全文获取类型
收费全文 | 2670篇 |
免费 | 321篇 |
出版年
2021年 | 27篇 |
2020年 | 20篇 |
2016年 | 39篇 |
2015年 | 50篇 |
2014年 | 58篇 |
2013年 | 116篇 |
2012年 | 102篇 |
2011年 | 117篇 |
2010年 | 80篇 |
2009年 | 64篇 |
2008年 | 78篇 |
2007年 | 93篇 |
2006年 | 88篇 |
2005年 | 101篇 |
2004年 | 82篇 |
2003年 | 101篇 |
2002年 | 88篇 |
2001年 | 80篇 |
2000年 | 89篇 |
1999年 | 60篇 |
1998年 | 28篇 |
1997年 | 28篇 |
1996年 | 28篇 |
1995年 | 28篇 |
1994年 | 26篇 |
1993年 | 24篇 |
1992年 | 52篇 |
1991年 | 53篇 |
1990年 | 66篇 |
1989年 | 60篇 |
1988年 | 54篇 |
1987年 | 58篇 |
1986年 | 38篇 |
1985年 | 46篇 |
1984年 | 66篇 |
1983年 | 48篇 |
1982年 | 28篇 |
1981年 | 25篇 |
1980年 | 26篇 |
1979年 | 39篇 |
1978年 | 29篇 |
1977年 | 42篇 |
1976年 | 33篇 |
1975年 | 34篇 |
1974年 | 24篇 |
1973年 | 38篇 |
1972年 | 30篇 |
1970年 | 36篇 |
1969年 | 27篇 |
1968年 | 34篇 |
排序方式: 共有2991条查询结果,搜索用时 15 毫秒
991.
Seeliger MA Nagar B Frank F Cao X Henderson MN Kuriyan J 《Structure (London, England : 1993)》2007,15(3):299-311
The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the PDGF receptor. Imatinib is less effective against c-Src, which is difficult to understand because residues interacting with imatinib in crystal structures of Abl and c-Kit are conserved in c-Src. The crystal structure of the c-Src kinase domain in complex with imatinib closely resembles that of Abl*imatinib and c-Kit*imatinib, and differs significantly from the inactive "Src/CDK" conformation of the Src family kinases. Attempts to increase the affinity of c-Src for imatinib by swapping residues with the corresponding residues in Abl have not been successful, suggesting that the thermodynamic penalty for adoption of the imatinib-binding conformation by c-Src is distributed over a broad region of the structure. Two mutations that are expected to destabilize the inactive Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the free-energy balance between different inactive states is a key to imatinib binding. 相似文献
992.
Structure of an IgNAR-AMA1 complex: targeting a conserved hydrophobic cleft broadens malarial strain recognition 总被引:3,自引:0,他引:3
Henderson KA Streltsov VA Coley AM Dolezal O Hudson PJ Batchelor AH Gupta A Bai T Murphy VJ Anders RF Foley M Nuttall SD 《Structure (London, England : 1993)》2007,15(11):1452-1466
Apical membrane antigen 1 (AMA1) is essential for invasion of erythrocytes and hepatocytes by Plasmodium parasites and is a leading malarial vaccine candidate. Although conventional antibodies to AMA1 can prevent such invasion, extensive polymorphisms within surface-exposed loops may limit the ability of these AMA1-induced antibodies to protect against all parasite genotypes. Using an AMA1-specific IgNAR single-variable-domain antibody, we performed targeted mutagenesis and selection against AMA1 from three P. falciparum strains. We present cocrystal structures of two antibody-AMA1 complexes which reveal extended IgNAR CDR3 loops penetrating deep into a hydrophobic cleft on the antigen surface and contacting residues conserved across parasite species. Comparison of a series of affinity-enhancing mutations allowed dissection of their relative contributions to binding kinetics and correlation with inhibition of erythrocyte invasion. These findings provide insights into mechanisms of single-domain antibody binding, and may enable design of reagents targeting otherwise cryptic epitopes in pathogen antigens. 相似文献
993.
994.
Beta-catenin is well-known as a key effector of Wnt signalling and aberrant expression is associated with several human cancers. Stabilisation of and atypical subcellular localisation of beta-catenin, regulated in part through specific protein-protein interactions has been linked to cancer development, however the mechanisms behind these pathologies is yet to be fully elucidated. Affinity purification and mass spectrometry were used to identify potential β-catenin interacting proteins in SW480 colon cancer cells. Recombinant β-catenin constructs were used to co-isolate interacting proteins from stable isotope labelled cells followed by detection using mass spectrometry. Several known and new putative interactors were observed. In particular, we identified interaction with a set of coatomer complex I subunits implicated in retrograde transport at the Golgi, and confirmed endogenous interaction of β-catenin with coatomer subunit COPB using immunoprecipitation assays and immunofluorescence microscopy. These observations suggest a hitherto unrecognised role for β-catenin in the secretory pathway and warrant further functional studies to unravel its activity at this cellular location. 相似文献
995.
Early life histories of the London poor using δ13C and δ15N stable isotope incremental dentine sampling
下载免费PDF全文
![点击此处可从《American journal of physical anthropology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Rowena C. Henderson Julia Lee‐Thorp Louise Loe 《American journal of physical anthropology》2014,154(4):585-593
High resolution incremental isotopic analysis of the dentine from early forming teeth, especially first molars (M1s), provides a means to assess the effects of poor childhood nutrition and healthcare on individuals in an assemblage where there are no infants to study. This approach is applied to an 18th and 19th century cemetery population associated with St Saviour's Almshouse burial ground in Southwark, London, to assess whether, or how, early dietary history, including weaning age, influenced health and nutritional status. The results show a general pattern in which non‐breast milk foods were introduced before or by 6 months of age, as indicated by elevated δ15N during this period. Almost all individuals for which we also have second molar (M2) records, showed lower δ15N values from a very young age (>1 year) until approximately 8–10 years, compared to adult values. The overall results show a significant difference in δ13C (p = 0 to 4sf, F = 17.327) and a weaker statistical difference in δ15N between males and females (p = 0.019, F = 5.581). One possible cause of this is a difference in the diet of males and females early in life, or alternatively, a greater susceptibility of males to nutritional deprivation compared to females. The latter argument is strengthened by a significant difference in the incidence of enamel hypoplasia between the males and females, with 7.7% of male teeth showing defects, compared to 3.9% of females. Am J Phys Anthropol 154:585–593, 2014. © 2014 Wiley Periodicals, Inc. 相似文献
996.
Peishen Zhao TinaMarie Lieu Nicholas Barlow Matthew Metcalf Nicholas A. Veldhuis Dane D. Jensen Martina Kocan Silvia Sostegni Silke Haerteis Vera Baraznenok Ian Henderson Erik Lindstr?m Raquel Guerrero-Alba Eduardo E. Valdez-Morales Wolfgang Liedtke Peter McIntyre Stephen J. Vanner Christoph Korbmacher Nigel W. Bunnett 《The Journal of biological chemistry》2014,289(39):27215-27234
Serine proteases such as trypsin and mast cell tryptase cleave protease-activated receptor-2 (PAR2) at R36↓S37 and reveal a tethered ligand that excites nociceptors, causing neurogenic inflammation and pain. Whether proteases that cleave PAR2 at distinct sites are biased agonists that also induce inflammation and pain is unexplored. Cathepsin S (Cat-S) is a lysosomal cysteine protease of antigen-presenting cells that is secreted during inflammation and which retains activity at extracellular pH. We observed that Cat-S cleaved PAR2 at E56↓T57, which removed the canonical tethered ligand and prevented trypsin activation. In HEK and KNRK cell lines and in nociceptive neurons of mouse dorsal root ganglia, Cat-S and a decapeptide mimicking the Cat-S-revealed tethered ligand-stimulated PAR2 coupling to Gαs and formation of cAMP. In contrast to trypsin, Cat-S did not mobilize intracellular Ca2+, activate ERK1/2, recruit β-arrestins, or induce PAR2 endocytosis. Cat-S caused PAR2-dependent activation of transient receptor potential vanilloid 4 (TRPV4) in Xenopus laevis oocytes, HEK cells and nociceptive neurons, and stimulated neuronal hyperexcitability by adenylyl cyclase and protein kinase A-dependent mechanisms. Intraplantar injection of Cat-S caused inflammation and hyperalgesia in mice that was attenuated by PAR2 or TRPV4 deletion and adenylyl cyclase inhibition. Cat-S and PAR2 antagonists suppressed formalin-induced inflammation and pain, which implicates endogenous Cat-S and PAR2 in inflammatory pain. Our results identify Cat-S as a biased agonist of PAR2 that causes PAR2- and TRPV4-dependent inflammation and pain. They expand the role of PAR2 as a mediator of protease-driven inflammatory pain. 相似文献
997.
Weston A. Nichols Brandon J. Henderson Caroline Yu Rell L. Parker Christopher I. Richards Henry A. Lester Julie M. Miwa 《The Journal of biological chemistry》2014,289(45):31423-31432
Glycosylphosphatidylinositol-anchored neurotoxin-like receptor binding proteins, such as lynx modulators, are topologically positioned to exert pharmacological effects by binding to the extracellular portion of nAChRs. These actions are generally thought to proceed when both lynx and the nAChRs are on the plasma membrane. Here, we demonstrate that lynx1 also exerts effects on α4β2 nAChRs within the endoplasmic reticulum. Lynx1 affects assembly of nascent α4 and β2 subunits and alters the stoichiometry of the receptor population that reaches the plasma membrane. Additionally, these data suggest that lynx1 shifts nAChR stoichiometry to low sensitivity (α4)3(β2)2 pentamers primarily through this interaction in the endoplasmic reticulum, rather than solely via direct modulation of activity on the plasma membrane. To our knowledge, these data represent the first test of the hypothesis that a lynx family member, or indeed any glycosylphosphatidylinositol-anchored protein, could act within the cell to alter assembly of a multisubunit protein. 相似文献
998.
The anatomy of the male and female reproductive systems was investigated in the long‐tailed butterfly ray Gymnura poecilura using gross observation and light microscopy. The testes are highly asymmetrical, to the extent that only the left testis is functional and the right testis is completely absent. Both of the male genital ducts are present and symmetrical, although spermatozoa only occur in the left duct. The genital ducts are straight and unconvoluted, with regular incomplete internal partitions throughout. Females do not possess a right ovary, nor do the oviducal glands exhibit distinct club and papillary zones, and the baffle zone lacks baffle plates. In all sections of the gland, the tubules display different secretory activities depending on the proximity to the gland lumen. The gland produces a thin egg membrane that encases each egg individually, while the endometrium is formed into trophonemata. 相似文献
999.
Brandon J. Henderson Rahul Srinivasan Weston A. Nichols Crystal N. Dilworth Diana F. Gutierrez Elisha D.W. Mackey Sheri McKinney Ryan M. Drenan Christopher I. Richards Henry A. Lester 《The Journal of general physiology》2014,143(1):51-66
Chronic exposure to nicotine up-regulates high sensitivity nicotinic acetylcholine receptors (nAChRs) in the brain. This up-regulation partially underlies addiction and may also contribute to protection against Parkinson’s disease. nAChRs containing the α6 subunit (α6* nAChRs) are expressed in neurons in several brain regions, but comparatively little is known about the effect of chronic nicotine on these nAChRs. We report here that nicotine up-regulates α6* nAChRs in several mouse brain regions (substantia nigra pars compacta, ventral tegmental area, medial habenula, and superior colliculus) and in neuroblastoma 2a cells. We present evidence that a coat protein complex I (COPI)-mediated process mediates this up-regulation of α6* or α4* nAChRs but does not participate in basal trafficking. We show that α6β2β3 nAChR up-regulation is prevented by mutating a putative COPI-binding motif in the β3 subunit or by inhibiting COPI. Similarly, a COPI-dependent process is required for up-regulation of α4β2 nAChRs by chronic nicotine but not for basal trafficking. Mutation of the putative COPI-binding motif or inhibition of COPI also results in reduced normalized Förster resonance energy transfer between α6β2β3 nAChRs and εCOP subunits. The discovery that nicotine exploits a COPI-dependent process to chaperone high sensitivity nAChRs is novel and suggests that this may be a common mechanism in the up-regulation of nAChRs in response to chronic nicotine. 相似文献
1000.