全文获取类型
收费全文 | 3738篇 |
免费 | 250篇 |
出版年
2023年 | 18篇 |
2022年 | 35篇 |
2021年 | 56篇 |
2020年 | 48篇 |
2019年 | 62篇 |
2018年 | 87篇 |
2017年 | 72篇 |
2016年 | 94篇 |
2015年 | 159篇 |
2014年 | 157篇 |
2013年 | 246篇 |
2012年 | 307篇 |
2011年 | 229篇 |
2010年 | 158篇 |
2009年 | 151篇 |
2008年 | 194篇 |
2007年 | 202篇 |
2006年 | 206篇 |
2005年 | 174篇 |
2004年 | 159篇 |
2003年 | 138篇 |
2002年 | 157篇 |
2001年 | 86篇 |
2000年 | 59篇 |
1999年 | 54篇 |
1998年 | 57篇 |
1997年 | 42篇 |
1996年 | 37篇 |
1995年 | 32篇 |
1994年 | 24篇 |
1993年 | 20篇 |
1992年 | 32篇 |
1991年 | 46篇 |
1990年 | 37篇 |
1989年 | 35篇 |
1988年 | 21篇 |
1987年 | 23篇 |
1986年 | 28篇 |
1985年 | 22篇 |
1984年 | 40篇 |
1983年 | 13篇 |
1982年 | 22篇 |
1981年 | 18篇 |
1980年 | 13篇 |
1979年 | 13篇 |
1978年 | 19篇 |
1977年 | 12篇 |
1976年 | 16篇 |
1975年 | 8篇 |
1974年 | 12篇 |
排序方式: 共有3988条查询结果,搜索用时 265 毫秒
961.
De Angeli A Monachello D Ephritikhine G Frachisse JM Thomine S Gambale F Barbier-Brygoo H 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2009,364(1514):195-201
Plants need nitrate for growth and store the major part of it in the central vacuole of cells from root and shoot tissues. Based on few studies on the two model plants Arabidopsis thaliana and rice, members of the large ChLoride Channel (CLC) family have been proposed to encode anion channels/transporters involved in nitrate homeostasis. Proteins from the Arabidopsis CLC family (AtClC, comprising seven members) are present in various membrane compartments including the vacuolar membrane (AtClCa), Golgi vesicles (AtClCd and AtClCf) or chloroplast membranes (AtClCe). Through a combination of electrophysiological and genetic approaches, AtClCa was shown to function as a 2NO3-/1H+ exchanger that is able to accumulate specifically nitrate into the vacuole, in agreement with the main phenotypic trait of knockout mutant plants that accumulate 50 per cent less nitrate than their wild-type counterparts. The set-up of a functional complementation assay relying on transient expression of AtClCa cDNA in the mutant background opens the way for studies on structure-function relationships of the AtClCa nitrate transporter. Such studies will reveal whether important structural determinants identified in bacterial or mammalian CLCs are also crucial for AtClCa transport activity and regulation. 相似文献
962.
Ana Carolina C. Asbahr Luzia Franco Andersson Barison Caroline W.P. Silva Humberto G. Ferraz Letícia N.C. Rodrigues 《Bioorganic & medicinal chemistry》2009,17(7):2718-2723
The aim of this study was to determine whether inclusion complexes between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and finasteride (FIN) are formed, and to characterize these. Equimolar FIN/HPβCD solid systems in the presence or absence of 0.1% (w/v) of polyvinylpyrrolidone K30 (PVP K30) or 0.3% of chitosan were prepared by coevaporation and freeze-drying methods. The systems were characterized by phase solubility, NMR, DSC, and XRD analysis. The results suggest that true binary and ternary inclusion complexes were formed. 相似文献
963.
Nicoletta Bodrato Luisa Franco Chiara Fresia Lucrezia Guida Cesare Usai Annalisa Salis Iliana Moreschi Chiara Ferraris Claudia Verderio Giovanna Basile Santina Bruzzone Sonia Scarf�� Antonio De Flora Elena Zocchi 《The Journal of biological chemistry》2009,284(22):14777-14787
Abscisic acid (ABA) is a phytohormone regulating important functions in
higher plants, notably responses to abiotic stress. Recently, chemical or
physical stimulation of human granulocytes was shown to induce production and
release of endogenous ABA, which activates specific cell functions. Here we
provide evidence that ABA stimulates several functional activities of the
murine microglial cell line N9 (NO and tumor necrosis factor-α
production, cell migration) through the second messenger cyclic ADP-ribose and
an increase of intracellular calcium. ABA production and release occur in N9
cells stimulated with bacterial lipopolysaccharide, phorbol myristate acetate,
the chemoattractant peptide f-MLP, or β-amyloid, the primary plaque
component in Alzheimer disease. Finally, ABA priming stimulates N9 cell
migration toward β-amyloid. These results indicate that ABA is a
pro-inflammatory hormone inducing autocrine microglial activation, potentially
representing a new target for anti-inflammatory therapies aimed at limiting
microglia-induced tissue damage in the central nervous system.Microglial cells are the monocyte/macrophage equivalent of the central
nervous system and represent the first line of defense in the brain, by
removing infectious agents and damaged cells
(1). Microglia can also release
a variety of trophic factors and cytokines able to regulate the communication
between neuronal and other glial cells and can contribute to tissue repair and
neuroprotection
(2–4).
Pathologic microglial activation, however, confers neurotoxic properties to
these cells, thereby causing neuronal degeneration
(5). Excessive activation of
microglia, under conditions of chronic inflammation, can contribute to the
pathogenesis of neurodegenerative diseases, such as multiple sclerosis and
Alzheimer and Parkinson diseases, by producing and releasing a number of
potentially cytotoxic substances, including pro-inflammatory cytokines and NO
(4,
6–8).
Therefore, identification of the molecular mechanisms underlying microglial
activation might lead to the development of new anti-inflammatory drugs for
the treatment of these diseases.Abscisic acid
(ABA)2 is a plant
hormone regulating important biological functions in higher plants, including
response to abiotic stress, control of stomatal closure, regulation of seed
dormancy, and germination (9).
Recently, ABA was shown to behave as an endogenous pro-inflammatory hormone in
human granulocytes (10),
stimulating several functional activities of these cells (migration,
phagocytosis, reactive oxygen species, and NO production) through a signaling
cascade that involves a protein kinase A-mediated ADP-ribosyl cyclase
phosphorylation and consequent overproduction of the universal Ca2+
mobilizer cyclic ADP-ribose (cADPR)
(11). This mechanism leads to
an increase of the intracellular Ca2+ concentration, which is
ultimately responsible for granulocyte activation
(10).The facts that microglial cells play a defensive role in the central
nervous system similar to that of granulocytes in other tissues and that cADPR
has been described as the second messenger involved in the activation of
microglia induced by lipopolysaccharide (LPS)
(12) prompted us to
investigate the effect of ABA in these cells.Indeed, exogenous ABA, at concentrations ranging from 250 nm to
20 μm, elicits functional activation of murine N9 cells,
stimulating TNF-α release and cell migration through activation of the
ADP-ribosyl cyclase CD38 and overproduction of cADPR. Moreover, N9 cells
produce and release ABA when stimulated with LPS, amyloid β-peptide
(βA), phorbol myristate acetate (PMA), or the chemoattractant peptide
f-MLP. These results indicate that ABA behaves as an endogenous,
pro-inflammatory hormone in murine microglia and provide a new target for
future investigations into the role of this hormone in inflammatory and
degenerative diseases of the central nervous system accompanied by microglial
activation. 相似文献
964.
Shira Corem Armando Carpaneto Paolo Soliani Laura Cornara Franco Gambale Joachim Scholz-Starke 《European biophysics journal : EBJ》2009,38(4):495-501
We applied the patch-clamp technique to investigate the transport properties of the Slow Vacuolar (SV) channel identified
in leaf vacuoles of Alyssum bertolonii Desv., a nickel hyperaccumulator plant growing in serpentine soil of the northern Apennines (Italy). SV currents recorded
in vacuoles from adult plants collected in their natural habitat showed high sensitivity towards cytosolic nickel. Dose-response
analyses indicated half-maximal current inhibition at submicromolar concentrations, i.e. up to three orders of magnitude lower
than previously reported values from other plant species. The voltage-dependent increase of residual currents at saturating
nickel concentrations could be interpreted as relief of channel block by nickel permeation at high positive membrane potentials.
Including young plants of A. bertolonii into the study, we found that SV channels from these plants did not display elevated nickel sensitivity. This difference
may be related to age-dependent changes in nickel hyperaccumulation of A. bertolonii leaf cells. 相似文献
965.
The structural basis of Arf effector specificity: the crystal structure of ARF6 in a complex with JIP4
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Karine Regazzoni Bertrand Raynal Fatima El Khadali Patrick England Michel Franco Philippe Chavrier Anne Houdusse Julie Ménétrey 《The EMBO journal》2009,28(18):2835-2845
The JNK‐interacting proteins, JIP3 and JIP4, are specific effectors of the small GTP‐binding protein ARF6. The interaction of ARF6–GTP with the second leucine zipper (LZII) domains of JIP3/JIP4 regulates the binding of JIPs to kinesin‐1 and dynactin. Here, we report the crystal structure of ARF6–GTP bound to the JIP4‐LZII at 1.9 Å resolution. The complex is a heterotetramer with dyad symmetry arranged in an ARF6–(JIP4)2–ARF6 configuration. Comparison of the ARF6–JIP4 interface with the equivalent region of ARF1 shows the structural basis of JIP4's specificity for ARF6. Using site‐directed mutagenesis and surface plasmon resonance, we further show that non‐conserved residues at the switch region borders are the key structural determinants of JIP4 specificity. A structure‐derived model of the association of the ARF6–JIP3/JIP4 complex with membranes shows that the JIP4‐LZII coiled‐coil should lie along the membrane to prevent steric hindrances, resulting in only one ARF6 molecule bound. Such a heterotrimeric complex gives insights to better understand the ARF6‐mediated motor switch regulatory function. 相似文献
966.
967.
Chiara Giommarelli Alessandro Corti Rosanna Supino Enrica Favini Aldo Paolicchi Alfonso Pompella Franco Zunino 《Free radical biology & medicine》2009,46(11):1516-1526
The cell ability of tumor cells to tolerate stress conditions is a typical feature of solid tumors. In particular, the resistance to oxidative stress of melanoma cells likely contributes to their intrinsic drug resistance. In an attempt to develop novel strategies for overcoming the mechanisms of cellular protection against oxidative stress, in this study we have explored the efficacy of the combination of two prooxidant agents in two human melanoma cell clones. The selected clones are characterized by a marked difference in expression of γ-glutamyltransferase, which is known to produce a persistent low level of oxidative stress resulting in the stimulation of protective systems. The γ-glutamyltransferase-overexpressing clone exhibited a low susceptibility to arsenic trioxide-induced apoptosis, associated with low reactive oxygen species induction and increased catalase activity. The combination of arsenic trioxide with subtoxic concentrations of ascorbic acid resulted in a sensitization to apoptotic cell death. The expression of protective mechanisms, in particular catalase activity, accounted for the behavior of the resistant clone. The sensitization achieved by the combination was associated with a cellular response involving the ASK1/p38 axis, which is implicated in the regulation of catalase expression and the activation of apoptotic signals. In conclusion, the results of our study provide evidence that a rational combination of prooxidant agents may be effective in overcoming cellular tolerance to oxidative stress. 相似文献
968.
The straightforward synthesis of a series of enantiomerically pure Lewis basic amides by simple condensation of commercially available enantiopure diamines with picolinic acid is reported. These compounds were shown to promote the enantioselective reduction of ketoimines with trichlorosilane. Working with the model substrate N-phenyl benzophenone imine, the new organocatalysts led to the formation of the corresponding amine, with excellent chemical efficiency (up to 99% chemical yield) and good stereoselectivity (up to 73% ee). Up to 83% of enantioselectivity was reached in the reduction of differently substituted imines. 相似文献
969.
Borys Szefczyk M. Natália D. S. Cordeiro Ricardo Franco José A. N. F. Gomes 《Journal of biological inorganic chemistry》2009,14(7):1119-1128
Molecular dynamics simulations of the wild-type and variant forms of the mouse ferrochelatase in complex with the product
(haem) have been performed using the GROMOS96 force field, in the NpT ensemble. Ferrochelatase, the last enzyme in the catalytic
pathway of the haem biosynthesis, catalyses the reaction of insertion of a ferrous ion into protoporphyrin IX by distorting
the planar geometry of the latter reactant. The simulations presented aim at understanding the role of active-site residues
in this catalytic process. Analysis of the simulation trajectories explains the consequences of the mutations introduced and
sheds more light on the role of the His209 residue in porphyrin macrocycle distortion. The function of residues coordinating
propionate groups of the haem molecule is discussed in terms of stability of the substrate and product complexes. 相似文献
970.
A highly stable functional composite film was prepared using polyazetidine prepolymer (PAP) with peroxidase from horseradish (HRP) and/or glucose oxidase (GOx). The good permeability of the PAP layer to classical electrochemical mediators, as evaluated by the determination of the diffusion coefficient of different redox molecules, is of great importance in view of the use of PAP as an immobilizing agent in second-generation biosensor development. Cyclic voltammetry of the HRP-PAP layer on a glassy carbon electrode (GCE) showed a pair of stable and quasi-reversible peaks for the HRP-Fe((III))/Fe((II)) redox couple at about -370 mV vs. Ag/AgCl electrode in pH 6.5 phosphate buffer. The electrochemical reaction of HRP entrapped in the PAP film exhibited a surface-controlled electrode process. This film and the successive modifications (HRP-PAP self-assembled monolayer (SAM) modified Au electrode) were used as a biological catalyst (hydrogen peroxide transducers) for glucose biosensors, after coupling to GOx. Both HRP/GOx-PAP and HRP/GOx-PAP SAM third generation biosensors were prepared and characterized. The use of PAP as immobilizing agent offers a biocompatible micro-environment for confining the enzyme and foreshadows the great potentiality of this immobilizing agent not only in theoretical studies on protein direct electron transfer but also from an applications point of view in the development of second- and third-generation biosensors. 相似文献