全文获取类型
收费全文 | 2128篇 |
免费 | 276篇 |
国内免费 | 34篇 |
出版年
2024年 | 3篇 |
2023年 | 80篇 |
2022年 | 59篇 |
2021年 | 124篇 |
2020年 | 90篇 |
2019年 | 116篇 |
2018年 | 115篇 |
2017年 | 96篇 |
2016年 | 101篇 |
2015年 | 98篇 |
2014年 | 127篇 |
2013年 | 192篇 |
2012年 | 82篇 |
2011年 | 112篇 |
2010年 | 72篇 |
2009年 | 90篇 |
2008年 | 119篇 |
2007年 | 97篇 |
2006年 | 71篇 |
2005年 | 60篇 |
2004年 | 64篇 |
2003年 | 43篇 |
2002年 | 67篇 |
2001年 | 35篇 |
2000年 | 32篇 |
1999年 | 31篇 |
1998年 | 23篇 |
1997年 | 12篇 |
1996年 | 18篇 |
1995年 | 13篇 |
1994年 | 9篇 |
1993年 | 18篇 |
1992年 | 15篇 |
1991年 | 16篇 |
1990年 | 20篇 |
1989年 | 12篇 |
1988年 | 12篇 |
1987年 | 14篇 |
1986年 | 14篇 |
1985年 | 9篇 |
1984年 | 11篇 |
1983年 | 4篇 |
1982年 | 8篇 |
1980年 | 7篇 |
1979年 | 4篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1973年 | 3篇 |
1972年 | 4篇 |
排序方式: 共有2438条查询结果,搜索用时 15 毫秒
1.
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
2.
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
3.
Nonparametric spline regression with prior information 总被引:1,自引:0,他引:1
4.
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
5.
《Neuron》2020,105(6):1062-1076.e6
6.
Robert D. Jurmain 《American journal of physical anthropology》1980,53(1):143-150
Patterns of degenerative joint disease are investigated in the shoulder, elbow, hip, and knee joints of the macerated remains of approximately 800 individuals from 20th century American and two prehistoric populations. Age is an important contributory factor in all joints, but its effects are seen most directly in the shoulder and hip. Patterns of right-left involvement also indicate the elbow is the most susceptible area to local factors. Multiple joint involvement is seen more often in females from contemporary populations but more often in males from archeological groups. No significant association is found between degenerative involvement and osteometric measurements, and cause of death is probably only incidentally associated with degenerative disease. 相似文献
7.
《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
8.
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
9.
10.
Michael R. Heaven Anthony W. Herren Daniel L. Flint Natasha L. Pacheco Jiangtao Li Alice Tang Fatima Khan James E. Goldman Brett S. Phinney Michelle L. Olsen 《Molecular & cellular proteomics : MCP》2022,21(1):100180
Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). In this report, a mouse model of AxD (GFAPTg;Gfap+/R236H) was analyzed that contains a heterozygous R236H point mutation in murine Gfap as well as a transgene with a GFAP promoter to overexpress human GFAP. Using label-free quantitative proteomic comparisons of brain tissue from GFAPTg;Gfap+/R236H versus wild-type mice confirmed upregulation of the glutathione metabolism pathway and indicated proteins were elevated in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which had not been reported previously in AxD. Relative protein-level differences were confirmed by a targeted proteomics assay, including proteins related to astrocytes and oligodendrocytes. Of particular interest was the decreased level of the oligodendrocyte protein, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (Ugt8), since Ugt8-deficient mice exhibit a phenotype similar to GFAPTg;Gfap+/R236H mice (e.g., tremors, ataxia, hind-limb paralysis). In addition, decreased levels of myelin-associated proteins were found in the GFAPTg;Gfap+/R236H mice, consistent with the role of Ugt8 in myelin synthesis. Fabp7 upregulation in GFAPTg;Gfap+/R236H mice was also selected for further investigation due to its uncharacterized association to AxD, critical function in astrocyte proliferation, and functional ability to inhibit the anti-inflammatory PPAR signaling pathway in models of amyotrophic lateral sclerosis (ALS). Within Gfap+ astrocytes, Fabp7 was markedly increased in the hippocampus, a brain region subjected to extensive pathology and chronic reactive gliosis in GFAPTg;Gfap+/R236H mice. Last, to determine whether the findings in GFAPTg;Gfap+/R236H mice are present in the human condition, AxD patient and control samples were analyzed by Western blot, which indicated that Type I AxD patients have a significant fourfold upregulation of FABP7. However, immunohistochemistry analysis showed that UGT8 accumulates in AxD patient subpial brain regions where abundant amounts of Rosenthal fibers are located, which was not observed in the GFAPTg;Gfap+/R236H mice. 相似文献