全文获取类型
收费全文 | 5400篇 |
免费 | 563篇 |
国内免费 | 3篇 |
出版年
2023年 | 22篇 |
2022年 | 62篇 |
2021年 | 119篇 |
2020年 | 78篇 |
2019年 | 84篇 |
2018年 | 132篇 |
2017年 | 94篇 |
2016年 | 198篇 |
2015年 | 300篇 |
2014年 | 302篇 |
2013年 | 332篇 |
2012年 | 414篇 |
2011年 | 379篇 |
2010年 | 244篇 |
2009年 | 239篇 |
2008年 | 279篇 |
2007年 | 338篇 |
2006年 | 261篇 |
2005年 | 249篇 |
2004年 | 200篇 |
2003年 | 189篇 |
2002年 | 219篇 |
2001年 | 101篇 |
2000年 | 76篇 |
1999年 | 88篇 |
1998年 | 54篇 |
1997年 | 57篇 |
1996年 | 35篇 |
1995年 | 30篇 |
1994年 | 44篇 |
1993年 | 28篇 |
1992年 | 71篇 |
1991年 | 51篇 |
1990年 | 45篇 |
1989年 | 48篇 |
1988年 | 25篇 |
1987年 | 34篇 |
1986年 | 31篇 |
1985年 | 40篇 |
1984年 | 47篇 |
1983年 | 28篇 |
1982年 | 36篇 |
1981年 | 23篇 |
1980年 | 18篇 |
1979年 | 15篇 |
1978年 | 22篇 |
1977年 | 19篇 |
1975年 | 15篇 |
1974年 | 12篇 |
1973年 | 18篇 |
排序方式: 共有5966条查询结果,搜索用时 718 毫秒
991.
Martínez-Pardo ME Hernández L Reyes-Frías Mde L Luna-Zaragoza D 《Cell and tissue banking》2010,11(4):393-395
This short communication describes how some Mexican tissue banks have established their own system for coding and traceability
of tissues. 相似文献
992.
João Gonçalves Sofia Nolasco Rute Nascimento Mónica Lopez Fanarraga Juan Carlos Zabala Helena Soares 《EMBO reports》2010,11(3):194-200
In animal cells the centrosome is positioned at the cell centre in close association with the nucleus. The mechanisms responsible for this are not completely understood. Here, we report the first characterization of human TBCC‐domain containing 1 (TBCCD1), a protein related to tubulin cofactor C. TBCCD1 localizes at the centrosome and at the spindle midzone, midbody and basal bodies of primary and motile cilia. Knockdown of TBCCD1 in RPE‐1 cells caused the dissociation of the centrosome from the nucleus and disorganization of the Golgi apparatus. TBCCD1‐depleted cells are larger, less efficient in primary cilia assembly and their migration is slower in wound‐healing assays. However, the major microtubule‐nucleating activity of the centrosome is not affected by TBCCD1 silencing. We propose that TBCCD1 is a key regulator of centrosome positioning and consequently of internal cell organization. 相似文献
993.
Enzymatic and nonenzymatic functions of viral RNA-dependent RNA polymerases within oligomeric arrays
Jeannie F. Spagnolo Evan Rossignol Esther Bullitt Karla Kirkegaard 《RNA (New York, N.Y.)》2010,16(2):382-393
Few antivirals are effective against positive-strand RNA viruses, primarily because the high error rate during replication of these viruses leads to the rapid development of drug resistance. One of the favored current targets for the development of antiviral compounds is the active site of viral RNA-dependent RNA polymerases. However, like many subcellular processes, replication of the genomes of all positive-strand RNA viruses occurs in highly oligomeric complexes on the cytosolic surfaces of the intracellular membranes of infected host cells. In this study, catalytically inactive polymerases were shown to participate productively in functional oligomer formation and catalysis, as assayed by RNA template elongation. Direct protein transduction to introduce either active or inactive polymerases into cells infected with mutant virus confirmed the structural role for polymerase molecules during infection. Therefore, we suggest that targeting the active sites of polymerase molecules is not likely to be the best antiviral strategy, as inactivated polymerases do not inhibit replication of other viruses in the same cell and can, in fact, be useful in RNA replication complexes. On the other hand, polymerases that could not participate in functional RNA replication complexes were those that contained mutations in the amino terminus, leading to altered contacts in the folded polymerase and mutations in a known polymerase–polymerase interaction in the two-dimensional protein lattice. Thus, the functional nature of multimeric arrays of RNA-dependent RNA polymerase supplies a novel target for antiviral compounds and provides a new appreciation for enzymatic catalysis on membranous surfaces within cells. 相似文献
994.
Stoeckli ET 《Current opinion in neurobiology》2006,16(1):35-39
Our knowledge about molecular mechanisms underlying axon guidance along the antero-posterior axis in contrast to the dorso-ventral axis of the developing nervous system is very limited. During the past two years in vitro and in vivo studies have indicated that morphogens have a role in longitudinal axon guidance. Morphogens are secreted proteins that act in a concentration-dependent manner on susceptible groups of precursor cells and induce their differentiation to a specific cell fate. Thus, gradients of morphogens are responsible for the appropriate patterning of the nervous system during early phases of neural development. Therefore, it was surprising to find that gradients of two of these morphogens, Wnt4 and Shh, can be re-used for longitudinal axon guidance during later stages of nervous system development. 相似文献
995.
996.
Bi X Lopez C Bacchi CJ Rattendi D Woster PM 《Bioorganic & medicinal chemistry letters》2006,16(12):3229-3232
A series of polyaminoguanidines and polyaminobiguanides were synthesized and evaluated as potential antitrypanosomal agents. These analogues inhibit trypanothione reductase (TR) with IC50 values as low as 0.95 microM, but do not inhibit the closely related human enzyme glutathione reductase (GR). The most effective analogues, 7a, 7b and 8d, inhibited parasitic growth in vitro with IC50 values of 0.18, 0.09 and 0.18 microM, respectively. These agents represent a promising new class of potential antitrypanosomal agents. 相似文献
997.
Mahmood NA Biemans-Oldehinkel E Patzlaff JS Schuurman-Wolters GK Poolman B 《The Journal of biological chemistry》2006,281(40):29830-29839
The ATPase subunit of the osmoregulatory ATP-binding cassette transporter OpuA from Lactococcus lactis has a C-terminal extension, the tandem cystathionine beta-synthase (CBS) domain, which constitutes the sensor that allows the transporter to sense and respond to osmotic stress (Biemans-Oldehinkel, E., Mahmood, N. A. B. N., and Poolman, B. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 10624-10629). C-terminal of the tandem CBS domain is an 18-residue anionic tail (DIPDEDEVEEIEKEEENK). To investigate the ion specificity of the full transporter, we probed the activity of inside-out reconstituted wild-type OpuA and the anionic tail deletion mutant OpuADelta12; these molecules have the tandem CBS domains facing the external medium. At a mole fraction of 40% of anionic lipids in the membrane, the threshold ionic strength for activation of OpuA was approximately 0.15, irrespective of the electrolyte composition of the medium. At equivalent concentrations, bivalent cations (Mg(2+) and Ba(2+)) were more effective in activating OpuA than NH(4)(+), K(+), Na(+), or Li(+), consistent with an ionic strength-based sensing mechanism. Surprisingly, Rb(+) and Cs(+) were potent inhibitors of wild-type OpuA, and 0.1 mM RbCl was sufficient to completely inhibit the transporter even in the presence of 0.2 M KCl. Rb(+) and Cs(+) were no longer inhibitory in OpuADelta12, indicating that the anionic C-terminal tail participates in the formation of a binding site for large alkali metal ions. Compared with OpuADelta12, wild-type OpuA required substantially less potassium ions (the dominant ion under physiological conditions) for activation. Our data lend new support for the contention that the CBS module in OpuA constitutes the ionic strength sensor whose activity is modulated by the C-terminal anionic tail. 相似文献
998.
Yannis Guillemin Jonathan Lopez Diana Gimenez Gustavo Fuertes Juan Garcia Valero Lo?c Blum Philippe Gonzalo Jesùs Salgado Agnès Girard-Egrot Abdel Aouacheria 《PloS one》2010,5(2)
Background
The BCL-2 family of proteins includes pro- and antiapoptotic members acting by controlling the permeabilization of mitochondria. Although the association of these proteins with the outer mitochondrial membrane is crucial for their function, little is known about the characteristics of this interaction.Methodology/Principal Findings
Here, we followed a reductionist approach to clarify to what extent membrane-active regions of homologous BCL-2 family proteins contribute to their functional divergence. Using isolated mitochondria as well as model lipid Langmuir monolayers coupled with Brewster Angle Microscopy, we explored systematically and comparatively the membrane activity and membrane-peptide interactions of fragments derived from the central helical hairpin of BAX, BCL-xL and BID. The results show a connection between the differing abilities of the assayed peptide fragments to contact, insert, destabilize and porate membranes and the activity of their cognate proteins in programmed cell death.Conclusion/Significance
BCL-2 family-derived pore-forming helices thus represent structurally analogous, but functionally dissimilar membrane domains. 相似文献999.
Meuwese MC Broekhuizen LN Kuikhoven M Heeneman S Lutgens E Gijbels MJ Nieuwdorp M Peutz CJ Stroes ES Vink H van den Berg BM 《PloS one》2010,5(12):e14262
Objective
Functional studies show that disruption of endothelial surface layer (ESL) is accompanied by enhanced sensitivity of the vasculature towards atherogenic stimuli. However, relevance of ESL disruption as causal mechanism for vascular dysfunction remains to be demonstrated. We examined if loss of ESL through enzymatic degradation would affect vascular barrier properties in an atherogenic model.Methods
Eight week old male apolipoprotein E deficient mice on Western-type diet for 10 weeks received continuous active or heat-inactivated hyaluronidase (10 U/hr, i.v.) through an osmotic minipump during 4 weeks. Blood chemistry and anatomic changes in both macrovasculature and kidneys were examined.Results
Infusion with active hyaluronidase resulted in decreased ESL (0.32±0.22 mL) and plasma volume (1.03±0.18 mL) compared to inactivated hyaluronidase (0.52±0.29 mL and 1.28±0.08 mL, p<0.05 respectively).Active hyaluronidase increased proteinuria compared to inactive hyaluronidase (0.27±0.02 vs. 0.15±0.01 µg/µg protein/creatinin, p<0.05) without changes in glomerular morphology or development of tubulo-interstitial inflammation. Atherosclerotic lesions in the aortic branches showed increased matrix production (collagen, 32±5 vs. 18±3%; glycosaminoglycans, 11±5 vs. 0.1±0.01%, active vs. inactive hyaluronidase, p<0.05).Conclusion
ESL degradation in apoE deficient mice contributes to reduced increased urinary protein excretion without significant changes in renal morphology. Second, the induction of compositional changes in atherogenic plaques by hyaluronidase point towards increased plaque vulnerability. These findings support further efforts to evaluate whether ESL restoration is a valuable target to prevent (micro) vascular disease progression. 相似文献1000.
Esther Conde Bárbara Angulo Pilar Redondo Oscar Toldos Elena García-García Ana Suárez-Gauthier Belén Rubio-Viqueira Carmen Marrón Ricardo García-Luján Montse Sánchez-Céspedes Angel López-Encuentra Luis Paz-Ares Fernando López-Ríos 《PloS one》2010,5(8)