, 1.78) in the left gluteus maximus. Subsequent magnetic resonance (MR) imaging revealed a well-defined ovoid mass with homogenous low signal intensity on T1-weighted sequences and markedly high signal intensity on T2-weighted sequences. Contrast-enhanced MR images showed heterogeneous enhancement throughout the mass. The diagnosis of intramuscular myxoma was confirmed on histopathology after surgical excision of the tumor. The patient had no local recurrence at one year follow-up. Our case suggests that intramuscular myxoma should be considered in the differential diagnosis of an oval-shaped intramuscular soft tissue mass with a mild FDG uptake. 相似文献
999.
Lee S Lee SY Park S Ryu JH Na JH Koo H Lee KE Jeon H Kwon IC Kim K Jeong SY 《Macromolecular bioscience》2012,12(6):849-856
To optimize tumor targetability of nanosized liposomes for application as drug carriers, various liposomes are prepared by incorporating different amounts (10, 30, and 50?wt%) of cationic, anionic, and PEGylated lipids into neutral lipid. In vivo near-infrared fluorescence images reveal that PEG-PE/PC liposomes display high tumor accumulation in tumor-bearing mice, while large amounts of DOTAP/PC liposomes are rapidly captured in the liver, resulting in poor tumor accumulation. These results demonstrate that optimization of the surface properties of liposomes is very important for their tumor targetability, and that in vivo imaging techniques are useful in developing and optimizing nanosized liposome-based drug carriers. 相似文献
1000.
PurposeStudies that analyzed single nucleotide polymorphisms (SNP) in various genes have shown that genetic factors are strongly associated with age-related macular degeneration (AMD) susceptibility. Copy number variation (CNV) may be an additional type of genetic variation that contributes to AMD pathogenesis. This study investigated CNV in 4 AMD-relevant genes in Korean AMD patients and control subjects.MethodsFour CNV candidate regions located in AMD-relevant genes (VEGFA, ARMS2/HTRA1, CFH and VLDLR), were selected based on the outcomes of our previous study which elucidated common CNVs in the Asian populations. Real-time PCR based TaqMan Copy Number Assays were performed on CNV candidates in 273 AMD patients and 257 control subjects.ResultsThe predicted copy number (PCN, 0, 1, 2 or 3+) of each region was called using the CopyCaller program. All candidate genes except ARMS2/HTRA1 showed CNV in at least one individual, in which losses of VEGFA and VLDLR represent novel findings in the Asian population. When the frequencies of PCN were compared, only the gain in VLDLR showed significant differences between AMD patients and control subjects (p = 0.025). Comparisons of the raw copy values (RCV) revealed that 3 of 4 candidate genes showed significant differences (2.03 vs. 1.92 for VEGFA, p<0.01; 2.01 vs. 1.97 for CFH, p<0.01; 1.97 vs. 2.01, p<0.01 for ARMS2/HTRA1).ConclusionCNVs located in AMD-relevant genes may be associated with AMD susceptibility. Further investigations encompassing larger patient cohorts are needed to elucidate the role of CNV in AMD pathogenesis. 相似文献