全文获取类型
收费全文 | 6664篇 |
免费 | 651篇 |
国内免费 | 3篇 |
专业分类
7318篇 |
出版年
2024年 | 9篇 |
2023年 | 77篇 |
2022年 | 145篇 |
2021年 | 276篇 |
2020年 | 155篇 |
2019年 | 226篇 |
2018年 | 181篇 |
2017年 | 190篇 |
2016年 | 297篇 |
2015年 | 510篇 |
2014年 | 555篇 |
2013年 | 567篇 |
2012年 | 728篇 |
2011年 | 665篇 |
2010年 | 371篇 |
2009年 | 325篇 |
2008年 | 411篇 |
2007年 | 368篇 |
2006年 | 309篇 |
2005年 | 278篇 |
2004年 | 236篇 |
2003年 | 155篇 |
2002年 | 140篇 |
2001年 | 29篇 |
2000年 | 11篇 |
1999年 | 17篇 |
1998年 | 10篇 |
1997年 | 13篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 5篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 5篇 |
1990年 | 2篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 3篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有7318条查询结果,搜索用时 15 毫秒
991.
992.
Chondroitin sulphate proteoglycans (CSPGs) are axon growth inhibitory molecules present in the glial scar that play a part in regeneration failure after damage to the CNS and which restrict CNS plasticity. Removal of chondroitin sulphate glycosaminoglycan (GAG) chains with chondroitinase-ABC (chABC) in models of CNS injury promotes both axon regeneration and plasticity. We have analysed the immediate and long-term effects of a single injection of chABC on CSPGs, GAGs and axon regeneration. We made unilateral nigrostriatal lesions in adult rats accompanied by an adjacent infusion of either chABC or a bacterial-derived control enzyme (penicillinase). Within 24 h of chABC treatment there was digestion of GAGs, including hyaluronan, and a reduction in neurocan in an area extending 1.5 mm around the injection site. Around 50% of GAG is inaccessible to chABC digestion, even in tissue digested in vitro, which probably represents intracellular stores. In control penicillinase treated animals, total GAGs recovered from the lesioned brains were up-regulated by 4-fold 7 days after injury and gradually decreased to normal at 28 days post-lesion. In chondroitinase-treated animals, the total GAG remained at low level throughout the 28-day experimental period. This suggests the persistence of active chABC for at least 10 days after injection which is able to digest CSPGs released from cells during this time. This was confirmed by immunological detection of enzyme for 10 days and by retrieval of active enzyme from the brain at 10 days after injection. Our results suggest that a single injection of chABC can produce an environment conducive to CNS repair for over 10 days. 相似文献
993.
Skov L Beurskens FJ Zachariae CO Reitamo S Teeling J Satijn D Knudsen KM Boot EP Hudson D Baadsgaard O Parren PW van de Winkel JG 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(1):669-679
IL-8 is a chemokine that has been implicated in a number of inflammatory diseases involving neutrophil activation. HuMab 10F8 is a novel fully human mAb against IL-8, which binds a discontinuous epitope on IL-8 overlapping the receptor binding site, and which effectively neutralizes IL-8-dependent human neutrophil activation and migration. We investigated whether interference in the cytokine network by HuMab 10F8 might benefit patients suffering from palmoplantar pustulosis, a chronic inflammatory skin disease. Treatment of patients with HuMab 10F8 was well tolerated and significantly reduced clinical disease activity at all five endpoints, which included a >or=50% reduction in the formation of fresh pustules. IL-8 neutralization was monitored at the site of inflammation by assessing exudates of palmoplantar pustulosis lesions. HuMab 10F8 sequestered IL-8 in situ, as observed by rapid dose-dependent decreases of IL-8 concentrations immediately following Ab infusion. These data demonstrate a critical role for IL-8 in the pathophysiology of palmoplantar pustulosis. HuMab 10F8 is capable of interrupting IL-8 activity in vivo and represents a candidate for treatment of inflammatory diseases and other pathological conditions associated with IL-8 overproduction. 相似文献
994.
Thakral D Dobbins J Devine L Kavathas PB 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(11):7431-7442
The CD8alphabeta heterodimer functions as a coreceptor with the TCR, influencing the outcome of CD8(+) T cell responses to pathogen-infected and tumor cells. In contrast to the murine CD8B gene, the human gene encodes alternatively spliced variants with different cytoplasmic tails (M-1, M-2, M-3, and M-4). At present, little is known about the expression patterns and functional significance of such variants. We used quantitative RT-PCR to demonstrate differential mRNA expression patterns of these splice variants in thymocytes and in resting, memory, and activated primary human CD8(+) T cells. In total CD8(+) T cells, mRNA levels of the M-1 variant were the most predominant and levels of M-3 were the least detected. The M-4 isoform was predominant in effector memory CD8(+) T cells. Upon stimulation of CD8(+) T cells, the M-2 variant mRNA levels were elevated 10-20-fold relative to resting cells in contrast to the other isoforms. Curiously, the M-2 isoform was not expressed on the cell surface in transfected cell lines. Using fluorescent chimeras of the extracellular domain of mouse CD8beta fused to the cytoplasmic tails of each isoform, the M-2 isoform was localized in a lysosomal compartment regulated by ubiquitination of a lysine residue (K215) in its cytoplasmic tail. In contrast, upon short-term stimulation, the M-2 protein localized to the cell surface with the TCR complex. The relatively recent evolution of CD8B gene splice variants in the chimpanzee/human lineage is most likely important for fine-tuning the CD8(+) T cell responses. 相似文献
995.
Bissonnette SL Teague JE Sherr DH Schlezinger JJ 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(3):1728-1736
Phthalate esters are ubiquitous environmental contaminants that are produced for a variety of common industrial and commercial purposes. We have shown that mono-(2-ethylhexyl) phthalate (MEHP), the toxic metabolite of di-(2-ethylhexyl) phthalate, induces bone marrow B cell apoptosis that is enhanced in the presence of the endogenous prostaglandin 15-deoxy-Delta((12, 14))-PGJ(2) (15d-PGJ(2)). Here, studies were performed to determine whether 15d-PGJ(2)-mediated enhancement of MEHP-induced apoptosis represents activation of an overlapping or complementary apoptosis pathway. MEHP and 15d-PGJ(2) induced significant apoptosis within 8 and 5 h, respectively, in a pro/pre-B cell line and acted cooperatively to induce apoptosis in primary pro-B cells. Apoptosis induced with each chemical was accompanied by activation of a combination of initiator caspases (caspases-2, -8, and -9) and executed by caspase-3. Apoptosis induced with MEHP and 15d-PGJ(2) was reduced in APAF1 null primary pro-B cells and accompanied by alteration of mitochondrial membranes, albeit with different kinetics, indicating an intrinsically activated apoptosis pathway. Significant Bax translocation to the mitochondria supports its role in initiating release of cytochrome c. Both chemicals induced Bid cleavage, a result consistent with a truncated Bid-mediated release of cytochrome c in an apoptosis amplification feedback loop; however, significantly more Bid was cleaved following 15d-PGJ(2) treatment, potentially differentiating the two pathways. Indeed, Bid cleavage and cytochrome c release following 15d-PGJ(2) but not MEHP treatment was profoundly inhibited by Z-VAD-FMK, suggesting that 15d-PGJ(2) activates apoptosis via two pathways, Bax mobilization and protease-dependent Bid cleavage. Thus, endogenous 15d-PGJ(2)-mediated enhancement of environmental chemical-induced apoptosis represents activation of an overlapping but distinct signaling pathway. 相似文献
996.
Taylor EM Copsey AC Hudson JJ Vidot S Lehmann AR 《Molecular and cellular biology》2008,28(4):1197-1206
The SMC protein complexes play important roles in chromosome dynamics. The function of the SMC5-6 complex remains unclear, though it is involved in resolution of different DNA structures by recombination. We have now identified and characterized the four non-SMC components of the human complex and in particular demonstrated that the MAGEG1 protein is part of this complex. MAGE proteins play important but as yet undefined roles in carcinogenesis, apoptosis, and brain development. We show that, with the exception of the SUMO ligase hMMS21/hNSE2, depletion of any of the components results in degradation of all the other components. Depletion also confers sensitivity to methyl methanesulfonate. Several of the components are modified by sumoylation and ubiquitination. 相似文献
997.
Grieves JL Hubbard GB Williams JT Vandeberg JL Dick EJ López-Alvarenga JC Schlabritz-Loutsevitch NE 《Journal of medical primatology》2008,37(6):318-328
Background Congenital transmission of Trypanosoma cruzi has been described in humans and experimental work has been conducted with mice, but not with non‐human primates (NHPs). Methods We conducted a retrospective study of female baboons (Papio hamadryas spp.) naturally seropositive or seronegative for T. cruzi with history of fetal loss, and we report a stillbirth in a cynomolgus macaque (Macaca fascicularis) with placental T. cruzi amastigotes. Results There were no differences in menstrual cycle parameters and the number of fetal losses between seropositive and seronegative baboons with history of fetal loss. The amount of parasite DNA detected using quantitative polymerase chain reaction (Q‐PCR) in M. fascicularis placenta was within the range detected in infected baboon tissues. Conclusions There is no evidence that chronic maternal T. cruzi infection causes fetal loss in baboons. Q‐PCR is a useful diagnostic tool to study archived NHP placentas. 相似文献
998.
Rumfeldt JA Galvagnion C Vassall KA Meiering EM 《Progress in biophysics and molecular biology》2008,98(1):61-84
The folding of multisubunit proteins is of tremendous biological significance since the large majority of proteins exist as protein-protein complexes. Extensive experimental and computational studies have provided fundamental insights into the principles of folding of small monomeric proteins. Recently, important advances have been made in extending folding studies to multisubunit proteins, in particular homodimeric proteins. This review summarizes the equilibrium and kinetic theory and models underlying the quantitative analysis of dimeric protein folding using chemical denaturation, as well as the experimental results that have been obtained. Although various principles identified for monomer folding also apply to the folding of dimeric proteins, the effects of subunit association can manifest in complex ways, and are frequently overlooked. Changes in molecularity typically give rise to very different overall folding behaviour than is observed for monomeric proteins. The results obtained for dimers have provided key insights pertinent to understanding biological assembly and regulation of multisubunit proteins. These advances have set the stage for future advances in folding involving protein-protein interactions for natural multisubunit proteins and unnatural assemblies involved in disease. 相似文献
999.
Ciferri C Pasqualato S Screpanti E Varetti G Santaguida S Dos Reis G Maiolica A Polka J De Luca JG De Wulf P Salek M Rappsilber J Moores CA Salmon ED Musacchio A 《Cell》2008,133(3):427-439
Kinetochores are proteinaceous assemblies that mediate the interaction of chromosomes with the mitotic spindle. The 180 kDa Ndc80 complex is a direct point of contact between kinetochores and microtubules. Its four subunits contain coiled coils and form an elongated rod structure with functional globular domains at either end. We crystallized an engineered "bonsai" Ndc80 complex containing a shortened rod domain but retaining the globular domains required for kinetochore localization and microtubule binding. The structure reveals a microtubule-binding interface containing a pair of tightly interacting calponin-homology (CH) domains with a previously unknown arrangement. The interaction with microtubules is cooperative and predominantly electrostatic. It involves positive charges in the CH domains and in the N-terminal tail of the Ndc80 subunit and negative charges in tubulin C-terminal tails and is regulated by the Aurora B kinase. We discuss our results with reference to current models of kinetochore-microtubule attachment and centromere organization. 相似文献
1000.
DNA damage causes checkpoint activation leading to cell cycle arrest and repair, during which the chromatin structure is disrupted. The mechanisms whereby chromatin structure and cell cycle progression are restored after DNA repair are largely unknown. We show that chromatin reassembly following double-strand break (DSB) repair requires the histone chaperone Asf1 and that absence of Asf1 causes cell death, as cells are unable to recover from the DNA damage checkpoint. We find that Asf1 contributes toward chromatin assembly after DSB repair by promoting acetylation of free histone H3 on lysine 56 (K56) via the histone acetyl transferase Rtt109. Mimicking acetylation of K56 bypasses the requirement for Asf1 for chromatin reassembly and checkpoint recovery, whereas mutations that prevent K56 acetylation block chromatin reassembly after repair. These results indicate that restoration of the chromatin following DSB repair is driven by acetylated H3 K56 and that this is a signal for the completion of repair. 相似文献