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981.
Korolyov A Dorbes S Azéma J Guidetti B Danel M Lamoral-Theys D Gras T Dubois J Kiss R Martino R Malet-Martino M 《Bioorganic & medicinal chemistry》2010,18(24):8537-8548
A convenient route for the synthesis of some acyloxymethyl esters and carboxamides of levofloxacin (LV) with modulated lipophilicity is described. The synthesized compounds were evaluated in vitro for their growth inhibitory effect in five human cancer cell lines. The most efficient LV derivatives (ester 2e and amide 4d) displayed IC(50) values in the 0.2-2.2 μM range, while IC(50) values for parent LV ranged between 70 and 622 μM depending on the cell line. The esters displayed no in vivo toxicity up to 80 mg/kg when administered intraperitoneally. This study thus shows that LV analogs displayed antitumor efficacy, at least in vitro, a feature that appeared to be independent from the lipophilicity of the grafted substituent. 相似文献
982.
Lactoferrin (Lf) is a mammalian exclusive protein widely distributed in milk and exocrine secretions exhibiting multifunctional
properties. Many of the proven or proposed functions of Lf, apart from its iron binding activity, depend on its capacity to
bind to other macromolecules. Lf can bind and sequester lipopolysaccharide (LPS), thus preventing pro-inflammatory pathway
activation, sepsis and tissue damage. However, the interplay between Lf and LPS is complex, and may result in different outcomes,
including both suppression of the inflammatory response and immune activation. These findings are critically relevant in the
development of Lf-based therapeutic interventions in humans. Understanding the molecular basis and functional consequences
of Lf-LPS interaction will provide insights for determining its role in health and disease. 相似文献
983.
984.
Krešimir Benci Karlo Wittine Malajka Radan Mario Cetina Mirela Sedić Sandra Kraljević Pavelić Krešimir Pavelić Erik De Clercq Mladen Mintas 《Bioorganic & medicinal chemistry》2010,18(17):6249-6257
A series of the novel acyclic unsaturated pyrimidine (1–12) and adenine (13) nucleoside analogues bearing conformationally restricted (Z)-2′-butenyl moiety were synthesized and evaluated for their antiviral and cytostatic activity potency against malignant tumor cell lines and normal human fibroblast (WI38). The N-1 and/or N-3 acyclic side chain substitution in pyrimidine ring in N-3 substituted 5-trifluoromethyluracil derivative (11), N-1, N-3 disubstituted 5-fluorouracil derivative (12) and adenine derivative (13) was deduced from their 1H and 13C NMR spectra and confirmed by single crystal X-ray structure analysis. The X-ray crystal structure analysis 11–13 revealed also supramolecular self-assemblies, in which infinite chains or dimers built two- and three-dimensional networks. The results of the in vitro cytostatic activity evaluations of 1–13 indicate that the majority of the compounds tested exhibited a non-specific and moderate antiproliferative effect at the highest concentration (100 μM). Of all evaluated compounds on the cell lines tested only the N-1 4″-fluoro-substituted-benzamide uracil derivative (7) showed rather marked and selective inhibitory activity against the growth of MCF-7 cells at a concentration of 2.7 μM and no cytotoxic effect on normal fibroblasts WI38. This compound can be therefore considered as a potential antitumor lead compound for further synthetic structure modification. 相似文献
985.
986.
Donghai Li Sandra L. Harper Hsin-Yao Tang Yelena Maksimova Patrick G. Gallagher David W. Speicher 《The Journal of biological chemistry》2010,285(38):29535-29545
Spectrin dimer-tetramer interconversion is a critical contributor to red cell membrane stability, but some properties of spectrin tetramer formation cannot be studied effectively using monomeric recombinant domains. To address these limitations, a fused αβ mini-spectrin was produced that forms wild-type divalent tetramer complexes. Using this mini-spectrin, a medium-resolution structure of a seven-repeat bivalent tetramer was produced using homology modeling coupled with chemical cross-linking. Inter- and intramolecular cross-links provided critical distance constraints for evaluating and optimizing the best conformational model and appropriate docking interfaces. The two strands twist around each other to form a super-coiled, rope-like structure with the AB helix face of one strand associating with the opposing AC helix face. Interestingly, two tetramer site hereditary anemia mutations that exhibit wild-type binding in univalent head-to-head assays are located in the interstrand region. This suggests that perturbations of the interstrand region can destabilize spectrin tetramers and the membrane skeleton. The α subunit N-terminal cross-links to multiple sites on both strands, demonstrating that this non-homologous tail remains flexible and forms heterogeneous structures in the tetramer complex. Although no cross-links were observed involving the β subunit non-homologous C-terminal tail, several cross-links were observed only when this domain was present, suggesting it induces subtle conformational changes to the tetramer site region. This medium-resolution model provides a basis for further studies of the bivalent spectrin tetramer site, including analysis of functional consequences of interstrand interactions and mutations located at substantial molecular distances from the tetramer site. 相似文献
987.
Gesa Rickheit Lena Wartosch Sven Schaffer Sandra M. Stobrawa Gaia Novarino Stefanie Weinert Thomas J. Jentsch 《The Journal of biological chemistry》2010,285(23):17595-17603
Inactivation of the mainly endosomal 2Cl−/H+-exchanger ClC-5 severely impairs endocytosis in renal proximal tubules and underlies the human kidney stone disorder Dent''s disease. In heterologous expression systems, interaction of the E3 ubiquitin ligases WWP2 and Nedd4-2 with a “PY-motif” in the cytoplasmic C terminus of ClC-5 stimulates its internalization from the plasma membrane and may influence receptor-mediated endocytosis. We asked whether this interaction is relevant in vivo and generated mice in which the PY-motif was destroyed by a point mutation. Unlike ClC-5 knock-out mice, these knock-in mice displayed neither low molecular weight proteinuria nor hyperphosphaturia, and both receptor-mediated and fluid-phase endocytosis were normal. The abundances and localizations of the endocytic receptor megalin and of the Na+-coupled phosphate transporter NaPi-2a (Npt2) were not changed, either. To explore whether the discrepancy in results from heterologous expression studies might be due to heteromerization of ClC-5 with ClC-3 or ClC-4 in vivo, we studied knock-in mice additionally deleted for those related transporters. Disruption of neither ClC-3 nor ClC-4 led to proteinuria or impaired proximal tubular endocytosis by itself, nor in combination with the PY-mutant of ClC-5. Endocytosis of cells lacking ClC-5 was not impaired further when ClC-3 or ClC-4 was additionally deleted. We conclude that ClC-5 is unique among CLC proteins in being crucial for proximal tubular endocytosis and that PY-motif-dependent ubiquitylation of ClC-5 is dispensable for this role. 相似文献
988.
Sandra Maria Sbeghen Ferreira de Freitas John Peter Scholz 《Journal of biomechanics》2010,43(4):775-777
Uncontrolled Manifold (UCM) analysis has been used to identify a component of joint variance leading to pointer-tip position variability and a component representing motor abundant joint combinations corresponding to an equivalent pointer-tip position. A Jacobian is required for UCM analysis, typically derived from an analytic model relating joint postures to pointer-tip position. Derivation of the Jacobian is often non-trivial, however, because of the complexity of the system being studied. In this article, we compared the effect of different methods of deriving the Jacobian on results of UCM analyses during reaching. Jacobian matrices were determined at each percentage of the reach across trials using one of three methods: (M1) partial derivatives of the geometric model relating ten joint postures, segment lengths and pointer length to the position of a hand-mounted pointer tip; or (M2–M3) as the coefficients of linear regression between the ten joint postures and either (M2) the pointer tip position measured directly from motion capture or (M3) the pointer-tip position estimated from the geometric model. For all methods, motor abundant joint variance (VUCM) was larger than joint variance leading to a variable pointer-tip position (VORT). Results did not differ among methods prior to the time of peak velocity. Thereafter, M2 yielded lower VORT and slightly higher VUCM compared to M1. Method M3 was used to disambiguate the possible effect of estimating model parameters for the geometric model on the M1–M2 comparison. The advantages of the use of linear regression method in the UCM approach are discussed. 相似文献
989.
Hesso Farhan Markus W. Wendeler Sandra Mitrovic Eugenio Fava Yael Silberberg Roded Sharan Marino Zerial Hans-Peter Hauri 《The Journal of cell biology》2010,189(6):997-1011
To what extent the secretory pathway is regulated by cellular signaling is unknown. In this study, we used RNA interference to explore the function of human kinases and phosphatases in controlling the organization of and trafficking within the secretory pathway. We identified 122 kinases/phosphatases that affect endoplasmic reticulum (ER) export, ER exit sites (ERESs), and/or the Golgi apparatus. Numerous kinases/phosphatases regulate the number of ERESs and ER to Golgi protein trafficking. Among the pathways identified, the Raf–MEK (MAPK/ERK [extracellular signal-regulated kinase] kinase)–ERK cascade, including its regulatory proteins CNK1 (connector enhancer of the kinase suppressor of Ras-1) and neurofibromin, controls the number of ERESs via ERK2, which targets Sec16, a key regulator of ERESs and COPII (coat protein II) vesicle biogenesis. Our analysis reveals an unanticipated complexity of kinase/phosphatase-mediated regulation of the secretory pathway, uncovering a link between growth factor signaling and ER export. 相似文献
990.
Marcel Mettlen Dinah Loerke Defne Yarar Gaudenz Danuser Sandra L. Schmid 《The Journal of cell biology》2010,188(6):919-933
Clathrin-mediated endocytosis of surface receptors and their bound ligands (i.e., cargo) is highly regulated, including by the cargo itself. One of the possible sources of the observed heterogeneous dynamics of clathrin-coated pits (CCPs) might be the different cargo content. Consistent with this, we show that CCP size and dynamic behavior varies with low density lipoprotein receptor (LDLR) expression levels in a manner dependent on the LDLR-specific adaptors, Dab2 and ARH. In Dab2-mCherry–expressing cells, varying LDLR expression leads to a progressive increase in CCP size and to the appearance of nonterminal endocytic events. In LDLR and ARH-mCherry–expressing cells in addition to an increase in CCP size, turnover of abortive CCPs increases, and the rate of CCP maturation decreases. Altogether, our results underscore the highly dynamic and cargo-responsive nature of CCP assembly and suggest that the observed heterogeneity is, in part, related to compositional differences (e.g., cargo and adaptors) between CCPs. 相似文献