全文获取类型
收费全文 | 1547篇 |
免费 | 145篇 |
国内免费 | 1篇 |
专业分类
1693篇 |
出版年
2023年 | 10篇 |
2022年 | 26篇 |
2021年 | 42篇 |
2020年 | 20篇 |
2019年 | 34篇 |
2018年 | 32篇 |
2017年 | 28篇 |
2016年 | 42篇 |
2015年 | 68篇 |
2014年 | 81篇 |
2013年 | 88篇 |
2012年 | 103篇 |
2011年 | 122篇 |
2010年 | 72篇 |
2009年 | 65篇 |
2008年 | 71篇 |
2007年 | 95篇 |
2006年 | 48篇 |
2005年 | 63篇 |
2004年 | 65篇 |
2003年 | 68篇 |
2002年 | 63篇 |
2001年 | 29篇 |
2000年 | 33篇 |
1999年 | 33篇 |
1998年 | 18篇 |
1997年 | 16篇 |
1996年 | 14篇 |
1995年 | 10篇 |
1994年 | 17篇 |
1993年 | 5篇 |
1992年 | 18篇 |
1991年 | 10篇 |
1990年 | 9篇 |
1989年 | 15篇 |
1988年 | 17篇 |
1987年 | 15篇 |
1986年 | 8篇 |
1985年 | 12篇 |
1984年 | 8篇 |
1983年 | 11篇 |
1982年 | 11篇 |
1981年 | 12篇 |
1980年 | 7篇 |
1979年 | 10篇 |
1977年 | 5篇 |
1975年 | 4篇 |
1973年 | 9篇 |
1970年 | 4篇 |
1966年 | 3篇 |
排序方式: 共有1693条查询结果,搜索用时 15 毫秒
71.
Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. 总被引:7,自引:2,他引:7 下载免费PDF全文
Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a rare, autosomal recessive disease of unregulated insulin secretion, defined by elevations in serum insulin despite severe hypoglycemia. We used the homozygosity gene-mapping strategy to localize this disorder to the region of chromosome 11p between markers D11S1334 and D11S899 (maximum LOD score 5.02 [theta = 0] at marker D11S926) in five consanguineous families of Saudi Arabian origin. These results extend those of a recent report that also placed PHHI on chromosome 11p, between markers D11S926 and D11S928. Comparison of the boundaries of these two overlapping regions allows the PHHI locus to be assigned to the 4-cM region between the markers D11S926 and D11S899. Identification of this gene may allow a better understanding of other disorders of glucose homeostasis, by providing insight into the regulation of insulin release. 相似文献
72.
Data assimilation (DA) is increasingly being employed to estimate the parameters and states of terrestrial ecosystem models from eddy covariance measurements of net carbon (C) fluxes. The length of the observation time series used varies for each study. The impact of these differences has not been quantified explicitly. Therefore, in this study, we investigate the importance of the time series length relative to observation noise and data gaps. Different length synthetic time series are used to determine the parameter and C stocks of a simple ecosystem C model. Two commonly used DA schemes are tested: the sequential Ensemble Kalman Filter (EnKF) and a batch Metropolis Markov chain Monte Carlo algorithm. Longer time series improve both the parameter and C pool estimates of the EnKF, while adversely affecting those of the Metropolis algorithm. For both DA approaches, the length of the time series has more influence on the parameter and pool estimates than the level of random noise or amount of data. In this study, the EnKF provides more robust parameter and C pool estimates than the Metropolis algorithm. Optimized parameters and states are often used as the basis for forecasting future responses. Despite having better parameter and C pool estimates, EnKF forecasts estimates have much larger uncertainties than the Metropolis algorithm forecast estimates. Finally, we suggest that the structure of simple box models, as used in this study, introduces a large degree of equifinality into DA. Neither DA scheme correctly accounts for the equifinality, but our results suggest that it is particularly problematic for the batch Metropolis algorithm. 相似文献
73.
Cyclic di-GMP (c-di-GMP), a ubiquitous bacterial second messenger, has emerged as a key controller of several biological processes. Numbers of reports that deal with the mechanistic aspects of this second messenger have appeared in the literature. However, the lack of a reporter tag attached to the c-di-GMP at times limits the understanding of further details. In this study, we have chemically coupled N-methylisatoic anhydride (MANT) with c-di-GMP, giving rise to Mant-(c-di-GMP) or MANT-CDG. We have characterized the chemical and physical properties and spectral behavior of MANT-CDG. The fluorescence of MANT-CDG is sensitive to changes in the microenvironment, which helped us study its interaction with three different c-di-GMP binding proteins (a diguanylate cyclase, a phosphodiesterase, and a PilZ domain-containing protein). In addition, we have shown here that MANT-CDG can inhibit diguanylate cyclase activity; however, it is hydrolyzed by c-di-GMP specific phosphodiesterase. Taken together, our data suggest that MANT-CDG behaves like native c-di-GMP, and this study raises the possibility that MANT-CDG will be a valuable research tool for the in vitro characterization of c-di-GMP signaling factors. 相似文献
74.
Chang Gong Ziliang Cheng Yaping Yang Jun Shen Yingying Zhu Li Ling Wanyi Lin Zhigang Yu Zhihua Li Weige Tan Chushan Zheng Wenbo Zheng Jiajie Zhong Xiang Zhang Yunjie Zeng Qiang Liu R.Stephanie Huang Andrzej L.Komorowski Eddy S.Yang Fran?ois Bertucci Francesco Ricci Armando Orlandi Gianluca Franceschini Kazuaki Takabe Suzanne Klimberg Naohiro Ishii Angela Toss Mona P.Tan Mathew A Cherian Erwei Song 《中国科学:生命科学英文版》2022,65(11):2205-2217
Patients with hormone receptor(HR)-positive tumors breast cancer usually experience a relatively low pathological complete response(p CR) to neoadjuvant chemotherapy(NAC). Here, we derived a 10-micro RNA risk score(10-mi RNA RS)-based model with better performance in the prediction of p CR and validated its relation with the disease-free survival(DFS) in 755 HRpositive breast cancer patients(273, 265, and 217 in the training, internal, and external validation sets, respectively). This model,pres... 相似文献
75.
Feng D Fisher M Liang GB Qian X Brown C Gurnett A Leavitt PS Liberator PA Mathew J Misura A Samaras S Tamas T Schmatz DM Wyvratt M Biftu T 《Bioorganic & medicinal chemistry letters》2006,16(23):5978-5981
Compounds 10a-10d and 10i are very potent inhibitors of Eimeria tenella cGMP-dependent protein kinase (0.081-0.32 nM) and are very efficacious antiparasitic agents in vivo when administered to chickens at 12.5-25 ppm levels in the feed. 相似文献
76.
Heat Shock Response and Protein Degradation: Regulation of HSF2 by the Ubiquitin-Proteasome Pathway 总被引:8,自引:3,他引:8 下载免费PDF全文
Anu Mathew Sameer K. Mathur Richard I. Morimoto 《Molecular and cellular biology》1998,18(9):5091-5098
Mammalian cells coexpress a family of heat shock factors (HSFs) whose activities are regulated by diverse stress conditions to coordinate the inducible expression of heat shock genes. Distinct from HSF1, which is expressed ubiquitously and activated by heat shock and other stresses that result in the appearance of nonnative proteins, the stress signal for HSF2 has not been identified. HSF2 activity has been associated with development and differentiation, and the activation properties of HSF2 have been characterized in hemin-treated human K562 erythroleukemia cells. Here, we demonstrate that a stress signal for HSF2 activation occurs when the ubiquitin-proteasome pathway is inhibited. HSF2 DNA-binding activity is induced upon exposure of mammalian cells to the proteasome inhibitors hemin, MG132, and lactacystin, and in the mouse ts85 cell line, which carries a temperature sensitivity mutation in the ubiquitin-activating enzyme (E1) upon shift to the nonpermissive temperature. HSF2 is labile, and its activation requires both continued protein synthesis and reduced degradation. The downstream effect of HSF2 activation by proteasome inhibitors is the induction of the same set of heat shock genes that are induced during heat shock by HSF1, thus revealing that HSF2 affords the cell with a novel heat shock gene-regulatory mechanism to respond to changes in the protein-degradative machinery. 相似文献
77.
78.
Jobin Mathew Savitha Balakrishnan Sherin Antony Pretty Mary Abraham CS Paulose 《Journal of biomedical science》2012,19(1):25
Abstact
Background
Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue.Methods
In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated.Results
Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAAά1, GABAAγ, GABAAδ, GABAB and GAD where down regulated (P < 0.001) in epileptic rats. GABAAά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance.Conclusions
Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management. 相似文献79.
80.
Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites 总被引:1,自引:0,他引:1
Gioeli D Ficarro SB Kwiek JJ Aaronson D Hancock M Catling AD White FM Christian RE Settlage RE Shabanowitz J Hunt DF Weber MJ 《The Journal of biological chemistry》2002,277(32):29304-29314
Activation of signal transduction kinase cascades has been shown to alter androgen receptor (AR) activity. Although it has been suggested that changes in AR phosphorylation might be directly responsible, the basal and regulated phosphorylations of the AR have not been fully determined. We have identified the major sites of AR phosphorylation on ARs expressed in COS-1 cells using a combination of peptide mapping, Edman degradation, and mass spectrometry. We describe the identification of seven AR phosphorylation sites, show that the phosphopeptides seen with exogenously expressed ARs are highly similar to those seen with endogenous ARs in LNCaP cells and show that specific agonists differentially regulate the phosphorylation state of endogenous ARs in LNCaP prostate cancer cells. Treatment of LNCaP cells with the synthetic androgen, R1881, elevates phosphorylation of serines 16, 81, 256, 308, 424, and 650. Ser-94 appears constitutively phosphorylated. Forskolin, epidermal growth factor, and phorbol 12-myristate 13-acetate increase the phosphorylation of Ser-650. The kinetics of phosphorylation of most sites in response to hormone or forskolin is temporally delayed, reaching a maximum at 2 h post-stimulation. The exception is Ser-81, which continues to display increasing phosphorylation at 6 h. These data provide a basis for analyzing mechanisms of cross-talk between growth factor signaling and androgen in prostate development, physiology, and cancer. 相似文献