全文获取类型
收费全文 | 2064篇 |
免费 | 170篇 |
专业分类
2234篇 |
出版年
2023年 | 1篇 |
2022年 | 23篇 |
2021年 | 31篇 |
2020年 | 24篇 |
2019年 | 26篇 |
2018年 | 36篇 |
2017年 | 28篇 |
2016年 | 48篇 |
2015年 | 108篇 |
2014年 | 107篇 |
2013年 | 128篇 |
2012年 | 196篇 |
2011年 | 154篇 |
2010年 | 135篇 |
2009年 | 124篇 |
2008年 | 139篇 |
2007年 | 154篇 |
2006年 | 163篇 |
2005年 | 122篇 |
2004年 | 138篇 |
2003年 | 115篇 |
2002年 | 112篇 |
2001年 | 15篇 |
2000年 | 19篇 |
1999年 | 16篇 |
1998年 | 21篇 |
1997年 | 13篇 |
1996年 | 11篇 |
1995年 | 6篇 |
1994年 | 8篇 |
1993年 | 6篇 |
1992年 | 4篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1983年 | 1篇 |
排序方式: 共有2234条查询结果,搜索用时 18 毫秒
51.
Vosshenrich CA Ranson T Samson SI Corcuff E Colucci F Rosmaraki EE Di Santo JP 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(3):1213-1221
NK cells differentiate in adult mice from bone marrow hemopoietic progenitors. Cytokines, including those that signal via receptors using the common cytokine receptor gamma-chain (gamma(c)), have been implicated at various stages of NK cell development. We have previously described committed NK cell precursors (NKPs), which have the capacity to generate NK cells, but not B, T, erythroid, or myeloid cells, after in vitro culture or transfer to a fetal thymic microenvironment. NKPs express the CD122 Ag (beta chain of the receptors for IL-2/IL-15), but lack other mature NK markers, including NK1.1, CD49b (DX5), or members of the Ly49 gene family. In this report, we have analyzed the roles for gamma(c)-dependent cytokines in the generation of bone marrow NKP and in their subsequent differentiation to mature NK cells in vivo. Normal numbers of NKPs are found in gamma(c)-deficient mice, suggesting that NK cell commitment is not dependent on IL-2, IL-4, IL-7, IL-9, IL-15, or IL-21. Although IL-2, IL-4, and IL-7 have been reported to influence NK cell differentiation, we find that mice deficient in any or all of these cytokines have normal NK cell numbers, phenotype, and effector functions. In contrast, IL-15 plays a dominant role in early NK cell differentiation by maintaining normal numbers of immature and mature NK cells in the bone marrow and spleen. Surprisingly, the few residual NK cells generated in absence of IL-15 appear relatively mature, expressing a variety of Ly49 receptors and demonstrating lytic and cytokine production capacity. 相似文献
52.
Tardy AL Giraudet C Rousset P Rigaudière JP Laillet B Chalancon S Salles J Loreau O Chardigny JM Morio B 《Journal of lipid research》2008,49(7):1445-1455
Epidemiological studies suggest that chronic consumption of trans MUFA may alter muscle insulin sensitivity. The major sources of dietary trans MUFA (dairy fat vs. industrially hydrogenated oils) have different isomeric profiles and thus probably different metabolic consequences. These effects may involve alterations in muscle mitochondrial oxidative capacity, which may in turn promote insulin resistance if fatty acid oxidation is reduced. We report that in Wistar rats, an 8 week diet enriched (4% of energy intake) in either dairy, industrial, or control MUFA did not alter insulin and glucose responses to an intraperitoneal glucose tolerance test (1g/kg). In C2C12 myotubes, vaccenic and elaidic acids did not modify insulin sensitivity compared with oleic acid. Furthermore, the ex vivo total, mitochondrial and peroxisomal oxidation rates of [1-(14)C]oleic, vaccenic, and elaidic acids were similar in soleus and tibialis anterior rat muscle. Finally, an 8 week diet enriched in either dairy or industrial trans MUFA did not alter mitochondrial oxidative capacity in these two muscles compared with control MUFA but did induce a specific reduction in soleus mitochondrial ATP and superoxide anion production (P<0.01 vs. control). In conclusion, dietary trans MUFA of dairy or industrial origin have similar effects and do not impair muscle mitochondrial capacity and insulin sensitivity. 相似文献
53.
Leblanc P Hasenkrug K Ward A Myers L Messer RJ Alais S Timmes A Priola SA Priola S 《PloS one》2012,7(1):e30872
Prion diseases are fatal, transmissible neurodegenerative diseases of the central nervous system. An abnormally protease-resistant and insoluble form (PrP(Sc)) of the normally soluble protease-sensitive host prion protein (PrP(C)) is the major component of the infectious prion. During the course of prion disease, PrP(Sc) accumulates primarily in the lymphoreticular and central nervous systems. Recent studies have shown that co-infection of prion-infected fibroblast cells with the Moloney murine leukemia virus (Mo-MuLV) strongly enhanced the release and spread of scrapie infectivity in cell culture, suggesting that retroviral coinfection might significantly influence prion spread and disease incubation times in vivo. We now show that another retrovirus, the murine leukemia virus Friend (F-MuLV), also enhanced the release and spread of scrapie infectivity in cell culture. However, peripheral co-infection of mice with both Friend virus and the mouse scrapie strain 22L did not alter scrapie disease incubation times, the levels of PrP(Sc) in the brain or spleen, or the distribution of pathological lesions in the brain. Thus, retroviral co-infection does not necessarily alter prion disease pathogenesis in vivo, most likely because of different cell-specific sites of replication for scrapie and F-MuLV. 相似文献
54.
I Blesneac S Ravaud P Machillot M Zoonens S Masscheylen B Miroux M Vivaudou E Pebay-Peyroula 《European biophysics journal : EBJ》2012,41(8):675-679
The uncoupling protein 1 (UCP1) is a mitochondrial protein that carries protons across the inner mitochondrial membrane. It has an important role in non-shivering thermogenesis, and recent evidence suggests its role in human adult metabolism. Using rapid solution exchange on solid supported membranes, we succeeded in measuring electrical currents generated by the transport activity of UCP1. The protein was purified from mouse brown adipose tissue, reconstituted in liposomes and absorbed on solid supported membranes. A fast pH jump activated the ion transport, and electrical signals could be recorded. The currents were characterized by a fast rise and a slow decay, were stable over time, inhibited by purine nucleotides and activated by fatty acids. This new assay permits direct observation of UCP1 activity in controlled cell-free conditions, and opens up new possibilities for UCP1 functional characterization and drug screening because of its robustness and its potential for automation. 相似文献
55.
56.
Mass spectrometric characterization of N- and O-glycans of plasma-derived coagulation factor VII 总被引:1,自引:0,他引:1
Fenaille F Groseil C Ramon C Riandé S Siret L Chtourou S Bihoreau N 《Glycoconjugate journal》2008,25(9):827-842
Factor VII (FVII) is a vitamin K-dependent glycoprotein which, in its activated form (FVIIa), participates in the coagulation
process by activating factor X and factor IX. FVII is secreted as single peptide chain of 406 residues. Plasma-derived FVII
undergoes many post-translational modifications such as γ-carboxylation, N- and O-glycosylation, β-hydroxylation. Despite
glycosylation of recombinant FVIIa has been fully characterized, nothing is reported on the N- and O-glycans of plasma-derived
FVII (pd-FVII) and on their structural heterogeneity at each glycosylation site. N- and O-glycosylation sites and site specific
heterogeneity of pd-FVII were studied by various complementary qualitative and quantitative techniques. A MALDI-MS analysis
of the native protein indicated that FVII is a 50.1 kDa glycoprotein modified on two sites by diantennary, disialylated non-fucosylated
(A2S2) glycans. LC–ESIMS/MS analysis revealed that both light chain and heavy chain were N-glycosylated mainly by A2S2 but
also by triantennary sialylated glycans. Nevertheless, lower amounts of triantennary structures were found on Asn322 compared to Asn145. Moreover, the triantennary glycans were shown to be fucosylated. In parallel, quantitative analysis of the isolated glycans
by capillary electrophoresis indicated that the diantennary structures represented about 50% of the total glycan content.
Glycan sequencing using different glycanases led to the identification of triantennary difucosylated structures. Last, MS
and MS/MS analysis revealed that FVII is O-glycosylated on the light chain at position Ser60 and Ser52 which are modified by oligosaccharide structures such as fucose and Glc(Xyl)0–1–2, respectively. These latter three O-glycans coexist in equal amounts in plasma-derived FVII. 相似文献
57.
58.
Ranquet C Ollagnier-de-Choudens S Loiseau L Barras F Fontecave M 《The Journal of biological chemistry》2007,282(42):30442-30451
Cobalt is toxic for cells, but mechanisms of this toxicity are largely unknown. The biochemical and genetic experiments reported here demonstrate that iron-sulfur proteins are greatly affected in cobalt-treated Escherichia coli cells. Exposure of a wild-type strain to intracellular cobalt results in the inactivation of three selected iron-sulfur enzymes, the tRNA methylthio-transferase, aconitase, and ferrichrome reductase. Consistently, mutant strains lacking the [Fe-S] cluster assembly SUF machinery are hypersensitive to cobalt. Last, expression of iron uptake genes is increased in cells treated with cobalt. In vitro studies demonstrated that cobalt does not react directly with fully assembled [Fe-S] clusters. In contrast, it reacts with labile ones present in scaffold proteins (IscU, SufA) involved in iron-sulfur cluster biosynthesis. We propose a model wherein cobalt competes out iron during synthesis of [Fe-S] clusters in metabolically essential proteins. 相似文献
59.
Elisabeth Le Bihan-Duval Javad Nadaf Cécile Berri Frédérique Pitel Beno?t Graulet Estelle Godet Sophie Y. Leroux Olivier Demeure Sandrine Lagarrigue Cécile Duby Larry A. Cogburn Catherine M. Beaumont Michel J. Duclos 《PloS one》2011,6(7)
Classical quantitative trait loci (QTL) analysis and gene expression QTL (eQTL) were combined to identify the causal gene (or QTG) underlying a highly significant QTL controlling the variation of breast meat color in a F2 cross between divergent high-growth (HG) and low-growth (LG) chicken lines. Within this meat quality QTL, BCMO1 (Accession number GenBank: ), encoding the β-carotene 15, 15′-monooxygenase, a key enzyme in the conversion of β-carotene into colorless retinal, was a good functional candidate. Analysis of the abundance of BCMO1 mRNA in breast muscle of the HG x LG F2 population allowed for the identification of a strong cis eQTL. Moreover, reevaluation of the color QTL taking BCMO1 mRNA levels as a covariate indicated that BCMO1 mRNA levels entirely explained the variations in meat color. Two fully-linked single nucleotide polymorphisms (SNP) located within the proximal promoter of BCMO1 gene were identified. Haplotype substitution resulted in a marked difference in BCMO1 promoter activity in vitro. The association study in the F2 population revealed a three-fold difference in BCMO1 expression leading to a difference of 1 standard deviation in yellow color between the homozygous birds at this haplotype. This difference in meat yellow color was fully consistent with the difference in carotenoid content (i.e. lutein and zeaxanthin) evidenced between the two alternative haplotypes. A significant association between the haplotype, the level of BCMO1 expression and the yellow color of the meat was also recovered in an unrelated commercial broiler population. The mutation could be of economic importance for poultry production by making possible a gene-assisted selection for color, a determining aspect of meat quality. Moreover, this natural genetic diversity constitutes a new model for the study of β-carotene metabolism which may act upon diverse biological processes as precursor of the vitamin A. AJ271386相似文献
60.
Chandor A Berteau O Douki T Gasparutto D Sanakis Y Ollagnier-de-Choudens S Atta M Fontecave M 《The Journal of biological chemistry》2006,281(37):26922-26931
The overwhelming majority of DNA photoproducts in UV-irradiated spores is a unique thymine dimer called spore photoproduct (SP, 5-thymine-5,6-dihydrothymine). This lesion is repaired by the spore photoproduct lyase (SP lyase) enzyme that directly reverts SP to two unmodified thymines. The SP lyase is an S-adenosylmethionine-dependent iron-sulfur protein that belongs to the radical S-adenosylmethionine superfamily. In this study, by using a well characterized preparation of the SP lyase enzyme from Bacillus subtilis, we show that SP in the form of a dinucleoside monophosphate (spore photoproduct of thymidilyl-(3'-5')-thymidine) is efficiently repaired, allowing a kinetic characterization of the enzyme. The preparation of this new substrate is described, and its identity is confirmed by mass spectrometry and comparison with authentic spore photoproduct. The fact that the spore photoproduct of thymidilyl-(3'-5')-thymidine dimer is repaired by SP lyase may indicate that the SP lesion does not absolutely need to be contained within a single- or double-stranded DNA for recognition and repaired by the SP lyase enzyme. 相似文献