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991.
PML regulates p53 stability by sequestering Mdm2 to the nucleolus 总被引:12,自引:0,他引:12
Bernardi R Scaglioni PP Bergmann S Horn HF Vousden KH Pandolfi PP 《Nature cell biology》2004,6(7):665-672
The promyelocytic leukaemia (PML) tumour-suppressor protein potentiates p53 function by regulating post-translational modifications, such as CBP-dependent acetylation and Chk2-dependent phosphorylation, in the PML-Nuclear Body (NB). PML was recently shown to interact with the p53 ubiquitin-ligase Mdm2 (refs 4-6); however, the mechanism by which PML regulates Mdm2 remains unclear. Here, we show that PML enhances p53 stability by sequestering Mdm2 to the nucleolus. We found that after DNA damage, PML and Mdm2 accumulate in the nucleolus in an Arf-independent manner. In addition, we found that the nucleolar localization of PML is dependent on ATR activation and phosphorylation of PML by ATR. Notably, in Pml(-/-) cells, sequestration of Mdm2 to the nucleolus was impaired, as well as p53 stabilization and the induction of apoptosis. Furthermore, we demonstrate that PML physically associates with the nucleolar protein L11, and that L11 knockdown impairs the ability of PML to localize to nucleoli after DNA damage. These findings demonstrate an unexpected role of PML in the nucleolar network for tumour suppression. 相似文献
992.
993.
Eukaryotic cells use endocytosis to internalise plasma membrane, surface receptors and their ligands, viruses and various extracellular soluble molecules. Endocytosis has been regarded as a long-term mechanism of signal attenuation via receptor clearance from the cell surface. However, additional, and quite unexpected, functions for endocytosis have emerged, which, together with its attenuation function, project a central role for this process in cellular homeostasis and control of proliferation. Subversion of endocytic control is thus predicted to play a causative role in hyperproliferative conditions, first and foremost cancer. 相似文献
994.
Kuo‐Chin Huang Bee‐Horng Lue Ruoh‐Fang Yen Christopher G. Shen Shiuh‐Rong Ho Tong‐Yuan Tai Wei‐Shiung Yang 《Obesity (Silver Spring, Md.)》2004,12(1):119-124
Objectives: The relationship of plasma adiponectin levels with various anthropometric and metabolic factors has been surveyed extensively in adults. However, how plasma adiponectin levels are related to various anthropometric indices and cardiovascular risk factors in adolescents is not as vigorously studied. In this study, we investigated this among healthy nondiabetic adolescents. Research Methods and Procedures: Two hundred thirty nondiabetic subjects (125 boys and 105 girls, ~10 to 19 years old) were included. The plasma adiponectin, fasting plasma glucose, insulin, lipids and anthropometric indices including body height, weight, waist circumference, and hip circumference were examined. Body fat mass (FM) and percentage were obtained from DXA scan. The homeostasis model assessment was applied to estimate the degree of insulin resistance. Results: The plasma adiponectin levels were significantly higher in girls (30.79 ± 14.48 μg/mL) than boys (22.87 ± 11.41 μg/mL). The plasma adiponectin levels were negatively related to BMI, FM, FM percentage, waist circumference, waist‐to‐hip ratio, insulin resistance, plasma insulin, triglycerides, and uric acid levels, but positively with high‐density lipoprotein cholesterol (HDL‐C) with the adjustment for age and gender. Using different multivariate linear regression models, only age and HDL‐C were consistently related to the plasma adiponectin levels after adjustment for the other variables. Discussion: The relationship between plasma adiponectin and various anthropometric indices and metabolic factors, especially HDL‐C, previously reported in adults was present in the healthy nondiabetic adolescents. Whether variation of plasma adiponectin levels in healthy nondiabetic adolescents may influence their future coronary artery disease risk warrants further investigation. 相似文献
995.
Coregonine fish represent the most successful evolutionary lineage of salmonids with Coregonus as the most speciose salmonid genus inhabiting numerous postglacial lakes across the northern hemisphere. We isolated and characterized 31 polymorphic microsatellite loci in Coregonus clupeaformis with an average number of 5.3 alleles per locus (range three to eight) and an overall expected heterozygosity of 0.74 ± 0.11. Two loci revealed significant linkage associations through analyses of mapping families. Six additional salmonid taxa assessed for cross‐species amplification revealed between 18 and 26 positive amplifications and between two and 12 polymorphic loci per species. 相似文献
996.
Penolazzi L Bianchini E Lambertini E Baraldi PG Romagnoli R Piva R Gambari R 《Journal of biomedical science》2005,12(6):1013-1020
Summary The P2X7 nucleotide receptor is an ATP-gated ion channel that plays an important role in bone cell function. Here, we investigated
the effects of L-tyrosine derivatives 1–3 as potent P2X7 antagonists on human primary osteoclasts. We found that the level of expression of P2X7 receptor increased after treatment with the derivatives 1–3, together with the induction of high levels of apoptosis. This effect is associated with activation of caspase-3 and inhibition
of expression of IL-6. Interestingly, no pro-apoptotic effect of compounds 1–3 was found on human osteoblasts. Our results suggest that the development of specific P2X7 receptor antagonists may be considered a useful tool to modulate apoptosis of human osteoclasts. Since bone loss due to osteoclast-mediated
resorption represents one of the major unsolved problem in osteopenic disorders, the identification of molecules able to induce
apoptosis of osteoclasts is of great interest for the development of novel therapeutic strategies. 相似文献
997.
Yao‐Bin Liu Yogendra Kharode Peter V.N. Bodine Paul J. Yaworsky John A. Robinson Julia Billiard 《Journal of cellular biochemistry》2010,109(4):794-800
The bioactive phospholipid, lysophosphatidic acid (LPA), acting through at least five distinct receptors LPA1–LPA5, plays important roles in numerous biological processes. Here we report that LPA induces osteoblastic differentiation of human mesenchymal stem cells hMSC‐TERT. We find that hMSC‐TERT mostly express two LPA receptors, LPA1 and LPA4, and undergo osteoblastic differentiation in serum‐containing medium. Inhibition of LPA1 with Ki16425 completely abrogates osteogenesis, indicating that this process is mediated by LPA in the serum through activation of LPA1. In contrast to LPA1, down‐regulation of LPA4 expression with shRNA significantly increases osteogenesis, suggesting that this receptor normally exerts negative effects on differentiation. Mechanistically, we find that in hMSC‐TERT, LPA induces a rise in both cAMP and Ca2+. The rise in Ca2+ is completely abolished by Ki16425, whereas LPA‐mediated cAMP increase is not sensitive to Ki16425. To test if LPA signaling pathways controlling osteogenesis in vitro translate into animal physiology, we evaluated the bones of LPA4‐deficient mice. Consistent with the ability of LPA4 to inhibit osteoblastic differentiation of stem cells, LPA4‐deficient mice have increased trabecular bone volume, number, and thickness. J. Cell. Biochem. 109: 794–800, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
998.
Robert Lam Vladimir Romanov Kathy Johns Kevin P. Battaile Jean Wu‐Brown Jennifer L. Guthrie Robert P. Hausinger Emil F. Pai Nickolay Y. Chirgadze 《Proteins》2010,78(13):2839-2848
Urease plays a central role in the pathogenesis of Helicobacter pylori in humans. Maturation of this nickel metalloenzyme in bacteria requires the participation of the accessory proteins UreD (termed UreH in H. pylori), UreF, and UreG, which form sequential complexes with the urease apoprotein as well as UreE, a metallochaperone. Here, we describe the crystal structure of C‐terminal truncated UreF from H. pylori (residues 1–233), the first UreF structure to be determined, at 1.55 Å resolution using SAD methods. UreF forms a dimer in vitro and adopts an all‐helical fold congruent with secondary structure prediction. On the basis of evolutionary conservation analysis, the structure reveals a probable binding surface for interaction with other urease components as well as key conserved residues of potential functional relevance. Proteins 2010. © 2010 Wiley‐Liss, Inc. 相似文献
999.
Oscar Fernandez‐Capetillo 《EMBO reports》2010,11(1):32-36
Ageing is an unavoidable corollary to being alive; the most intuitive interpretation of ageing being that it is the consequence of progressive body degeneration. In agreement with this, current models propose that ageing occurs through a stepwise accumulation of DNA damage, which ultimately limits the regenerative capacity of tissues. On the other hand, there is increasing evidence that fetal distress can influence the development of disease in adult life, a phenomenon known as ‘intrauterine programming’. The extent to which an intrauterine exposure to DNA damage can compromise lifespan remains unclear. My group has recently generated a murine model of a human syndrome linked to defective DNA repair and observed that these animals age prematurely, but the accumulation of DNA damage is restricted mostly to the embryonic period. Here, I discuss the implications of this finding and propose that ageing can be influenced by fetal distress. 相似文献
1000.
Large filament proteins in muscle sarcomeres comprise many immunoglobulin‐like domains that provide a molecular platform for self‐assembly and interactions with heterologous protein partners. We have unravelled the molecular basis for the head‐to‐tail interaction of the carboxyl terminus of titin and the amino‐terminus of obscurin‐like‐1 by X‐ray crystallography. The binary complex is formed by a parallel intermolecular β‐sheet that presents a novel immunoglobulin‐like domain‐mediated assembly mechanism in muscle filament proteins. Complementary binding data show that the assembly is entropy‐driven rather than dominated data by specific polar interactions. The assembly observed leads to a V‐shaped zipper‐like arrangement of the two filament proteins. 相似文献