全文获取类型
收费全文 | 164篇 |
免费 | 4篇 |
出版年
2022年 | 2篇 |
2021年 | 3篇 |
2019年 | 2篇 |
2018年 | 1篇 |
2017年 | 1篇 |
2016年 | 4篇 |
2015年 | 1篇 |
2014年 | 7篇 |
2013年 | 4篇 |
2012年 | 16篇 |
2011年 | 14篇 |
2010年 | 6篇 |
2009年 | 9篇 |
2008年 | 15篇 |
2007年 | 12篇 |
2006年 | 16篇 |
2005年 | 10篇 |
2004年 | 10篇 |
2003年 | 9篇 |
2002年 | 10篇 |
2001年 | 3篇 |
1999年 | 2篇 |
1995年 | 3篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1984年 | 2篇 |
1981年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
排序方式: 共有168条查询结果,搜索用时 15 毫秒
91.
The Maillard reaction is a complex network of reactions that has been shown to result in the non-enzymatic crosslinking of proteins. Recent attention has focussed on the role of alpha-dicarbonyl compounds as important in vivo contributors to protein crosslinking but, despite extensive research, the molecular mechanisms of the crosslinking reaction remain open to conjecture. In particular, no relationship between the structure of the carbonyl-containing compounds and their activity as crosslinking agents has been established. In an effort to elucidate a structure-reactivity relationship, a wide range of dicarbonyl compounds, including linear, cyclic, di-aldehyde and di-ketone compounds, were reacted with the model protein ribonuclease A and their crosslinking activity assessed. Methylglyoxal and glutaraldehyde were found to be the most efficient crosslinkers, whilst closely related molecules effected crosslinking at a much lower rate. Cyclopentan-1,2-dione was also shown to be a reactive crosslinking agent. The efficiency of methylglyoxal and glutaraldehyde at crosslinking is thought to be related to their ability to form stable heterocyclic compounds that are the basis of protein crosslinks. The reasons for the striking reactivity of these two compounds, compared to closely related structures is explained by subtle balances between competing pathways in a complex reaction network. 相似文献
92.
93.
Jeong JY Einhorn Z Mathur P Chen L Lee S Kawakami K Guo S 《Development (Cambridge, England)》2007,134(1):127-136
The forebrain constitutes the most anterior part of the central nervous system, and is functionally crucial and structurally conserved in all vertebrates. It includes the dorsally positioned telencephalon and eyes, the ventrally positioned hypothalamus, and the more caudally located diencephalon [from rostral to caudal: the prethalamus, the zona limitans intrathalamica (ZLI), the thalamus and the pretectum]. Although antagonizing Wnt proteins are known to establish the identity of the telencephalon and eyes, it is unclear how various subdivisions are established within the diencephalon--a complex integration center and relay station of the vertebrate brain. The conserved forebrain-specific zinc-finger-containing protein Fezl plays a crucial role in regulating neuronal differentiation in the vertebrate forebrain. Here, we report a new and essential role of zebrafish Fezl in establishing regional subdivisions within the diencephalon. First, reduced activity of fezl results in a deficit of the prethalamus and a corresponding expansion of the ZLI. Second, Gal4-UAS-mediated fezl overexpression in late gastrula is capable of expanding the prethalamus telencephalon and hypothalamus at the expense of the ZLI and other fore- and/or mid-brain regions. Such altered brain regionalization is preceded by the early downregulation of wnt expression in the prospective diencephalon. Finally, fezl overexpression is able to restore the anterior forebrain and downregulate wnt expression in Headless- and/or Tcf3 (also known as Tcf7l1a)-deficient embryos. Our findings reveal that Fezl is crucial for establishing regional subdivisions within the diencephalon and may also play a role in the development of the telencephalon and hypothalamus. 相似文献
94.
95.
96.
Ham YW Humphreys DJ Choi S Dayton DL 《Bioorganic & medicinal chemistry letters》2011,21(17):5071-5074
Riboswitches are noncoding RNA elements embedded in 5′-untranslated region of many bacterial mRNAs regulating gene expression in response to essential metabolites. They are unique from other RNA targets because they have evolved to form specific structural receptors for the purpose of binding small molecular metabolites suggesting that structure-based rational drug design approach may be used in designing metabolite mimics targeting riboswitches. We have developed a fluorescence binding assay for SAM-II riboswitch aptamer and identified an S-adenosylmethionine (SAM) analogue that selectively binds to SAM-II riboswitch aptamer with comparable binding affinity to its native metabolite using structure-based design approach. 相似文献
97.
Youngblood DS Hatlevig SA Hassinger JN Iversen PL Moulton HM 《Bioconjugate chemistry》2007,18(1):50-60
Cell penetrating peptides (CPPs) have been shown to enhance the cellular uptake of antisense oligonucleotides (AOs). However, the effectiveness of the CPPs for cytoplasmic or nuclear delivery of therapeutic AOs must take into account the possible entrapment of the CPP-AO conjugates in endosomes/lysosomes and the overall stability of the CPP-AO conjugates to enzymes. This includes the stabilities of the CPPs and AOs themselves as well as the linkage between them. In this study, we investigated the effects of several structural features of arginine-rich CPPs on the metabolic stability of CPP conjugated to phosphorodiamidate morpholino oligomers (PMOs) in human serum and in cells. Those structural features include amino acid configurations (d or l), incorporation of non-alpha-amino acids, peptide sequences, and types of linkages between CPPs and PMOs. Using matrix-assisted laser desorption ionization time-of-flight mass spectrometry, we found that the stability of the CPP portion was varied although the PMO portion of the conjugate was completely stable both in cells and in human serum. d-Configuration CPPs were completely stable, while l-CPPs were degraded in both serum and HeLa cells. Insertions of 6-aminohexanoic acid residues (X) into an R8 peptide increased the corresponding CPP's serum stability with the degree of stability being dependent upon the positions of X. However, X-containing CPPs were degraded rapidly intracellularly. Insertions of beta-alanines (B) into the R8 peptide increased its serum stability and intracellular stability. An amide or a maleimide linkage was stable in both serum and cells; however, an unhindered disulfide linkage was not stable in either. By using fluorescent microscopy, flow cytometry, and an antisense splice correction assay, the cellular uptakes of an X-containing conjugate and its fragments were compared to their antisense activities. We found that a large fraction of the conjugate was trapped within vesicles and the degraded fragments cannot escape from the vesicles. This study indicates that the incorporation of non-alpha-amino acids into l-CPPs can increase the metabolic stability of CPP-PMOs without using costly d-CPPs. However, the position and type of non-alpha-amino acids affect the degree of stability extracellularly and intracellularly. In addition, this study reveals that the degradation of an X-containing CPP-PMO conjugate is a more rapid process than degradation of a B-containing conjugate. Last, the endosomal/lysosomal trapping limits the effectiveness of a CPP-PMO conjugate, and the stability of the CPP is one of the factors affecting the ability of the conjugate to escape the endosomes/lysosomes. 相似文献
98.
99.
Gary Wulfsberg Eleonora Kravchenko Susie Miller Taylor Barnes Preston MacDougall 《Inorganica chimica acta》2008,361(8):2471-2482
Silver complexes of halocarbons and silver salts of halogenated organic acids (for example, silver chloroacetate) often show secondary Ag?X bonding interactions and unusually low 35Cl NQR frequencies, due to secondary bonding of chlorines to silver atoms. The crystal structure of silver dichloroacetate has been determined at 100 K and shows six crystallographically-inequivalent chlorines. The structure is built from Ag2(OOCCHCl2)2 dimers, similar to those found in silver chloroacetate; in both compounds the dimers are linked by additional Ag-O and Ag-Cl bonds. In the structure of silver dichloroacetate, two distinct conformations of the dichloromethyl groups are present. Two chlorines have no silver neighbors closer than 3.50 Å; two bridge to one Ag atom each, at Ag?Cl secondary bond distances of 2.8203(4) and 3.0196(4) Å, and two are apical, coordinating to at least two Ag neighbors each, at longer bond distances of 3.1401 (3)-3.3704(4) Å. Such very long distances are nevertheless shorter than the sum of the van der Waals radii of silver and chlorine, ca. 3.45 Å.The 35Cl NQR spectrum of silver dichloroacetate at 77 K shows six signals scattered over the broad range from 35.600 to 38.498 MHz. Their EFG asymmetry parameters η were measured by the Fourier analysis of the slow beats in the spin echo envelope of the NQR signal of polycrystalline samples. The two highest-frequency chlorines have relatively low η values, 0.075 and 0.106, as befits Cl atoms not coordinated to Ag, and are placed by their conformations far from the carboxylate plane. The two middle-frequency chlorines have higher η values, 0.167 and 0.168, as expected for bridging Cl atoms. The two low-frequency chlorines have lower η values of 0.114 and 0.129, as expected for apical Cl atoms. For purposes of comparison, η values for Ag2(OOCCH2Cl)2, Na(OOCCH2Cl), and Ca(OOCCH2Cl)2 · H2O were also recorded. So far, we have not observed any significant effect on the 35Cl NQR parameters of halogenated organic anions coordinated to hard-acid metal ions (K+, Rb+, Ca2+). The effects of the different conformations of the Cl2CH groups on the broad NQR frequency range are also discussed. 相似文献
100.
Susie Fisher 《Journal of the history of biology》2010,43(4):661-696
During the 1960s, Howard M. Temin (1934–1994), dared to advocate a “heretical” hypothesis that appeared to be at variance
with the central dogma of molecular biology, understood by many to imply that information transfer in nature occurred only
from DNA to RNA. Temin’s provirus hypothesis offered a simple explanation of both virus replication and viral-induced cancer
and stated that Rous sarcoma virus, an RNA virus, is replicated via a DNA intermediate. Popular accounts of this scientific
episode, written after the discovery of an RNA-directed DNA polymerase in 1970, tend to describe the reaction to his proposition
as ardent opposition. Typically these accounts use a ‹molecular biology’ standpoint emphasizing the central dogma’s part in
its rejection. In this article, however, this episode will be examined from a joint perspective of virology and experimental
cancer research. From this perspective it is clear that Temin’s work was well within the epistemological and methodological
boundaries of virology and cancer research. Still, scientists did have␣reasons to doubt the provirus hypothesis, but these
do not seem to be good enough to either justify an account that portrays Temin as a renegade or his ideas as heretical. 相似文献