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91.
目的已知特发性室速主要起源于右室流出道(RVOT),由于技术上的困难,目前对特发性右室流出道室速(RVOT-VT)的离子通道机制研究很少,本实验意在探索右室心室肌(RV)和RVOT的双孔钾通道电流(IK2p)的特性及其在RVOT-VT发生机制中可能参与的作用。方法采用全细胞膜片钳技术记录右室和右室流出道心肌细胞的单细胞电流。结果 RVOT的稳态外向电流较右室的小。对稳态电流进一步研究发现,右室流出道和右室心肌细胞上均存在IK2p。右室流出道细胞的IK2p电流密度明显小于右室细胞。结论首次在电生理水平上,证实了家兔右室心肌细胞上存在IK2p,RVOT心肌细胞的IK2p电流密度小于RV心肌细胞,是构成右室流出道APD离散度增大及外向电流降低的基础,从而易出现EAD,进而促进RVOT-VT的发生。 相似文献
92.
Anne E. Barañano Pearse A. Keane Humberto Ruiz‐Garcia Alexander C. Walsh Srinivas R. Sadda 《Acta ophthalmologica. Supplement》2012,90(4):e274-e280
Purpose: To determine the effect of optical coherence tomography (OCT) B‐scan density on the qualitative assessment of neovascular age‐related macular degeneration (AMD). Methods: Data were collected from 59 patients imaged with Topcon 3D OCT‐1000 (128 B‐scans × 512 A‐scans). Custom software was used to generate less dense subsets of scans: 1/16 (eight B‐scans), 1/8 (16 B‐scans), 1/4 (32 B‐scans) and 1/2 (64 B‐scans). At each B‐scan density, scans were assessed for cystoid spaces, subretinal fluid (SRF), subretinal tissue (SRT) and pigment epithelium detachment (PED). For each sampling density, sensitivity, specificity and predictive values were calculated using the full volume scan (128 B‐scans) as the reference standard. Results: For cystoid spaces, the detection sensitivity was 76.3% at 1/16 density; this rose to 89.5% with a 1/4 density. For SRF, the detection sensitivity was 75.0% at a 1/16 density; this increased to 91.1% with 1/4 density. For PED, even at the lowest sampling density (1/16) the detection sensitivity was 86.4%; this rose to 94.9% at 1/4 density. For SRT, detection sensitivity at a 1/16 density was 64.7% and only rose above 90% with the densest sampling subset (1/2). Conclusions: Use of scanning protocols with reduced sampling densities resulted in decreased detection of key features of neovascular AMD; despite this, a sampling density reduced to 1/4 appeared to allow accurate assessment for most features. Current management of neovascular AMD is dependent on qualitative assessment of OCT images; with the recent proliferation of OCT systems, optimization and standardization of scanning protocols may be of value. 相似文献
93.
阿尔茨海默病(AD)是一种年龄高度相关的神经系统疾病,是造成老年期痴呆的最主要原因,亦是导致老年人丧失日常生活能力的最常见疾病,将给患者、家庭及社会带来沉重的精神负担和经济压力。中医可将其归属于“痴呆”“呆门”“呆病”等疾患范畴,传统认为以肾虚为本,多从肾论治。课题组结合肝的生理病理特性,提出了“肝肾同调”是防治AD的重要思路。AD以β淀粉样蛋白(Aβ)沉积和神经原纤维缠结(NFT)为主要病理表现,其发病机制复杂。越来越多的研究表明,免疫炎症在AD的发病过程中起着重要作用,通过核转录因子-κB(NF-κB)/NOD样受体热蛋白结构域3(NLRP3)/胱天蛋白酶-1(Caspase-1)/白细胞介素-1β(IL-1β)信号通路调控神经免疫炎症将是治疗AD的重要靶点。该文基于“肝肾同调”的重要思路,遴选其代表名方黑逍遥散,从调控NF-κB/NLRP3/Caspase-1/IL-1β信号通路进而抑制神经免疫炎症角度探析防治AD的作用与机制,以期进一步推进黑逍遥散防治AD的深入研究,亦为中医药防治AD的思路策略抛砖引玉。 相似文献
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96.
D. M. Silevitch G. Aeppli T. F. Rosenbaum 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(7):2797-2800
The intended use of a magnetic material, from information storage to power conversion, depends crucially on its domain structure, traditionally crafted during materials synthesis. By contrast, we show that an external magnetic field, applied transverse to the preferred magnetization of a model disordered uniaxial ferromagnet, is an isothermal regulator of domain pinning. At elevated temperatures, near the transition into the paramagnet, modest transverse fields increase the pinning, stabilize the domain structure, and harden the magnet, until a point where the field induces quantum tunneling of the domain walls and softens the magnet. At low temperatures, tunneling completely dominates the domain dynamics and provides an interpretation of the quantum phase transition in highly disordered magnets as a localization/delocalization transition for domain walls. While the energy scales of the rare earth ferromagnet studied here restrict the effects to cryogenic temperatures, the principles discovered are general and should be applicable to existing classes of highly anisotropic ferromagnets with ordering at room temperature or above. 相似文献
97.
Predicted hexameric structure of the Agrobacterium VirB4 C terminus suggests VirB4 acts as a docking site during type IV secretion
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Middleton R Sjölander K Krishnamurthy N Foley J Zambryski P 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(5):1685-1690
The Agrobacterium T-DNA transporter belongs to a growing class of evolutionarily conserved transporters, called type IV secretion systems (T4SSs). VirB4, 789 aa, is the largest T4SS component, providing a rich source of possible structural domains. Here, we use a variety of bioinformatics methods to predict that the C-terminal domain of VirB4 (including the Walker A and B nucleotide-binding motifs) is related by divergent evolution to the cytoplasmic domain of TrwB, the coupling protein required for conjugative transfer of plasmid R388 from Escherichia coli. This prediction is supported by detailed sequence and structure analyses showing conservation of functionally and structurally important residues between VirB4 and TrwB. The availability of a solved crystal structure for TrwB enables the construction of a comparative model for VirB4 and the prediction that, like TrwB, VirB4 forms a hexamer. These results lead to a model in which VirB4 acts as a docking site at the entrance of the T4SS channel and acts in concert with VirD4 and VirB11 to transport substrates (T-strand linked to VirD2 or proteins such as VirE2, VirE3, or VirF) through the T4SS. 相似文献
98.
Vishnu Priyanka Reddy Chichili Ti Weng Chew Srihari Shankar Shi Yin Er Cheen Fei Chin Chacko Jobichen Catherine Qiurong Pan Yiting Zhou Foong May Yeong Boon Chuan Low J. Sivaraman 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(21)
Spatiotemporal regulation of signaling cascades is crucial for various biological pathways, under the control of a range of scaffolding proteins. The BNIP-2 and Cdc42GAP Homology (BCH) domain is a highly conserved module that targets small GTPases and their regulators. Proteins bearing BCH domains are key for driving cell elongation, retraction, membrane protrusion, and other aspects of active morphogenesis during cell migration, myoblast differentiation, and neuritogenesis. We previously showed that the BCH domain of p50RhoGAP (ARHGAP1) sequesters RhoA from inactivation by its adjacent GAP domain; however, the underlying molecular mechanism for RhoA inactivation by p50RhoGAP remains unknown. Here, we report the crystal structure of the BCH domain of p50RhoGAP Schizosaccharomyces pombe and model the human p50RhoGAP BCH domain to understand its regulatory function using in vitro and cell line studies. We show that the BCH domain adopts an intertwined dimeric structure with asymmetric monomers and harbors a unique RhoA-binding loop and a lipid-binding pocket that anchors prenylated RhoA. Interestingly, the β5-strand of the BCH domain is involved in an intermolecular β-sheet, which is crucial for inhibition of the adjacent GAP domain. A destabilizing mutation in the β5-strand triggers the release of the GAP domain from autoinhibition. This renders p50RhoGAP active, thereby leading to RhoA inactivation and increased self-association of p50RhoGAP molecules via their BCH domains. Our results offer key insight into the concerted spatiotemporal regulation of Rho activity by BCH domain–containing proteins.Small GTPases are molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state and are primarily involved in cytoskeletal reorganization during cell motility, morphogenesis, and cytokinesis (1, 2). These small GTPases are tightly controlled by activators and inactivators, such as guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), respectively (3, 4), which are multidomain proteins that are themselves regulated through their interactions with other proteins, lipids, secondary messengers, and/or by posttranslational modifications (5–7). Despite our understanding of the mechanisms of action of GTPases, GAPs, and GEFs, little is known about how they are further regulated by other cellular proteins in tightly controlled local environments.The BNIP-2 and Cdc42GAP Homology (BCH) domain has emerged as a highly conserved and versatile scaffold protein domain that targets small GTPases, their GEFs, and GAPs to carry out various cellular processes in a spatial, temporal, and kinetic manner (8–15). BCH domain–containing proteins are classified into a distinct functional subclass of the CRAL_TRIO/Sec14 superfamily, with ∼175 BCH domain–containing proteins (in which 14 of them are in human) present across a range of eukaryotic species (16). Some well-studied BCH domain–containing proteins include BNIP-2, BNIP-H (CAYTAXIN), BNIP-XL, BNIP-Sα, p50RhoGAP (ARHGAP1), and BPGAP1 (ARHGAP8), with evidence to show their involvement in cell elongation, retraction, membrane protrusion, and other aspects of active morphogenesis during cell migration, growth activation and suppression, myoblast differentiation, and neuritogenesis (17–21). Aside from interacting with small GTPases and their regulators, some of these proteins can also associate with other signaling proteins, such as fibroblast growth factor receptor tyrosine kinases, myogenic Cdo receptor, p38-MAP kinase, Mek2/MP1, and metabolic enzymes, such as glutaminase and ATP-citrate lyase (17–26). Despite the functional diversity and versatility of BCH domain–containing proteins, the structure of the BCH domain and its various modes of interaction remain unknown. The BCH domain resembles the Sec14 domain (from the CRAL-TRIO family) (16, 27, 28), a domain with lipid-binding characteristics, which may suggest that the BCH domain could have a similar binding strategy. However, to date, the binding and the role of lipids in BCH domain function remain inconclusive.Of the BCH domain–containing proteins, we have focused on the structure and function of p50RhoGAP. p50RhoGAP comprises an N-terminal BCH domain and a C-terminal GAP domain separated by a proline-rich region. We found that p50RhoGAP contains a noncanonical RhoA-binding motif in its BCH domain and is associated with GAP-mediated cell rounding (13). Further, we showed previously that deletion of the BCH domain dramatically enhanced the activity of the adjacent GAP domain (13); however, the full dynamics of this interaction is unclear. Previously, it has been reported that the BCH and other domains regulate GAP activity in an autoinhibited manner (18, 21, 29, 30) involving the interactions of both the BCH and GAP domains, albeit the mechanism remains to be investigated. It has also been shown that a lipid moiety on Rac1 (a Rho GTPase) is necessary for its inactivation by p50RhoGAP (29, 31), which may imply a role in lipid binding. An understanding of how the BCH domain coordinates with the GAP domain to affect the local activity of RhoA and other GTPases would offer a previously unknown insight into the multifaceted regulation of Rho GTPase inactivation.To understand the BCH domain–mediated regulation of p50RhoGAP and RhoA activities, we have determined the crystal structure of a homologous p50RhoGAP BCH domain from S. pombe for functional interrogation. We show that the BCH domain adopts an intertwined dimeric structure with asymmetric monomers and harbors a unique RhoA-interacting loop and a lipid-binding pocket. Our results show that the lipid-binding region of the BCH domain helps to anchor the prenylation tail of RhoA while the loop interacts directly with RhoA. Moreover, we show that a mutation in the β5-strand releases the autoinhibition of the GAP domain by the BCH domain. This renders the GAP domain active, leading to RhoA inactivation and the associated phenotypic effects in yeast and HeLa cells. The released BCH domain also contributes to enhanced p50RhoGAP–p50RhoGAP interaction. Our findings offer crucial insights into the regulation of Rho signaling by BCH domain–containing proteins. 相似文献
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100.