全文获取类型
收费全文 | 275篇 |
免费 | 29篇 |
专业分类
304篇 |
出版年
2022年 | 2篇 |
2021年 | 4篇 |
2020年 | 2篇 |
2019年 | 1篇 |
2018年 | 5篇 |
2017年 | 4篇 |
2016年 | 2篇 |
2015年 | 9篇 |
2014年 | 12篇 |
2013年 | 12篇 |
2012年 | 14篇 |
2011年 | 7篇 |
2010年 | 10篇 |
2009年 | 4篇 |
2008年 | 21篇 |
2007年 | 13篇 |
2006年 | 13篇 |
2005年 | 8篇 |
2004年 | 17篇 |
2003年 | 9篇 |
2002年 | 14篇 |
2001年 | 13篇 |
2000年 | 14篇 |
1999年 | 10篇 |
1998年 | 1篇 |
1997年 | 3篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1994年 | 5篇 |
1993年 | 1篇 |
1992年 | 7篇 |
1991年 | 9篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1984年 | 5篇 |
1983年 | 6篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有304条查询结果,搜索用时 15 毫秒
71.
Amino acids were transformed and coupled to chlorambucil, a well-known chemotherapeutic agent, in an attempt to create new anticancer drugs with selectivity for breast cancer cells. Among the amino acids available, tyrosine was selected to act as an estrogenic ligand. It is hypothesized that tyrosine, which shows some structural similitude with estradiol, could possibly mimic the natural hormone and, subsequently, bind to the estrogen receptor. In this exploratory study, several tyrosine-drug conjugates have been designed. Thus, ortho-, meta- and para-tyrosine-chlorambucil analogs were synthesized in order to generate new anticancer drugs with structural diversity, more specifically in regards to the phenol group location. These new analogs were produced in good yield following efficient synthetic methodology. All the tyrosine-chlorambucil hybrids were more effective than the parent drug, chlorambucil. In vitro biological evaluation on estrogen receptor positive and estrogen receptor negative (ER(+) and ER(-)) breast cancer cell lines revealed an enhanced cytotoxic activity for compounds with the phenol function located at position meta. Molecular docking calculations were performed for the pure L-ortho, L-meta- and L-para-tyrosine phenolic regioisomers. The synthesis of all tyrosine-chlorambucil hybrid regioisomers and their biological activity are reported herein. Possible orientations within the targeted protein [estrogen receptor alpha (ERα)] are discussed in relation to the biological activity. 相似文献
72.
Rational design of peptides is a challenge, which would benefit from a better knowledge of the rules of sequence-structure-function relationships. Peptide structures can be approached by spectroscopy and NMR techniques but data from these approaches too frequently diverge. Structures can also be calculated in silico from primary sequence information using three algorithms: Pepstr, Robetta, and PepLook. The most recent algorithm, PepLook introduces indexes for evaluating structural polymorphism and stability. For peptides with converging experimental data, calculated structures from PepLook and, to a lesser extent from Pepstr, are close to NMR models. The PepLook index for polymorphism is low and the index for stability points out possible binding sites. For peptides with divergent experimental data, calculated and NMR structures can be similar or, can be different. These differences are apparently due to polymorphism and to different conditions of structure assays and calculations. The PepLook index for polymorphism maps the fragments encoding disorder. This should provide new means for the rational design of peptides. 相似文献
73.
Alzbeta Hulikova Eliska Svastova Robert Brasseur Claudiu T. Supuran Jaromir Pastorek Silvia Pastorekova 《FEBS letters》2009,583(22):3563-3402
Carbonic anhydrase IX (CA IX) is a tumor-associated, hypoxia-induced enzyme involved in pH regulation and cell adhesion. Its catalytically active ectodomain (ECD) is linked to a transmembrane region and a short intracellular (IC) tail. Removal of the IC tail causes intracellular localization of CA IX. Mutations of basic amino acids within IC do not perturb the membrane position, but reduce shedding of the CA IX ectodomain as well as CA IX-mediated cell dissociation. Moreover, they abolish the CA IX capacity to acidify extracellular pH (pHe) and bind CA IX-selective sulfonamide inhibitor in hypoxia. These findings provide the first evidence for the critical contribution of the IC tail to the proper functioning of CA IX.
Structured summary
MINT-7293982: E-cadherin (uniprotkb:Q95LE0) and CA IX (genbank_protein_gi:223556027) colocalize (MI:0403) by fluorescence microscopy (MI:0416) 相似文献74.
Stanley Tam Haiyuan Yu Kavitha Venkatesan Danny Mou Venus Swearingen Muhammed A Yildirim Han Yan Amélie Dricot David Szeto Chenwei Lin Tong Hao Changyu Fan Stuart Milstein Denis Dupuy Robert Brasseur David E Hill Michael E Cusick Marc Vidal 《Molecular systems biology》2009,5(1)
Cellular functions are mediated through complex systems of macromolecules and metabolites linked through biochemical and physical interactions, represented in interactome models as ‘nodes’ and ‘edges’, respectively. Better understanding of genotype‐to‐phenotype relationships in human disease will require modeling of how disease‐causing mutations affect systems or interactome properties. Here we investigate how perturbations of interactome networks may differ between complete loss of gene products (‘node removal’) and interaction‐specific or edge‐specific (‘edgetic’) alterations. Global computational analyses of ~50 000 known causative mutations in human Mendelian disorders revealed clear separations of mutations probably corresponding to those of node removal versus edgetic perturbations. Experimental characterization of mutant alleles in various disorders identified diverse edgetic interaction profiles of mutant proteins, which correlated with distinct structural properties of disease proteins and disease mechanisms. Edgetic perturbations seem to confer distinct functional consequences from node removal because a large fraction of cases in which a single gene is linked to multiple disorders can be modeled by distinguishing edgetic network perturbations. Edgetic network perturbation models might improve both the understanding of dissemination of disease alleles in human populations and the development of molecular therapeutic strategies. 相似文献
75.
Otavia L. Caballero Qi Zhao Donata Rimoldi Brian J. Stevenson Suzanne Svobodová Sylvie Devalle Ute F. R?hrig Anna Pagotto Olivier Michielin Daniel Speiser Jedd D. Wolchok Cailian Liu Tanja Pejovic Kunle Odunsi Francis Brasseur Benoit J. Van den Eynde Lloyd J. Old Xin Lu Jonathan Cebon Robert L. Strausberg Andrew J. Simpson 《PloS one》2010,5(9)
Background
Cancer/testis (CT) genes are expressed only in the germ line and certain tumors and are most frequently located on the X-chromosome (the CT-X genes). Amongst the best studied CT-X genes are those encoding several MAGE protein families. The function of MAGE proteins is not well understood, but several have been shown to potentially influence the tumorigenic phenotype.Methodology/Principal Findings
We undertook a mutational analysis of coding regions of four CT-X MAGE genes, MAGEA1, MAGEA4, MAGEC1, MAGEC2 and the ubiquitously expressed MAGEE1 in human melanoma samples. We first examined cell lines established from tumors and matching blood samples from 27 melanoma patients. We found that melanoma cell lines from 37% of patients contained at least one mutated MAGE gene. The frequency of mutations in the coding regions of individual MAGE genes varied from 3.7% for MAGEA1 and MAGEA4 to 14.8% for MAGEC2. We also examined 111 fresh melanoma samples collected from 86 patients. In this case, samples from 32% of the patients exhibited mutations in one or more MAGE genes with the frequency of mutations in individual MAGE genes ranging from 6% in MAGEA1 to 16% in MAGEC1.Significance
These results demonstrate for the first time that the MAGE gene family is frequently mutated in melanoma. 相似文献76.
Human disease-related mutations in cytochrome b studied in yeast 总被引:1,自引:0,他引:1
Fisher N Castleden CK Bourges I Brasseur G Dujardin G Meunier B 《The Journal of biological chemistry》2004,279(13):12951-12958
Several mutations in the mitochondrially encoded cytochrome b have been reported in patients. To characterize their effect, we introduced six "human" mutations, namely G33S, S152P, G252D, Y279C, G291D, and Delta252-259 in the highly similar yeast cytochrome b. G252D showed wild type behavior in standard conditions. However, Asp-252 may interfere with structural lipid and, in consequence, destabilize the enzyme assembly, which could explain the pathogenicity of the mutation. The mutations G33S, S152P, G291D, and Delta252-259 were clearly pathogenic. They caused a severe decrease of the respiratory function and altered the assembly of the iron-sulfur protein in the bc(1) complex, as observed by immunodetection. Suppressor mutations that partially restored the respiratory function impaired by S152P or G291D were found in or close to the hinge region of the iron-sulfur protein, suggesting that this region may play a role in the stable binding of the subunit to the bc(1) complex. Y279C caused a significant decrease of the bc(1) function and perturbed the quinol binding. The EPR spectra showed an altered signal, indicative of a lower occupancy of the Q(o) site. The effect of human mutation of residue 279 was confirmed by another change, Y279A, which had a more severe effect on Q(o) site properties. Thus by using yeast as a model system, we identified the molecular basis of the respiratory defect caused by the disease mutations in cytochrome b. 相似文献
77.
The AAA ATPase p97/VCP forms complexes with different adapters to fulfill distinct cellular functions. We analyzed the structural organization of the Ufd1-Npl4 adapter complex and its interaction with p97 and compared it with another adapter, p47. We found that the binary Ufd1-Npl4 complex forms a heterodimer that cooperatively interacts with p97 via a bipartite binding mechanism. Binding site 1 (BS1) is a short hydrophobic stretch in the C-terminal domain of Ufd1. The second binding site is located at the N terminus of Npl4 and is activated upon binding of Ufd1 to Npl4. It consists of about 80 amino acids that are predicted to form a ubiquitin fold domain (UBD). Despite the lack of overall homology between Ufd1-Npl4 and p47, both adapters use identical binding mechanisms. Like the ubiquitin fold ubiquitin regulatory X (UBX) domain in p47, the Npl4-UBD interacts with p97 via the loop between its strands 3 and 4 and a conserved arginine in strand 1. Furthermore, we identified a region in p47 homologous to Ufd1-BS1. The UBD/UBX and the BS1 of both adapters interact with p97 independently, whereas homologous binding sites in both adapters compete for binding to p97. In contrast to p47, however, Ufd1-Npl4 does not regulate the ATPase activity of p97; nor does a variant of p47 that contains both binding sites but lacks the N-terminal domains. Therefore, the binding sites alone do not regulate p97 directly but rather serve as anchor points to position adapter-specific domains at critical locations to modulate p97-mediated reactions. 相似文献
78.
Cellular uptake of Antennapedia Penetratin peptides is a two-step process in which phase transfer precedes a tryptophan-dependent translocation 总被引:6,自引:1,他引:5 下载免费PDF全文
Dom G Shaw-Jackson C Matis C Bouffioux O Picard JJ Prochiantz A Mingeot-Leclercq MP Brasseur R Rezsohazy R 《Nucleic acids research》2003,31(2):556-561
Several homeodomains and homeodomain-containing proteins enter live cells through a receptor- and energy-independent mechanism. Translocation through biological membranes is conferred by the third α-helix of the homeodomain, also known as Penetratin. Biophysical studies demonstrate that entry of Penetratin into cells requires its binding to surface lipids but that binding and translocation are differentially affected by modifications of some physico-chemical properties of the peptide, like helical amphipathicity or net charge. This suggests that the plasma membrane lipid composition affects the internalization of Penetratin and that internalization requires both lipid binding and other specific properties. Using a phase transfer assay, it is shown that negatively charged lipids promote the transfer of Penetratin from a hydrophilic into a hydrophobic environment, probably through charge neutralization. Accordingly, transfer into a hydrophobic milieu can also be obtained in the absence of negatively charged lipids, by the addition of DNA oligonucleotides. Strikingly, phase transfer by charge neutralization was also observed with a variant peptide of same charge and hydrophobicity in which the tryptophan at position 6 was replaced by a phenylalanine. However, Penetratin, but not its mutant version, is internalized by live cells. This underscores that charge neutralization and phase transfer represent only a first step in the internalization process and that further crossing of a biological membrane necessitates the critical tryptophan residue at position 6. 相似文献
79.
Engelhard GH Brasseur SM Hall AJ Burton HR Reijnders PJ 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2002,172(4):315-328
We examined the cortisol responses to chemical and physical restraint stress in southern elephant seal Mirounga leonina females and their pups at three stages during lactation. In anaesthetised females the serum cortisol levels changed moderately during the 45-min sampling period following restraint, with average peaks at 23 min after anaesthetic administration. Overall, cortisol was relatively low 2 days postpartum and increased throughout lactation. In physically restrained pups serum cortisol increased rapidly after capture; the response was milder at age 2 days than at 11 days and 21 days. Levels were higher in female pups than in males. In order to test whether cortisol levels and/or responses became chronically (i.e. days to weeks) altered due to restraint, we compared the cortisol response at a late stage of lactation between three groups of mother-pup pairs previously given different levels of chemical (mothers) or physical (pups) restraint stress: control (not handled previously), moderate treatment (previously handled twice), and high treatment (previously handled 3-4 times). Pups of the three treatment groups showed similar adrenocortical responses suggesting no chronic effect of repeated physical restraint, despite the clear acute effects. Mothers of the control and moderate treatment groups showed similar cortisol responses; however, mothers of the high treatment group showed significantly attenuated responses. This indicated that elephant seals tolerated moderate degrees of handling disturbance; however, repeated (3-4) chemical immobilisations in lactating females may reduce their adrenocortical responsiveness for a period of days or weeks. 相似文献
80.
Laurence Lins Robert Brasseur Maryvonne Rosseneu Chao -Yuh Yang Doris A. Sparrow James T. Sparrow Antonio M. Gotto Jean -Marie Ruysschaert 《Journal of Protein Chemistry》1994,13(1):77-88
Peptides corresponding to lipid binding domains of Apo B-100 were synthesized, purified, and incubated with dimyristoylphosphatidylcholine (DMPC) liposomes. The secondary structure of the apo B-100 peptide-lipid complexes was evaluated by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). Those peptides belonging to the hydrophobic core domain of apo B-100 when associated with phospholipids were rich in sheet structure; a predominant helical conformation was shown to be associated with one peptide located in a surface region of apo B-100. IR dichroic spectra revealed, in the case of the core peptides, that the sheet component is the only oriented structure with respect to the phospholipid acyl chains. This orientation of the sheet was recently found in LDL particles after proteolytic digestion by trypsin (Goormaghtigh, E., Cabiaux, V., De Meutter, J., Rosseneu, M., and Ruysschaert, J. M., 1993,Biochemistry
32, 6104–6110). Altogether, the data suggest that sheet, present in a high proportion in the native apo B-100, is probably another protein structure in addition to the amphipathic helix which strongly interacts with the lipid outer layer surrounding the LDL particle.Abbreviations used Apo
apolipoprotein
- ATR
attenuated total reflection
- CD
circular dichroism
- DMPC
dimyris-toylphosphatidylcholine
- DMSO
dimethylsulfoxide
- FTIR
Fourier transform infrared spectroscopy
- HPLC
high-performance liquid chromatography
- LDL
low density lipoprotein
- TFA
trifluoroacetic acid
- Cx
apoB-100 core peptide corresponding to the following residues: C2, 2462–2482; C3, 4208–4231; C5, 4493–4513; and C7, 4271–4288
- S6
apoB-100 surface Peptide Corresponding to Residues 374–400 相似文献