全文获取类型
收费全文 | 666篇 |
免费 | 71篇 |
国内免费 | 1篇 |
出版年
2023年 | 5篇 |
2022年 | 6篇 |
2021年 | 11篇 |
2020年 | 8篇 |
2019年 | 8篇 |
2018年 | 14篇 |
2017年 | 12篇 |
2016年 | 13篇 |
2015年 | 33篇 |
2014年 | 41篇 |
2013年 | 33篇 |
2012年 | 39篇 |
2011年 | 37篇 |
2010年 | 24篇 |
2009年 | 16篇 |
2008年 | 33篇 |
2007年 | 31篇 |
2006年 | 35篇 |
2005年 | 31篇 |
2004年 | 28篇 |
2003年 | 19篇 |
2002年 | 22篇 |
2001年 | 14篇 |
2000年 | 16篇 |
1999年 | 11篇 |
1998年 | 8篇 |
1996年 | 3篇 |
1993年 | 3篇 |
1992年 | 13篇 |
1991年 | 14篇 |
1990年 | 5篇 |
1989年 | 16篇 |
1988年 | 11篇 |
1987年 | 7篇 |
1986年 | 10篇 |
1985年 | 8篇 |
1984年 | 3篇 |
1983年 | 7篇 |
1981年 | 6篇 |
1980年 | 3篇 |
1979年 | 7篇 |
1978年 | 4篇 |
1976年 | 5篇 |
1975年 | 8篇 |
1974年 | 14篇 |
1973年 | 9篇 |
1972年 | 7篇 |
1971年 | 3篇 |
1970年 | 7篇 |
1968年 | 3篇 |
排序方式: 共有738条查询结果,搜索用时 359 毫秒
91.
Yip DJ Corcoran CP Alvarez-Saavedra M DeMaria A Rennick S Mears AJ Rudnicki MA Messier C Picketts DJ 《Developmental cell》2012,22(4):871-878
Balancing progenitor cell self-renewal and differentiation is essential for brain development and is regulated by the activity of chromatin remodeling complexes. Nevertheless, linking chromatin changes to specific pathways that control cortical histogenesis remains a challenge. Here we identify a genetic interaction between the chromatin remodeler Snf2l and Foxg1, a key regulator of neurogenesis. Snf2l mutant mice exhibit forebrain hypercellularity arising from increased Foxg1 expression, increased progenitor cell expansion, and delayed differentiation. We demonstrate that Snf2l binds to the Foxg1 locus at midneurogenesis and that the phenotype is rescued by reducing Foxg1 dosage, thus revealing that Snf2l and Foxg1 function antagonistically to regulate brain size. 相似文献
92.
Tang CS Cheng G So MT Yip BH Miao XP Wong EH Ngan ES Lui VC Song YQ Chan D Cheung K Yuan ZW Lei L Chung PH Liu XL Wong KK Marshall CR Scherer SW Scherer S Cherny SS Sham PC Tam PK Garcia-Barceló MM 《PLoS genetics》2012,8(5):e1002687
Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs) to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified NRG1 as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs (p = 1.50 × 10(-5)), particularly for those encompassing genes (p = 5.00 × 10(-6)). Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (p = 1.64 × 10(-3)). Subsequent follow-up (96 additional patients and 220 controls) on NRG3 revealed 9 deletions (combined p = 3.36 × 10(-5)) and 2 de novo duplications among patients and two deletions among controls. Importantly, NRG3 is a paralog of NRG1. Stratification of patients by presence/absence of HSCR-associated syndromes showed that while syndromic-HSCR patients carried significantly longer CNVs than the non-syndromic or controls (p = 1.50 × 10(-5)), non-syndromic patients were enriched in CNV number when compared to controls (p = 4.00 × 10(-6)) or the syndromic counterpart. Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR. 相似文献
93.
94.
Yen-Ching Chen Ping-Keung Yip Yi-Ling Huang Yu Sun Li-Li Wen Yi-Min Chu Ta-Fu Chen 《PloS one》2012,7(12)
Background
Toll like receptor 4 (TLR4) has been related to inflammation and beta-amyloid deposition in Alzheimer''s disease (AD) brain. No study has explored the association between haplotype-tagging single nucleotide polymorphisms (htSNPs) of TLR4 and AD risk previously and ApoE e4 status alone showed low sensitivity in identifying late-onset AD (LOAD) patients.Methods
A total of 269 LOAD patients were recruited from three hospitals in northern Taiwan (2007–2010). Controls (n = 449) were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) TLR4 htSNPs were selected to assess the association between TLR4 polymorphisms and the risk of LOAD in the Chinese ethnic population.Results
Homozygosity of TLR4 rs1927907 was significantly associated with an increased risk of LOAD [TT vs. CC: adjusted odds ratio (AOR) = 2.45, 95% confidence interval (CI) = 1.30–4.64]. After stratification, the association increased further in ApoE e4 non-carriers (AOR = 3.07) and in hypertensive patients (AOR = 3.60). Haplotype GACGG was associated with a decreased risk of LOAD (1 vs. 0 copies: AOR = 0.59, 95% CI = 0.36–0.96; 2 vs. 0 copies: AOR = 0.31, 95% CI = 0.14–0.67) in ApoE e4 non-carriers. ApoE e4 status significantly modified this association (p interaction = 0.01). These associations remained significant after correction for multiple tests.Conclusions
Sequence variants of TLR4 were associated with an increased risk of LOAD, especially in ApoE e4 non-carriers and in hypertensive patients. The combination of TLR4 rs1927907 and ApoE e4 significantly increased the screening sensitivity in identifying LOAD patients from 0.4 to 0.7. 相似文献95.
Yip SC Eddy RJ Branch AM Pang H Wu H Yan Y Drees BE Neilsen PO Condeelis J Backer JM 《The Biochemical journal》2008,411(2):441-448
Class IA PI3Ks (phosphoinositide 3-kinases) generate the secondary messenger PtdIns(3,4,5)P(3), which plays an important role in many cellular responses. The accumulation of PtdIns(3,4,5)P(3) in cell membranes is routinely measured using GFP (green fluorescent protein)-labelled PH (pleckstrin homology) domains. However, the kinetics of membrane PtdIns(3,4,5)P(3) synthesis and turnover as detected by PH domains have not been validated using an independent method. In the present study, we measured EGF (epidermal growth factor)-stimulated membrane PtdIns(3,4,5)P(3) production using a specific monoclonal anti-PtdIns(3,4,5)P(3) antibody, and compared the results with those obtained using PH-domain-dependent methods. Anti-PtdIns(3,4,5)P(3) staining rapidly accumulated at the leading edge of EGF-stimulated carcinoma cells. PtdIns(3,4,5)P(3) levels were maximal at 1 min, and returned to basal levels by 5 min. In contrast, membrane PtdIns(3,4,5)P(3) production, measured by the membrane translocation of an epitope-tagged (BTK)PH (PH domain of Bruton's tyrosine kinase), remained approx. 2-fold above basal level throughout 4-5 min of EGF stimulation. To determine the reason for this disparity, we measured the rate of PtdIns(3,4,5)P(3) hydrolysis by measuring the decay of the PtdIns(3,4,5)P(3) signal after LY294002 treatment of EGF-stimulated cells. LY294002 abolished anti-PtdIns(3,4,5)P(3) membrane staining within 10 s of treatment, suggesting that PtdIns(3,4,5)P(3) turnover occurs within seconds of synthesis. In contrast, (BTK)PH membrane recruitment, once initiated by EGF, was relatively insensitive to LY294002. These data suggest that sequestration of PtdIns(3,4,5)P(3) by PH domains may affect the apparent kinetics of PtdIns(3,4,5)P(3) accumulation and turnover; consistent with this hypothesis, we found that GRP-1 (general receptor for phosphoinositides 1) PH domains [which, like BTK, are specific for PtdIns(3,4,5)P(3)] inhibit PTEN (phosphatase and tensin homologue deleted on chromosome 10) dephosphorylation of PtdIns(3,4,5)P(3) in vitro. These data suggest that anti-PtdIns(3,4,5)P(3) antibodies are a useful tool to detect localized PtdIns(3,4,5)P(3), and illustrate the importance of using multiple approaches for the estimation of membrane phosphoinositides. 相似文献
96.
Bauhinia blakeana Dunn is the Hong Kong Special Administrative Region emblem and a popular horticultural species in many Asian countries. It was first described as a new species from Hong Kong almost a century ago. This plant is sterile and has long been considered a hybrid, possibly from two related species, B. purpurea and B. variegata. However, not much evidence based on molecular methods was available to support this hypothesis. In this study, sequences of internal transcribed spacer I (ITS1), rbcL and atpB-rbcL intergenic spacer for five Bauhinia species and two varieties of one of the species were determined and compared. There were two types of ITS1 sequences in B. blakeana, one indistinguishable from that of B. purpurea and the other one identical to that of B. variegata. This confirmed that B. blakeana was a hybrid of these two species. Chloroplast atpB-rbcL intergenic spacer sequence of B. blakeana was identical to that of B. purpurea, indicating that B. purpurea was the female parent. The hybridization event seemed to occur only recently and was a rare incident. Its occurrence was likely facilitated by interspecific pollen competition. It appeared that human efforts played a crucial role in the preservation and ubiquity of B. blakeana. 相似文献
97.
Toh GT Kang P Lee SS Lee DS Lee SY Selamat S Mohd Taib NA Yoon SY Yip CH Teo SH 《PloS one》2008,3(4):e2024
Background
In Asia, breast cancer is characterised by an early age of onset: In Malaysia, approximately 50% of cases occur in women under the age of 50 years. A proportion of these cases may be attributable, at least in part, to genetic components, but to date, the contribution of genetic components to breast cancer in many of Malaysia''s ethnic groups has not been well-characterised.Methodology
Given that hereditary breast carcinoma is primarily due to germline mutations in one of two breast cancer susceptibility genes, BRCA1 and BRCA2, we have characterised the spectrum of BRCA mutations in a cohort of 37 individuals with early-onset disease (≤40 years) and no reported family history. Mutational analysis of BRCA1 and BRCA2 was conducted by full sequencing of all exons and intron-exon junctions.Conclusions
Here, we report a total of 14 BRCA1 and 17 BRCA2 sequence alterations, of which eight are novel (3 BRCA1 and 5 BRCA2). One deleterious BRCA1 mutation and 2 deleterious BRCA2 mutations, all of which are novel mutations, were identified in 3 of 37 individuals. This represents a prevalence of 2.7% and 5.4% respectively, which is consistent with other studies in other Asian ethnic groups (4–9%). 相似文献98.
RhoA/ROCK-mediated switching between Cdc42- and Rac1-dependent protrusion in MTLn3 carcinoma cells 总被引:1,自引:0,他引:1
El-Sibai M Pertz O Pang H Yip SC Lorenz M Symons M Condeelis JS Hahn KM Backer JM 《Experimental cell research》2008,314(7):1540-1552
Rho GTPases are versatile regulators of cell shape that act on the actin cytoskeleton. Studies using Rho GTPase mutants have shown that, in some cells, Rac1 and Cdc42 regulate the formation of lamellipodia and filopodia, respectively at the leading edge, whereas RhoA mediates contraction at the rear of moving cells. However, recent reports have described a zone of RhoA/ROCK activation at the front of cells undergoing motility. In this study, we use a FRET-based RhoA biosensor to show that RhoA activation localizes to the leading edge of EGF-stimulated cells. Inhibition of Rho or ROCK enhanced protrusion, yet markedly inhibited cell motility; these changes correlated with a marked activation of Rac-1 at the cell edge. Surprisingly, whereas EGF-stimulated protrusion in control MTLn3 cells is Rac-independent and Cdc42-dependent, the opposite pattern is observed in MTLn3 cells after inhibition of ROCK. Thus, Rho and ROCK suppress Rac-1 activation at the leading edge, and inhibition of ROCK causes a switch between Cdc42 and Rac-1 as the dominant Rho GTPase driving protrusion in carcinoma cells. These data describe a novel role for Rho in coordinating signaling by Rac and Cdc42. 相似文献
99.
Summary . We derive estimates of the minimum capture proportion required to obtain a reliable estimate of the population size for several continuous and discrete-time capture–recapture models. The models considered are , and in the notation of Otis et al. , (1978, Wildlife Monograph 62 , 1–135). Numerical results with simulation studies are given, and two real examples for the model are also considered. Potential applications of these results are suggested. 相似文献
100.
Balasubramanian L Yip KP Hsu TH Lo CM 《American journal of physiology. Cell physiology》2008,295(4):C954-C965
Impedance of renal vascular smooth muscle cells (VSMCs) cultured on microelectrodes was measured by electric cell-substrate impedance sensing. Changes in measured impedance as a function of frequency were compared with the calculated values obtained from an extended cell-electrode model to estimate the junctional resistance, distance between the ventral cell surface and the substratum, and apical and basolateral membrane capacitances of renal VSMCs. This cell-electrode model was derived to accommodate the slender and rectangular shape of VSMCs. The calculated changes in impedance (Zcal) based on the model agreed well with the experimental measurement (Zexp), and the percentage error defined as |(Zcal – Zexp)/Zexp| was 1.0%. To test the sensitivity of the new model for capturing changes in cell-cell and cell-substrate interactions induced by changes in cellular environment, we then applied this model to analyze timpedance changes induced by an integrin binding peptide in renal VSMCs. Our result demonstrates that integrin binding peptide decreases junctional resistance between cells, increases the distance between the basolateral cell surface and substratum, and increases the apical membrane capacitance, whereas the basolateral membrane capacitance stays relatively stable. This model provides a generic approach for impedance analysis of cell layers composed of slender, rectangular cells. electric cell-substrate impedance sensing; cell attachment; cell adhesion; extracellular matrix; integrin 相似文献