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101.
102.
Background
We consider the problem of parameter estimation (model calibration) in nonlinear dynamic models of biological systems. Due to the frequent ill-conditioning and multi-modality of many of these problems, traditional local methods usually fail (unless initialized with very good guesses of the parameter vector). In order to surmount these difficulties, global optimization (GO) methods have been suggested as robust alternatives. Currently, deterministic GO methods can not solve problems of realistic size within this class in reasonable computation times. In contrast, certain types of stochastic GO methods have shown promising results, although the computational cost remains large. Rodriguez-Fernandez and coworkers have presented hybrid stochastic-deterministic GO methods which could reduce computation time by one order of magnitude while guaranteeing robustness. Our goal here was to further reduce the computational effort without loosing robustness. 相似文献103.
Helen E. Driessen Magda S. Fontes Leonie van Stuijvenberg Maike A. Brans Marie‐Jose Goumans Marc A. Vos Toon A. van Veen 《Journal of cellular and molecular medicine》2020,24(15):8417-8429
In the diseased and remodelled heart, increased activity and expression of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), an excess of fibrosis, and a decreased electrical coupling and cellular excitability leads to disturbed calcium homeostasis and tissue integrity. This subsequently leads to increased arrhythmia vulnerability and contractile dysfunction. Here, we investigated the combination of CaMKII inhibition (using genetically modified mice expressing the autocamtide‐3‐related‐peptide (AC3I)) together with eplerenone treatment (AC3I‐Epler) to prevent electrophysiological remodelling, fibrosis and subsequent functional deterioration in a mouse model of chronic pressure overload. We compared AC3I‐Epler mice with mice only subjected to mineralocorticoid receptor (MR) antagonism (WT‐Epler) and mice with only CaMKII inhibition (AC3I‐No). Our data show that a combined CaMKII inhibition together with MR antagonism mitigates contractile deterioration as was manifested by a preservation of ejection fraction, fractional shortening, global longitudinal strain, peak strain and contractile synchronicity. Furthermore, patchy fibrosis formation was reduced, potentially via inhibition of pro‐fibrotic TGF‐β/SMAD3 signalling, which related to a better global contractile performance and a slightly depressed incidence of arrhythmias. Furthermore, the level of patchy fibrosis appeared significantly correlated to eplerenone dose. The addition of eplerenone to CaMKII inhibition potentiates the effects of CaMKII inhibition on pro‐fibrotic pathways. As a result of the applied strategy, limiting patchy fibrosis adheres to a higher synchronicity of contraction and an overall better contractile performance which fits with a tempered arrhythmogenesis. 相似文献
104.
David García‐Bernal Marta Palomo Carlos M. Martínez Jos E. Milln‐Rivero Ana I. García‐Guilln Miguel Blanquer Maribel Díaz‐Ricart Robert Sackstein Enric Carreras Jose M. Moraleda 《Journal of cellular and molecular medicine》2020,24(14):8031-8044
Allogeneic hematopoietic stem cell transplantation (allo‐HCT) is an effective therapy for the treatment of high‐risk haematological malignant disorders and other life‐threatening haematological and genetic diseases. Acute graft‐versus‐host disease (aGvHD) remains the most frequent cause of non‐relapse mortality following allo‐HCT and limits its extensive clinical application. Current pharmacologic agents used for prophylaxis and treatment of aGvHD are not uniformly successful and have serious secondary side effects. Therefore, more effective and safe prophylaxis and therapy for aGvHD are an unmet clinical need. Defibrotide is a multi‐target drug successfully employed for prophylaxis and treatment of veno‐occlusive disease/sinusoidal obstruction syndrome. Recent preliminary clinical data have suggested some efficacy of defibrotide in the prevention of aGvHD after allo‐HCT. Using a fully MHC‐mismatched murine model of allo‐HCT, we report here that defibrotide, either in prophylaxis or treatment, is effective in preventing T cell and neutrophil infiltration and aGvHD‐associated tissue injury, thus reducing aGvHD incidence and severity, with significantly improved survival after allo‐HCT. Moreover, we performed in vitro mechanistic studies using human cells revealing that defibrotide inhibits leucocyte‐endothelial interactions by down‐regulating expression of key endothelial adhesion molecules involved in leucocyte trafficking. Together, these findings provide evidence that defibrotide may represent an effective and safe clinical alternative for both prophylaxis and treatment of aGvHD after allo‐HCT, paving the way for new therapeutic approaches. 相似文献
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108.
Jonas Morales-Linares José G. García-Franco Alejandro Flores-Palacios Thorsten Krömer Tarin Toledo-Aceves 《Journal of Plant Ecology》2020,13(1):27
生境丧失和破碎化是热带森林生物多样性的主要威胁。遮荫的可可种植园(SCP)等农业生态系统为热带森林生物群提供了庇护。然而,在这些转化后的生境中是否还维持种间生态的相互作用,目前尚鲜为人知。我们评定附生兰花群落的多样性、繁殖状态和光合代谢(CAM或C3),以及与热带雨林(TRF)相比,它们与SCP中寄主树种(附生植物)之间的相互作用。在墨西哥东南部,对TRF和SCP中各三个采样地点进行研究。每个采样地点建立了4个400平方米的样地,调查记录所有兰花及其附生植物。我们依据花/果实(或残体)是否存在来确定每个兰花个体的繁殖(成体)或非繁殖(幼体)状态,并根据文献确定每种兰花的光合作用途径。我们采用真正的分集和生态网络的方法分别分析兰花的多样性以及兰科与附生植物间的相互作用。我们一共记录了47个兰花种的607个个体。在TRF (19个有效物种)中的兰花多样性高于SCP (11个有效物种),两个生境之间仅共享7个物种。SCP (53%)中的CAM兰花物种比TRF (14%)更常见。在群落水平上,SCP维持了非生殖兰花和生殖兰花的比例以及TRF兰科附生植物网络的嵌套结构和特异化水平。然而,SCP中仅保留一部分的TRF附生兰花,突显出保护TRF的重要性。尽管存在这种差异,诸如SCP类型的遮荫农业生态系统仍然可以维持天然林的一些多样性和功能,因为SCP附生兰花群落主要由CAM物种组成,其附生植物构成了一个嵌套的相互作用网络,对干扰形成了更强的抗性。 相似文献
109.
Javier Murciano‐Calles Andrea Coello Ana Cmara‐Artigas Jose C. Martinez 《Journal of molecular recognition : JMR》2020,33(4)
N‐Methyl‐D‐aspartate (NMDA) receptors are key components in synaptic communication and are highly relevant in central nervous disorders, where they trigger excessive calcium entry into the neuronal cells causing harmful overproduction of nitric oxide by the neuronal nitric oxide synthase (nNOS) protein. Remarkably, NMDA receptor activation is aided by a second protein, postsynaptic density of 95 kDa (PSD95), forming the ternary protein complex NMDA/PSD95/nNOS. To minimize the potential side effects derived from blocking this ternary complex or either of its protein components, a promising approach points to the disruption of the PSD‐95/nNOS interaction which is mediated by a PDZ/PDZ domain complex. Since the rational development of molecules targeting such protein‐protein interaction relies on energetic and structural information herein, we include a thermodynamic and structural analysis of the PSD95‐PDZ2/nNOS‐PDZ. Two energetically relevant events are structurally linked to a “two‐faced” or two areas of recognition between both domains. First, the assembly of a four‐stranded antiparallel β‐sheet between the β hairpins of nNOS and of PSD95‐PDZ2, mainly enthalpic in nature, contributes 80% to the affinity. Second, binding is entropically reinforced by the hydrophobic interaction between side chains of the same nNOS β‐hairpin with the side chains of α2‐helix at the binding site of PSD95‐PDZ2, contributing the remaining 20% of the total affinity. These results suggest strategies for the future rational design of molecules able to disrupt this complex and constitute the first exhaustive thermodynamic analysis of a PDZ/PDZ interaction. 相似文献
110.
David S. Goodsell Christine Zardecki Luigi Di Costanzo Jose M. Duarte Brian P. Hudson Irina Persikova Joan Segura Chenghua Shao Maria Voigt John D. Westbrook Jasmine Y. Young Stephen K. Burley 《Protein science : a publication of the Protein Society》2020,29(1):52-65
Analyses of publicly available structural data reveal interesting insights into the impact of the three‐dimensional (3D) structures of protein targets important for discovery of new drugs (e.g., G‐protein‐coupled receptors, voltage‐gated ion channels, ligand‐gated ion channels, transporters, and E3 ubiquitin ligases). The Protein Data Bank (PDB) archive currently holds > 155,000 atomic‐level 3D structures of biomolecules experimentally determined using crystallography, nuclear magnetic resonance spectroscopy, and electron microscopy. The PDB was established in 1971 as the first open‐access, digital‐data resource in biology, and is now managed by the Worldwide PDB partnership (wwPDB; wwPDB.org ). US PDB operations are the responsibility of the Research Collaboratory for Structural Bioinformatics PDB (RCSB PDB). The RCSB PDB serves millions of RCSB.org users worldwide by delivering PDB data integrated with ~40 external biodata resources, providing rich structural views of fundamental biology, biomedicine, and energy sciences. Recently published work showed that the PDB archival holdings facilitated discovery of ~90% of the 210 new drugs approved by the US Food and Drug Administration 2010–2016. We review user‐driven development of RCSB PDB services, examine growth of the PDB archive in terms of size and complexity, and present examples and opportunities for structure‐guided drug discovery for challenging targets (e.g., integral membrane proteins). 相似文献