全文获取类型
收费全文 | 1146篇 |
免费 | 82篇 |
出版年
2023年 | 6篇 |
2022年 | 18篇 |
2021年 | 21篇 |
2020年 | 19篇 |
2019年 | 19篇 |
2018年 | 50篇 |
2017年 | 20篇 |
2016年 | 43篇 |
2015年 | 68篇 |
2014年 | 79篇 |
2013年 | 73篇 |
2012年 | 95篇 |
2011年 | 108篇 |
2010年 | 57篇 |
2009年 | 35篇 |
2008年 | 54篇 |
2007年 | 71篇 |
2006年 | 44篇 |
2005年 | 46篇 |
2004年 | 43篇 |
2003年 | 45篇 |
2002年 | 44篇 |
2001年 | 22篇 |
2000年 | 18篇 |
1999年 | 15篇 |
1998年 | 5篇 |
1997年 | 7篇 |
1996年 | 7篇 |
1995年 | 7篇 |
1994年 | 7篇 |
1993年 | 9篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 5篇 |
1989年 | 2篇 |
1988年 | 7篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 4篇 |
1982年 | 2篇 |
1980年 | 3篇 |
1979年 | 8篇 |
1978年 | 6篇 |
1977年 | 4篇 |
1975年 | 2篇 |
1968年 | 1篇 |
1965年 | 2篇 |
1960年 | 1篇 |
1951年 | 1篇 |
1947年 | 1篇 |
排序方式: 共有1228条查询结果,搜索用时 15 毫秒
41.
Mia Petljak Ludmil B. Alexandrov Jonathan S. Brammeld Stacey Price David C. Wedge Sebastian Grossmann Kevin J. Dawson Young Seok Ju Francesco Iorio Jose M.C. Tubio Ching Chiek Koh Ilias Georgakopoulos-Soares Bernardo Rodríguez–Martín Burçak Otlu Sarah O’Meara Adam P. Butler Andrew Menzies Shriram G. Bhosle Michael R. Stratton 《Cell》2019,176(6):1282-1294.e20
42.
Jon Ochoa Adrin Valli Mar Martín‐Trillo Carmen Simn‐Mateo Juan Antonio García Bernardo Rodamilans 《Plant, cell & environment》2019,42(11):3015-3026
Plants use RNA silencing as a strong defensive barrier against virus challenges, and viruses counteract this defence by using RNA silencing suppressors (RSSs). With the objective of identifying host factors helping either the plant or the virus in this interaction, we have performed a yeast two‐hybrid screen using P1b, the RSS protein of the ipomovirus Cucumber vein yellowing virus (CVYV, family Potyviridae), as a bait. The C‐8 sterol isomerase HYDRA1 (HYD1), an enzyme involved in isoprenoid biosynthesis and cell membrane biology, and required for RNA silencing, was isolated in this screen. The interaction between CVYV P1b and HYD1 was confirmed in planta by Bimolecular Fluorescence Complementation assays. We demonstrated that HYD1 negatively impacts the accumulation of CVYV P1b in an agroinfiltration assay. Moreover, expression of HYD1 inhibited the infection of the potyvirus Plum pox virus, especially when antiviral RNA silencing was boosted by high temperature or by coexpression of homologous sequences. Our results reinforce previous evidence highlighting the relevance of particular composition and structure of cellular membranes for RNA silencing and viral infection. We report a new interaction of an RSS protein from the Potyviridae family with a member of the isoprenoid biosynthetic pathway. 相似文献
43.
44.
Weinman EJ Evangelista CM Steplock D Liu MZ Shenolikar S Bernardo A 《The Journal of biological chemistry》2001,276(45):42339-42346
Prior studies have indicated a requirement for the PDZ domain-containing protein, Na(+)/H(+) Exchanger Regulatory Factor (NHERF), for protein kinase A (PKA)-mediated inhibition of the renal basolateral Na(+)-HCO(3)(-) co-transporter (NBC). The present studies explore the potential mechanisms by which NHERF transduces cAMP signals to inhibit NBC. In BSC-1 cells, cells that express NBC but lack NHERF, 8-bromo-cAMP (100 microm for 15 min) failed to inhibit transport until wild-type mNHERF-(1-355) was expressed. mNHERF-(116-355) containing PDZ II and C-terminal ezrin-binding sequences or a mutant unphosphorylated form of rabbit NHERF effectively transduced the cAMP signals that inhibited NBC. By contrast, mNHERF-(1-126) encompassing N-terminal PDZ I and mNHERF-(1-325), which lacks ezrin-binding, failed to support cAMP inhibition of NBC activity. NBC and NHERF did not associate with each other in yeast two-hybrid or co-immunoprecipitation assays, and confocal microscopy indicated distinct subcellular localization of the two proteins. NBC was phosphorylated in BSC-1 cells, but its phosphorylation was not increased by cAMP nor was immunoprecipitated NBC phosphorylated by PKA in vitro. Acute exposure of mNHERF-(1-355)-expressing BSC-1 cells to cAMP did not change cell surface expression of NBC. Although these results established an essential role for NHERF in cAMP-mediated inhibition of NBC in BSC-1 cells, they also suggest a novel mechanism for NHERF-mediated signal transduction distinct from that previously characterized from studies of other NHERF targets. 相似文献
45.
Kleifeld O Kotra LP Gervasi DC Brown S Bernardo MM Fridman R Mobashery S Sagi I 《The Journal of biological chemistry》2001,276(20):17125-17131
Malignant tumors express high levels of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs), which are thought to facilitate tumor metastasis and angiogenesis by hydrolyzing components of the extracellular matrix. Of these enzymes, gelatinases A (MMP-2) and B (MMP-9), have especially been implicated in malignant processes, and thus, they have been a target for drugs designed to block their activity. Therefore, understanding their molecular structure is key for a rational approach to inhibitor design. Here, we have conducted x-ray absorption spectroscopy of the full-length human MMP-2 in its latent, active, and inhibited states and report the structural changes at the zinc ion site upon enzyme activation and inhibition. We have also examined the molecular structure of MMP-2 in complex with SB-3CT, a recently reported novel mechanism-based synthetic inhibitor that was designed to be highly selective in gelatinases. It is shown that SB-3CT directly binds the catalytic zinc ion of MMP-2. Interestingly, the novel mode of binding of the inhibitor to the catalytic zinc reconstructs the conformational environment around the active site metal ion back to that of the proenzyme. 相似文献
46.
Malaria parasites (species of the genus Plasmodium) harbor a relict chloroplast (the apicoplast) that is the target of novel antimalarials. Numerous nuclear-encoded proteins are translocated into the apicoplast courtesy of a bipartite N-terminal extension. The first component of the bipartite leader resembles a standard signal peptide present at the N-terminus of secreted proteins that enter the endomembrane system. Analysis of the second portion of the bipartite leaders of P. falciparum, the so-called transit peptide, indicates similarities to plant transit peptides, although the amino acid composition of P. falciparum transit peptides shows a strong bias, which we rationalize by the extraordinarily high AT content of P. falciparum DNA. 786 plastid transit peptides were also examined from several other apicomplexan parasites, as well as from angiosperm plants. In each case, amino acid biases were correlated with nucleotide AT content. A comparison of a spectrum of organisms containing primary and secondary plastids also revealed features unique to secondary plastid transit peptides. These unusual features are explained in the context of secondary plastid trafficking via the endomembrane system. 相似文献
47.
Striatal medium spiny neurons (MSNs) in vivo undergo large membrane depolarizations known as state transitions. Calcium (Ca) entry into MSNs triggers diverse downstream cellular processes. However, little is known about Ca signals in MSN dendrites and spines and how state transitions influence these signals. Here, we develop a novel approach, combining 2-photon Ca imaging and 2-photon glutamate uncaging, to examine how voltage-sensitive Ca channels (VSCCs) and ionotropic glutamate receptors contribute to Ca signals in MSNs. We find that upstate transitions switch the VSCCs available in dendrites and spines, decreasing T-type while enhancing L-type channels. Moreover, these transitions change the dominant synaptic Ca source from Ca-permeable AMPA receptors to NMDA receptors. Finally, pairing bAPs with synaptic inputs generates additional synaptic Ca signals due to enhanced Ca influx through NMDA receptors. By altering the sources, amplitude, and kinetics of spine Ca signals, state transitions may gate synaptic plasticity and gene expression in MSNs. 相似文献
48.
Miguel?PetrereJr.Email author Ronaldo?Borges?Barthem Edwin?Agudelo?Córdoba Bernardo?Corrales?Gómez 《Reviews in Fish Biology and Fisheries》2004,14(4):403-414
In this paper we describe the present status of the large migratory catfish fisheries in the Upper Amazon. We present biological information about the main species and we give strong evidence that the stock of piraíba (Brachyplatystoma filamentosum),the largest catfish in the Amazon Basin is probably over-exploited. In conclusion, we raise some hypotheses about the causes and prospects for the future. 相似文献
49.
Barrera NP Morales B Villalón M 《American journal of physiology. Cell physiology》2004,287(4):C1114-C1124
An increase in intracellular free Ca2+ concentration ([Ca2+]i) has been shown to be involved in the increase in ciliary beat frequency (CBF) in response to ATP; however, the signaling pathways associated with inositol 1,4,5-trisphosphate (IP3) receptor-dependent Ca2+ mobilization remain unresolved. Using radioimmunoassay techniques, we have demonstrated the appearance of two IP3 peaks occurring 10 and 60 s after ATP addition, which was strongly correlated with a release of intracellular Ca2+ from internal stores and an influx of extracellular Ca2+, respectively. In addition, ATP-dependent Ca2+ mobilization required protein kinase C (PKC) and Ca2+/calmodulin-dependent protein kinase II activation. We found an increase in PKC activity in response to ATP, with a peak at 60 s after ATP addition. Xestospongin C, an IP3 receptor blocker, significantly diminished both the ATP-induced increase in CBF and the initial transient [Ca2+]i component. ATP addition in the presence of xestospongin C or thapsigargin revealed that the Ca2+ influx is also dependent on IP3 receptor activation. Immunofluorescence and confocal microscopic studies showed the presence of IP3 receptor types 1 and 3 in cultured ciliated cells. Immunogold electron microscopy localized IP3 receptor type 3 to the nucleus, the endoplasmic reticulum, and, interestingly, the plasma membrane. In contrast, IP3 receptor type 1 was found exclusively in the nucleus and the endoplasmic reticulum. Our study demonstrates for the first time the presence of IP3 receptor type 3 in the plasma membrane in ciliated cells and leads us to postulate that the IP3 receptor can directly trigger Ca2+ influx in response to ATP. transduction mechanisms; P2Y receptor; calcium influx 相似文献
50.
González-Alvarez M Alzuet G Borrás J del Castillo Agudo L García-Granda S Montejo Bernardo JM 《Journal of inorganic biochemistry》2004,98(2):189-198
Copper(II) complexes of N-benzothiazolsulfonamides, [Cu(N-2-(5,6-dimethylbenzothiazole)toluenesulfonamidate)(2)(dmso)(2)] (1), [Cu(N-2-(6-chlorobenzothiazole)benzenesulfonamidate)(2)(dmso)(2)] (2) and [Cu(N-2-(6-chlorobenzothiazole)toluenesulfonamidate)(2)(dmso)(2)] (3) with interesting protective properties against superoxide radicals have been prepared. The compounds have been characterized by X-ray diffraction and their chemical properties have been studied by spectroscopic methods. The crystal structure of 1 shows that the copper(II) is surrounded by two benzothiazole N atoms from the sulfonamide ligands and two O atoms from the dimethylsulfoxide molecules in a square planar arrangement. The coordination polyhedron around copper(II) in 2 and 3 is distorted square pyramidal being the metal ion linked to benzothiazole N and sulfonamidate O atoms of the ligand and to two dimethylsulfoxide O atoms. The three complexes have a strong protective action over Delta sod1 mutant of Saccharomyces cerevisiae against reactive oxygen radicals derived from respiration and against those generated by hydrogen peroxide and menadione. 相似文献