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81.
Jinwang Ye Yaling Yin Huanhuan Liu Lin Fang Xiaoqing Tao Linyu Wei Yue Zuo Ying Yin Dan Ke Jian‐Zhi Wang 《Aging cell》2020,19(1)
Intraneuronal accumulation of wild‐type tau plays a key role in Alzheimer's disease, while the mechanisms underlying tauopathy and memory impairment remain unclear. Here, we report that overexpressing full‐length wild‐type human tau (hTau) in mouse hippocampus induces learning and memory deficits with remarkably reduced levels of multiple synapse‐ and memory‐associated proteins. Overexpressing hTau inhibits the activity of protein kinase A (PKA) and decreases the phosphorylation level of cAMP‐response element binding protein (CREB), GluA1, and TrkB with reduced BDNF mRNA and protein levels both in vitro and in vivo. Simultaneously, overexpressing hTau increased PKAR2α (an inhibitory subunit of PKA) in nuclear fraction and inactivated proteasome activity. With an increased association of PKAR2α with PA28γ (a nuclear proteasome activator), the formation of PA28γ‐20S proteasome complex remarkably decreased in the nuclear fraction, followed by a reduced interaction of PKAR2α with 20S proteasome. Both downregulating PKAR2α by shRNA and upregulating proteasome by expressing PA28γ rescued hTau‐induced PKA inhibition and CREB dephosphorylation, and upregulating PKA improved hTau‐induced cognitive deficits in mice. Together, these data reveal that intracellular tau accumulation induces synapse and memory impairments by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling, and deficit of PA28γ‐20S proteasome complex formation contributes to PKAR2α elevation and PKA inhibition. 相似文献
82.
Zhongli Shi Kaixia Zhang Huimin Zhou Lei Jiang Bing Xie Ruiyuan Wang Wenzhen Xia Yajuan Yin Zhaoyu Gao Dongsheng Cui Rui Zhang Shunjiang Xu 《Aging cell》2020,19(3)
Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD. 相似文献
83.
Oleg O. Glebov 《Cell biology international》2020,44(1):336-342
Polymerization of filamentous (F)‐actin at the neuronal synapse plays an important role in neuronal function. However, the regulatory mechanisms controlling the levels of synaptic actin remain incompletely understood. Here, I used established pharmacological blockers to acutely disrupt the function of actin polymerization machinery, then quantified their effect on synaptic F‐actin levels. Synaptic F‐actin was modestly decreased by inhibition of Arp2/3‐dependent actin branching. Blockade of formin‐dependent actin elongation resulted in an Arp2/3‐dependent increase in synaptic actin that could be mimicked by limited actin depolymerization. Limited actin depolymerization was also sufficient to reverse a decrease in synaptic F‐actin caused by prolonged blockade of synaptic NMDA‐type glutamate receptors. These results suggest that interplay between different actin polymerization pathways may regulate synaptic actin dynamics. 相似文献
84.
Jukka Keklinen Annalaura Jokiniemi Matti Janhunen Hannu Huuskonen 《Journal of evolutionary biology》2020,33(5):584-594
In a large majority of animal species, the only contribution of males to the next generation has been assumed to be their genes (sperm). However, along with sperm, seminal plasma contains a wide array of extracellular factors that have many important functions in reproduction. Yet, the potential intergenerational effects of these factors are virtually unknown. We investigated these effects in European whitefish (Coregonus lavaretus) by experimentally manipulating the presence and identity of seminal plasma and by fertilizing the eggs of multiple females with the manipulated and unmanipulated semen of several males in a full‐factorial breeding design. The presence of both own seminal plasma and foreign seminal plasma inhibited sperm motility, and the removal of own seminal plasma decreased embryo survival. Embryos hatched significantly earlier after both semen manipulations than in control fertilizations; foreign seminal plasma also increased offspring aerobic swimming performance. Given that our experimental design allowed us to control potentially confounding sperm‐mediated (sire) effects and maternal effects, our results indicate that seminal plasma may have direct intergenerational consequences for offspring phenotype and performance. This novel source of offspring phenotypic variance may provide new insights into the evolution of polyandry and mechanisms that maintain heritable variation in fitness and associated female mating preferences. 相似文献
85.
Central pattern generator (CPG) networks rely on a balance of intrinsic and network properties to produce reliable, repeatable activity patterns. This balance is maintained by homeostatic plasticity where alterations in neuronal properties dynamically maintain appropriate neural output in the face of changing environmental conditions and perturbations. However, it remains unclear just how these neurons and networks can both monitor their ongoing activity and use this information to elicit homeostatic physiological responses to ensure robustness of output over time. Evidence exists that CPG networks use a mixed strategy of activity‐dependent, activity‐independent, modulator‐dependent, and synaptically regulated homeostatic plasticity to achieve this critical stability. In this review, we focus on some of the current understanding of the molecular pathways and mechanisms responsible for this homeostatic plasticity in the context of central pattern generator function, with a special emphasis on some of the smaller invertebrate networks that have allowed for extensive cellular‐level analyses that have brought recent insights to these questions. 相似文献
86.
87.
Major depressive disorder takes at least 3 weeks for clinical anti‐depressants, such as serotonin selective reuptake inhibitors, to take effect, and only one‐third of patients remit. Ketamine, a kind of anaesthetic, can alleviate symptoms of major depressive disorder patients in a short time and is reported to be effective to treatment‐resistant depression patients. The rapid and strong anti‐depressant‐like effects of ketamine cause wide concern. In addition to ketamine, caloric restriction and sleep deprivation also elicit similar rapid anti‐depressant‐like effects. However, mechanisms about the rapid anti‐depressant‐like effects remain unclear. Elucidating the mechanisms of rapid anti‐depressant effects is the key to finding new therapeutic targets and developing therapeutic patterns. Therefore, in this review we summarize potential molecular and cellular mechanisms of rapid anti‐depressant‐like effects based on the pre‐clinical and clinical evidence, trying to provide new insight into future therapy. 相似文献
88.
《Current biology : CB》2020,30(7):1167-1176.e2
89.
《Current biology : CB》2020,30(21):4177-4187.e4
90.
Jrme Bartholom Andr Mabiala Rgis Burlett Didier Bert Jean‐Charles Lepl Christophe Plomion Jean‐Marc Gion 《The Plant journal : for cell and molecular biology》2020,103(1):338-356
The pulse of the tree (diurnal cycle of stem radius fluctuations) has been widely studied as a way of analyzing tree responses to the environment, including the phenotypic plasticity of tree–water relationships in particular. However, the genetic basis of this daily phenotype and its interplay with the environment remain largely unexplored. We characterized the genetic and environmental determinants of this response, by monitoring daily stem radius fluctuation (dSRF) on 210 trees from a Eucalyptus urophylla × E. grandis full‐sib family over 2 years. The dSRF signal was broken down into hydraulic capacitance, assessed as the daily amplitude of shrinkage (DA), and net growth, estimated as the change in maximum radius between two consecutive days (ΔR). The environmental determinants of these two traits were clearly different: DA was positively correlated with atmospheric variables relating to water demand, while ΔR was associated with soil water content. The heritability for these two traits ranged from low to moderate over time, revealing a time‐dependent or environment‐dependent complex genetic determinism. We identified 686 and 384 daily quantitative trait loci (QTL) representing 32 and 31 QTL regions for DA and ΔR, respectively. The identification of gene networks underlying the 27 major genomics regions for both traits generated additional hypotheses concerning the biological mechanisms involved in response to water demand and supply. This study highlights that environmentally induced changes in daily stem radius fluctuation are genetically controlled in trees and suggests that these daily responses integrated over time shape the genetic architecture of mature traits. 相似文献