全文获取类型
收费全文 | 1553篇 |
免费 | 227篇 |
国内免费 | 23篇 |
出版年
2024年 | 3篇 |
2023年 | 73篇 |
2022年 | 68篇 |
2021年 | 122篇 |
2020年 | 82篇 |
2019年 | 90篇 |
2018年 | 86篇 |
2017年 | 68篇 |
2016年 | 70篇 |
2015年 | 75篇 |
2014年 | 94篇 |
2013年 | 172篇 |
2012年 | 79篇 |
2011年 | 99篇 |
2010年 | 49篇 |
2009年 | 68篇 |
2008年 | 76篇 |
2007年 | 73篇 |
2006年 | 46篇 |
2005年 | 43篇 |
2004年 | 50篇 |
2003年 | 29篇 |
2002年 | 37篇 |
2001年 | 19篇 |
2000年 | 9篇 |
1999年 | 23篇 |
1998年 | 14篇 |
1997年 | 8篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 6篇 |
1993年 | 7篇 |
1992年 | 9篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 7篇 |
1988年 | 1篇 |
1987年 | 3篇 |
1986年 | 1篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1974年 | 1篇 |
排序方式: 共有1803条查询结果,搜索用时 15 毫秒
1.
Theofilos Papadopoulos Rudolf Schemm Helmut Grubmüller Nils Brose 《The Journal of biological chemistry》2015,290(13):8256-8270
Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects—or synaptopathies—are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the CbR290H mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans. 相似文献
2.
目的:研究优质护理模式对心肌梗死康复期患者心理障碍及不良情绪的影响程度,旨在为康复期患者护理方式的选取提供理论依据。方法:将本院2014年1月~2014年12月的70例心肌梗死康复期患者遵照随机数字表法分为对照组和观察组各35例,对照组采用常规的康复护理进行干预,观察组则以优质护理理念为指导进行护理干预,然后将两组护理前和护理后2周、4周及8周的心理障碍及不良情绪状态采用SECD6量表及HAD量表进行评估,并将评估结果进行比较。结果:观察组护理后2周、4周及8周的SECD6量表及HAD量表评估结果均明显优于对照组,P均0.05,均有显著性差异。结论:优质护理模式对心肌梗死康复期患者治疗信心及不良情绪的影响相对更为积极,为患者康复治疗的顺利进行奠定了基础。 相似文献
3.
D. Speijer G. R. Manjeri R. Szklarczyk 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2014,369(1646)
Oxygen radical formation in mitochondria is an incompletely understood attribute of eukaryotic cells. Recently, a kinetic model was proposed, in which the ratio between electrons entering the respiratory chain via FADH2 or NADH determines radical formation. During glucose breakdown, the ratio is low; during fatty acid breakdown, the ratio is high (the ratio increasing—asymptotically—with fatty acid length to 0.5, when compared with 0.2 for glucose). Thus, fatty acid oxidation would generate higher levels of radical formation. As a result, breakdown of fatty acids, performed without generation of extra FADH2 in mitochondria, could be beneficial for the cell, especially in the case of long and very long chained ones. This possibly has been a major factor in the evolution of peroxisomes. Increased radical formation, as proposed by the model, can also shed light on the lack of neuronal fatty acid oxidation and tells us about hurdles during early eukaryotic evolution. We specifically focus on extending and discussing the model in light of recent publications and findings. 相似文献
4.
The groundbreaking technologies of induced pluripotency and lineage conversion have generated a genuine opportunity to address fundamental aspects of the diseases that affect the nervous system. These approaches have granted us unrestricted access to the brain and spinal cord of patients and have allowed for the study of disease in the context of human cells, expressing physiological levels of proteins and under each patient's unique genetic constellation. Along with this unprecedented opportunity have come significant challenges, particularly in relation to patient variability, experimental design and data interpretation. Nevertheless, significant progress has been achieved over the past few years both in our ability to create the various neural subtypes that comprise the nervous system and in our efforts to develop cellular models of disease that recapitulate clinical findings identified in patients. In this Review, we present tables listing the various human neural cell types that can be generated and the neurological disease modeling studies that have been reported, describe the current state of the field, highlight important breakthroughs and discuss the next steps and future challenges. 相似文献
5.
Eun Jin Park Joon Young Song Min Ju Choi Ji Ho Jeon Jah-yeon Choi Tae Un Yang Kyung Wook Hong Ji Yun Noh Hee Jin Cheong Woo Joo Kim 《The Korean journal of parasitology》2014,52(4):425-428
A 45-year-old-male who had underlying ulcerative colitis and presented with fever and dry cough. Initially, the patient was considered to have invasive aspergillosis due to a positive galactomannan assay. He was treated with amphotericin B followed by voriconazole. Nevertheless, the patient deteriorated clinically and radiographically. The lung biopsy revealed eosinophilic pneumonia, and ELISA for Toxocara antigen was positive, leading to a diagnosis of pulmonary toxocariasis. After a 10-day treatment course with albendazole and adjunctive steroids, the patient recovered completely without any sequelae. Pulmonary toxocariasis may be considered in patients with subacute or chronic pneumonia unresponsive to antibiotic agents, particularly in cases with eosinophilia. 相似文献
6.
《Neuron》2020,105(6):1062-1076.e6
7.
P. Gerrans 《Biology & philosophy》2007,22(1):35-56
Delusions are currently characterised as false beliefs produced by incorrect inference about external reality (DSM IV). This
inferential conception has proved hard to link to explanations pitched at the level of neurobiology and neuroanatomy. This
paper provides that link via a neurocomputational theory, based on evolutionary considerations, of the role of the prefrontal
cortex in regulating offline cognition. When pathologically neuromodulated the prefrontal cortex produces hypersalient experiences
which monopolise offline cognition. The result is characteristic psychotic experiences and patterns of thought. This bottom-up
account uses neural network theory to integrate recent theories of the role of dopamine in delusion with the insights of inferential
accounts. It also provides a general model for evolutionary psychiatry which avoids theoretical problems imported from evolutionary
psychology. 相似文献
8.
《Journal of molecular biology》2021,433(5):166809
Macroautophagy is a bulk degradation mechanism in eukaryotic cells. Efficiency of an essential step of this process in yeast, Atg8 lipidation, relies on the presence of Atg16, a subunit of the Atg12–Atg5-Atg16 complex acting as the E3-like enzyme in the ubiquitination-like reaction. A current view on the functional structure of Atg16 in the yeast S. cerevisiae comes from the two crystal structures that reveal the Atg5-interacting α-helix linked via a flexible linker to another α-helix of Atg16, which then assembles into a homodimer. This view does not explain the results of previous in vitro studies revealing Atg16-dependent deformations of membranes and liposome-binding of the Atg12–Atg5 conjugate upon addition of Atg16. Here we show that Atg16 acts as both a homodimerizing and peripheral membrane-binding polypeptide. These two characteristics are imposed by the two distinct regions that are disordered in the nascent protein. Atg16 binds to membranes in vivo via the amphipathic α-helix (amino acid residues 113–131) that has a coiled-coil-like propensity and a strong hydrophobic face for insertion into the membrane. The other protein region (residues 64–99) possesses a coiled-coil propensity, but not amphipathicity, and is dispensable for membrane anchoring of Atg16. This region acts as a Leu-zipper essential for formation of the Atg16 homodimer. Mutagenic disruption in either of these two distinct domains renders Atg16 proteins that, in contrast to wild type, completely fail to rescue the autophagy-defective phenotype of atg16Δ cells. Together, the results of this study yield a model for the molecular mechanism of Atg16 function in macroautophagy. 相似文献
9.
Elucidation of the pathogenesis in respiratory chain diseases is of great importance for developing specific treatments. The limitations inherent to the use of patient material make studies of human tissues often difficult and the mouse has therefore emerged as a suitable model organism for studies of respiratory chain diseases. In this review, we present an overview of the field and discuss in depth a few examples of animal models reproducing pathology of human disease with primary and secondary respiratory chain involvement. 相似文献
10.