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71.
Aikaterini A. Zompra Vassiliki Magafa Dimitra G. Chryssanthi Fotini N. Lamari Georgios A. Spyroulias Theodosia Maina Berthold A. Nock Nikos K. Karamanos Paul Cordopatis 《International journal of peptide research and therapeutics》2007,13(1-2):143-149
GnRH analogues have been extensively used in oncology to induce reversible chemical castration due to their hypophysiotropic
action. In addition to that, it has recently been shown that many malignant cells, such as breast cancer cells, locally produce
GnRH and express the GnRH receptor/s. In order to investigate the structure-activity relationships in both pituitary and extrapituitary
biological systems, we synthesized eight new GnRH analogues with modifications in the N-terminal part and/or in position 6
and studied their pituitary binding affinity (in αT3-1 cell membranes) and effect on breast cancer (MCF-7) cell proliferation.
2-Amino-4-pyrrolidinothieno[2,3-d]pyrimidine-6-carboxylic acid (ATPC) was incorporated instead of pGlu1-His2- and/or Gly6 was substituted by α-aminoisobutyric acid, D-Leu and D-Lys (alone or covalently linked to Gly, Ala, Sar, ATPC). Most GnRH
analogues lacked the carboxy-terminal Gly10-amide of GnRH and an ethylamide residue was added to Pro9, a modification common in many potent GnRH agonists, such as leuprolide ([D-Leu6, des-Gly10]-GnRH-NHEt. Results show differential impact of these modifications on the binding affinity to the GnRH receptor in mouse
pituitary cells and on the inhibition of human breast cancer cell proliferation. ATPC in the N-terminus resulted in analogues
with low binding affinity but high antiproliferative effect. Substitutions in position 6 always resulted in high binding affinities.
In particular, [D-Lys6(Gly), desGly10]-GnRH-NHEt and [D-Lys6(Sar), desGly10]-GnRH-NHEt have higher pituitary binding affinity than leuprolide, but only the latter had significant antiproliferative
effect on both MCF-7 and MDA-MB-231 cells. These results contribute to the on-going research for more potent GnRH analogues.
Abbreviations of common amino acids are in accordance with the recommendations of IUPAC-IUB Joint Commission on Biochemical
Nomenclature: Arch. Biochem. Biophys. 206, pp.v-xxii (1988), J. Biol. Chem. 264, 668–673 (1989) or J. Peptide Sci. 9, 1–8
(2003). 相似文献
72.
Laura L. Eggink Georgios A. Spyroulias Norman G. Jones Carl V. Hanson J. Kenneth Hoober 《PloS one》2015,10(6)
We previously identified several peptide sequences that mimicked the terminal sugars of complex glycans. Using plant lectins as analogs of lectin-type cell-surface receptors, a tetravalent form of a peptide with the sequence NPSHPLSG, designated svH1C, bound with high avidity to lectins specific for glycans with terminal 5-acetylneuraminic acid (Neu5Ac)-galactose (Gal)/N-acetylgalactosamine (GalNAc) sequences. In this report, we show by circular dichroism and NMR spectra that svH1C lacks an ordered structure and thus interacts with binding sites from a flexible conformation. The peptide binds with high avidity to several recombinant human siglec receptors that bind preferentially to Neu5Ac(α2,3)Gal, Neu5Ac(α2,6)GalNAc or Neu5Ac(α2,8)Neu5Ac ligands. In addition, the peptide bound the receptor NKG2D, which contains a lectin-like domain that binds Neu5Ac(α2,3)Gal. The peptide bound to these receptors with a KD in the range of 0.6 to 1 μM. Binding to these receptors was inhibited by the glycoprotein fetuin, which contains multiple glycans that terminate in Neu5Ac(α2,3)Gal or Neu5Ac(α2,6)Gal, and by sialyllactose. Binding of svH1C was not detected with CLEC9a, CLEC10a or DC-SIGN, which are lectin-type receptors specific for other sugars. Incubation of neuraminidase-treated human peripheral blood mononuclear cells with svH1C resulted in binding of the peptide to a subset of the CD14+ monocyte population. Tyrosine phosphorylation of siglecs decreased dramatically when peripheral blood mononuclear cells were treated with 100 nM svH1C. Subcutaneous, alternate-day injections of svH1C into mice induced several-fold increases in populations of several types of immune cells in the peritoneal cavity. These results support the conclusion that svH1C mimics Neu5Ac-containing sequences and interacts with cell-surface receptors with avidities sufficient to induce biological responses at low concentrations. The attenuation of inhibitory receptors suggests that svH1C has characteristics of a checkpoint inhibitor. 相似文献
73.
ERRATUM: Macho GA and Spears IR. 1999. Effects of Loading on the Biomechanical Behavior of Molars of Homo, Pan, and Pongo. Am J Phys Anthropol 109:211–227. The correct title of the article is given above. The word “biochemical” should be read as “biomechanical.” 相似文献
74.
75.
目的:比较不同时期颈髓损伤的MRI表现及DTI的应用价值。方法:收集急性颈髓压迫病例15例、慢性颈髓压迫病例23例、颈髓慢性压迫合并急性压迫病例12例。15例健康志愿者作为对照组。进行常规MRI检查,应用DTI检查测量表现扩散系数(ADC)值和各向异性分数(FA)。比较各组间ADC值和FA值,并进行统计学分析。结果:急性颈髓迫病例,常规MRI显示颈髓增粗,呈等T1长T2信号;慢性颈髓压迫病例,9例呈长T1长T2信号,14例呈等T1长T2信号;慢性颈髓压迫并急性压迫病例颈髓明显增粗,呈等、长T1明显长T2信号。与对照组比较:急性颈髓压迫组的ADC值和FA值均明显降低,两组的差异有显著性;慢性颈髓压迫组的FA值降低,ADC值增高,两组的差异有显著性;慢性脊髓压迫合并急性脊髓压迫组ADC值与对照组比较无差异,FA值低于对照组。颈髓压迫各组间ADC值及FA值比较差异显著。结论:不同时期颈髓损伤常规MRI图像缺乏特异性,根据ADC值及FA值可判断颈髓损伤的时期。 相似文献
76.
77.
van Neerven SG Bozkurt A O'Dey DM Scheffel J Boecker AH Stromps JP Dunda S Brook GA Pallua N 《Journal of brachial plexus and peripheral nerve injury》2012,7(1):5-7
ABSTRACT: Evaluation of functional and structural recovery after peripheral nerve injury is crucial to determine the therapeutic effect of a nerve repair strategy. In the present study, we examined the relationship between the structural evaluation of regeneration by means of retrograde tracing and the functional evaluation analysis of toe spreading. Two standardized rat sciatic nerve injury models were used to address this relationship. As such, animals received either a 2 cm sciatic nerve defect (neurotmesis) followed by autologous nerve transplantation (ANT animals) or a crush injury with spontaneous recovery (axonotmesis; CI animals). Functional recovery of toe spreading was observed over an observation period of 84 days. In contrast to CI animals, ANT animals did not reach pre-surgical levels of toe spreading. After the observation period, the lipophilic dye DiI was applied to label sensory and motor neurons in dorsal root ganglia (DRG; sensory neurons) and spinal cord (motor neurons), respectively. No statistical difference in motor or sensory neuron counts could be detected between ANT and CI animals. In the present study we could indicate that there was no direct relationship between functional recovery (toe spreading) measured by SSI and the number of labelled (motor and sensory) neurons evaluated by retrograde tracing. The present findings demonstrate that a multimodal approach with a variety of independent evaluation tools is essential to understand and estimate the therapeutic benefit of a nerve repair strategy. 相似文献
78.
GA Bray 《Obesity (Silver Spring, Md.)》1997,5(3):271-274
It is often difficult to identify the ‘who, when, and where’ of advances in medicine and surgery because it's a rare advance indeed (such as the use of digitalis by William Withering) that can be clearly related to the astuteness of one person at one time and place. 相似文献
79.
Kappa-chain constant-region gene sequences in genus Rattus: coding regions are diverging more rapidly than noncoding regions 总被引:2,自引:0,他引:2
We have determined the nucleotide sequence of a 1,200-base pair (bp)
genomic fragment that includes the kappa-chain constant-region gene (C
kappa) from two species of native Australian rodents, Rattus leucopus
cooktownensis and Rattus colletti. Comparison of these sequences with each
other and with other rodent C kappa genes shows three surprising features.
First, the coding regions are diverging at a rate severalfold higher than
that of the nearby noncoding regions. Second, replacement changes within
the coding region are accumulating at a rate at least as great as that of
silent changes. Third, most of the amino acid replacements are localized in
one region of the C kappa domain--namely, the carboxy-terminal "bends" in
the alpha-carbon backbone. These three features have previously been
described from comparisons of the two allelic forms of C kappa genes in R.
norvegicus. These data imply the existence of considerable evolutionary
constraints on the noncoding regions (based on as yet undetermined
functions) or powerful positive selection to diversify a portion of the
constant-region domain (whose physiological significance is not known).
These surprising features of C kappa evolution appear to be characteristic
only of closely related C kappa genes, since comparison of rodent with
human sequences shows the expected greater conservation of coding regions,
as well as a predominance of silent nucleotide substitutions within the
coding regions.
相似文献
80.