全文获取类型
收费全文 | 327篇 |
免费 | 19篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 12篇 |
2020年 | 2篇 |
2019年 | 13篇 |
2018年 | 5篇 |
2017年 | 4篇 |
2016年 | 7篇 |
2015年 | 13篇 |
2014年 | 22篇 |
2013年 | 19篇 |
2012年 | 31篇 |
2011年 | 23篇 |
2010年 | 17篇 |
2009年 | 18篇 |
2008年 | 20篇 |
2007年 | 17篇 |
2006年 | 20篇 |
2005年 | 15篇 |
2004年 | 11篇 |
2003年 | 19篇 |
2002年 | 15篇 |
2001年 | 6篇 |
2000年 | 2篇 |
1999年 | 4篇 |
1998年 | 3篇 |
1997年 | 5篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1989年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1983年 | 2篇 |
1979年 | 2篇 |
1951年 | 1篇 |
1948年 | 1篇 |
排序方式: 共有346条查询结果,搜索用时 15 毫秒
71.
Canario AV Rotllant J Fuentes J Guerreiro PM Rita Teodósio H Power DM Clark MS 《FEBS letters》2006,580(1):291-299
We report the identification, gene expression and biological activity of two parathyroid hormones (PTH; PTHA and PTHB), two PTH-related peptides (PTHrP; PTHrPA and PTHrPB) and a PTH-like ligand (PTH-L) with hybrid characteristics in puffer fishes (Takifugu rubripes and Tetraodon fluviatilis). Experimental data are consistent with PTH-L and PTHrPA having calciotropic activities equivalent, respectively, to tetrapod PTH and PTHrP. We hypothesise on the basis of phylogenetic and functional analysis that PTH-L could be a fish relic of an ancestral PTH/PTHrP gene. 相似文献
72.
Biochemical interactions among intercellular adhesion molecules expressed by airway epithelial cells
Intercellular adhesion between adjacent airway epithelial cells plays a critical role in maintaining the barrier function of the respiratory mucosa. In the current study, we examined the expression and interaction of cell surface adhesion molecules (E-cadherin, ICAM-1, and MUC1) and their intracellular binding partners (alpha-catenin, beta-catenin, gamma-catenin, and ezrin) in 16HBE14o-, HBE1, 1HAEo-, BEAS-2B, A549, and NCI-H292 human airway epithelial cells. Expression of E-cadherin and MUC1, both in whole cell lysates and biotinylated surface proteins, was observed in 16HBE14o-, HBE1, A549, and NCI-H292 cells, while ICAM-1 was detected only in NCI-H292. In contrast, alpha-, beta-, and gamma-catenin and ezrin were expressed in all of the cells. E-cadherin formed coimmunoprecipitation complexes with beta- and gamma-catenin, whereas MUC1 only associated with beta-catenin. ICAM-1, but not MUC1, coimmunoprecipitated with ezrin in NCI-H292 cells. We conclude that airway epithelial cell-cell adhesion involves a complex network of protein-protein interactions mediated by a diverse array of membrane-bound and cytosolic protein partners. 相似文献
73.
Angela G. Fowler‐Brown Gary G. Bennett Melody S. Goodman Christina C. Wee Giselle M. Corbie‐Smith Sherman A. James 《Obesity (Silver Spring, Md.)》2009,17(11):2106-2109
Adverse psychosocial exposures may partially drive the high rates of obesity among blacks. The objective of this study was to prospectively examine the relationship between perceived psychosocial stress and percent change in BMI among adult black men and women. We used data from 756 women and 416 men who were participants in the Pitt County Study, a community‐based, prospective cohort study of blacks in eastern North Carolina. Participants were aged 25–50 years of age on entry into the study in 1988 and follow‐up was obtained in 2001. Using multivariable linear regression, we calculated the adjusted mean percentage change in BMI over the follow‐up period for each tertile of baseline measures of the Perceived Stress Scale (low, medium, and high), adjusted for potential confounders. For black women, higher levels of psychosocial stress at baseline predicted higher adjusted percentage increase in BMI over the 13‐year follow‐up: low stress 12.0% (95% CI 9.6–14.4), medium stress 16.3% (95% CI 13.7–18.9), and high stress 15.5% (95% CI 13.1–17.8). For black men, perceived stress was not associated with percent BMI change. These data suggest that interventions targeting obesity in black women should consider the potential impact of emotional stress on weight change. 相似文献
74.
David Metzgar Darcie Baynes Christian J. Hansen Erin A. McDonough Daisy R. Cabrera Melody M. Ellorin Patrick J. Blair Kevin L. Russell Dennis J. Faix 《PloS one》2009,4(9)
Background
Group A Streptococcus pyogenes (GAS) exhibits a high degree of clinically relevant phenotypic diversity. Strains vary widely in terms of antibiotic resistance (AbR), clinical severity, and transmission rate. Currently, strain identification is achieved by emm typing (direct sequencing of the genomic segment coding for the antigenic portion of the M protein) or by multilocus genotyping methods. Phenotype analysis, including critical AbR typing, is generally achieved by much slower and more laborious direct culture-based methods.Methodology/Principal Findings
We compare genotype identification (by emm typing and PCR/ESI-MS) with directly measured phenotypes (AbR and outbreak associations) for 802 clinical isolates of GAS collected from symptomatic patients over a period of 6 years at 10 military facilities in the United States. All independent strain characterization methods are highly correlated. This shows that recombination, horizontal transfer, and other forms of reassortment are rare in GAS insofar as housekeeping genes, primary virulence and antibiotic resistance determinants, and the emm gene are concerned. Therefore, genotyping methods offer an efficient way to predict emm type and the associated AbR and virulence phenotypes.Conclusions/Significance
The data presented here, combined with much historical data, suggest that emm typing assays and faster molecular methods that infer emm type from genomic signatures could be used to efficiently infer critical phenotypic characteristics based on robust genotype: phenotype correlations. This, in turn, would enable faster and better-targeted responses during identified outbreaks of constitutively resistant or particularly virulent emm types. 相似文献75.
The Antarctic limpet, Nacella concinna, exhibits the classical heat shock response, with up-regulation of duplicated forms of the inducible heat shock protein 70
(HSP70) gene in response to experimental manipulation of seawater temperatures. However, this response only occurs in the
laboratory at temperatures well in excess of any experienced in the field. Subsequent environmental sampling of inter-tidal
animals also showed up-regulation of these genes, but at temperature thresholds much lower than those required to elicit a
response in the laboratory. It was hypothesised that this was a reflection of the complexity of the stresses encountered in
the inter-tidal region. Here, we describe a further series of experiments comprising both laboratory manipulation and environmental
sampling of N. concinna. We investigate the expression of HSP70 gene family members (HSP70A, HSP70B, GRP78 and HSC70) in response to a further suite
of environmental stressors: seasonal and experimental cold, freshwater, desiccation, chronic heat and periodic emersion. Lowered
temperatures (−1.9°C and −1.6°C), generally produced a down-regulation of all HSP70 family members, with some up-regulation
of HSC70 when emerging from the winter period and increasing sea temperatures. There was no significant response to freshwater
immersion. In response to acute and chronic heat treatments plus simulated tidal cycles, the data showed a clear pattern.
HSP70A showed a strong but very short-term response to heat whilst the duplicated HSP70B also showed heat to be a trigger,
but had a more sustained response to complex stresses. GRP78 expression indicates that it was acting as a generalised stress
response under the experimental conditions described here. HSC70 was the major chaperone invoked in response to long-term
stresses of varying types. These results provide intriguing clues not only to the complexity of HSP70 gene expression in response
to environmental change but also insights into the stress response of a non-model species. 相似文献
76.
Yung‐Hsiang Kao Daniel P. Hewitt Melody Trexler‐Schmidt Michael W. Laird 《Biotechnology and bioengineering》2010,107(4):622-632
We recently observed a significant disulfide reduction problem during the scale‐up of a manufacturing process for a therapeutic antibody using a CHO expression system. Under certain conditions, extensive reduction of inter‐chain disulfide bonds of an antibody produced by CHO cell culture may occur during the harvest operations and/or the protein A chromatography step, resulting in the observation of antibody fragments (light chain, heavy chain, and various combination of both) in the protein A pools. Although all conditions leading to disulfide reduction have not been completely identified, an excessive amount of mechanical cell lysis generated at the harvest step appears to be an important requirement for antibody reduction (Trexler‐Schmidt et al., 2010 ). We have been able to determine the mechanism by which the antibody is reduced despite the fact that not all requirements for antibody reduction were identified. Here we present data strongly suggesting that the antibody reduction was caused by a thioredoxin system or other reducing enzymes with thioredoxin‐like activity. The intracellular reducing enzymes and their substrates/cofactors apparently were released into the harvest cell culture fluid (HCCF) when cells were exposed to mechanical cell shear during harvest operations. Surprisingly, the reducing activity in the HCCF can last for a long period of time, causing the reduction of inter‐chain disulfide bonds in an antibody. Our findings provide a basis for designing methods to prevent the antibody reduction during the manufacturing process. Biotechnol. Bioeng. 2010;107:622–632. © 2010 Wiley Periodicals, Inc. 相似文献
77.
Carmen Bonvin Jan Overney Adrian C. Shieh J. Brandon Dixon Melody A. Swartz 《Biotechnology and bioengineering》2010,105(5):982-991
Interstitial flow is an important biophysical cue that can affect capillary morphogenesis, tumor cell migration, and fibroblast remodeling of the extracellular matrix, among others. Current models that incorporate interstitial flow and that are suitable for live imaging lack the ability to perform multiple simultaneous experiments, for example, to compare effects of growth factors, extracellular matrix composition, etc. We present a nine‐chamber radial flow device that allows simultaneous 3D fluidic experiments for relatively long‐term culture with live imaging capabilities. Flow velocity profiles were characterized by fluorescence recovery after photobleaching (FRAP) for flow uniformity and estimating the hydraulic conductivity. We demonstrate lymphatic and blood capillary morphogenesis in fibrin gels over 10 days, comparing flow with static conditions as well as the effects of an engineered variant of VEGF that binds fibrin via Factor XIII. We also demonstrate the culture of contractile fibroblasts and co‐cultures with tumor cells for modeling the tumor microenvironment. Therefore, this device is useful for studies of capillary morphogenesis, cell migration, contractile cells like fibroblasts, and multicellular cultures, all under interstitial flow. Biotechnol. Bioeng. 2010;105: 982–991. © 2009 Wiley Periodicals, Inc. 相似文献
78.
79.
Zilun Hu Xiangjun Jiang Charles F. Albright Nilsa Graciani Eddy Yue Mingzhu Zhang Shu-Yun Zhang Robert Bruckner Melody Diamond Randine Dowling Maria Rafalski Swamy Yeleswaram George L. Trainor Steven P. Seitz Wei Han 《Bioorganic & medicinal chemistry letters》2010,20(3):853-856
To selectively target doxorubicin (Dox) to tumor tissue and thereby improve the therapeutic index and/or efficacy of Dox, matrix metalloproteinases (MMP) activated peptide–Dox prodrugs were designed and synthesized by coupling MMP-cleavable peptides to Dox. Preferred conjugates were good substrates for MMPs, poor substrates for neprilysin, an off-target proteinase, and stable in blood ex vivo. When administered to mice with HT1080 xenografts, conjugates, such as 19, preferentially released Dox in tumor relative to heart tissue and prevented tumor growth with less marrow toxicity than Dox. 相似文献
80.
Brendan P. Flynn Amit P. Bhole Nima Saeidi Melody Liles Charles A. DiMarzio Jeffrey W. Ruberti 《PloS one》2010,5(8)