全文获取类型
收费全文 | 1071篇 |
免费 | 67篇 |
国内免费 | 1篇 |
出版年
2022年 | 9篇 |
2021年 | 22篇 |
2020年 | 17篇 |
2019年 | 20篇 |
2018年 | 27篇 |
2017年 | 31篇 |
2016年 | 19篇 |
2015年 | 50篇 |
2014年 | 56篇 |
2013年 | 73篇 |
2012年 | 76篇 |
2011年 | 80篇 |
2010年 | 36篇 |
2009年 | 39篇 |
2008年 | 39篇 |
2007年 | 55篇 |
2006年 | 50篇 |
2005年 | 50篇 |
2004年 | 48篇 |
2003年 | 42篇 |
2002年 | 42篇 |
2001年 | 11篇 |
2000年 | 24篇 |
1999年 | 15篇 |
1998年 | 12篇 |
1997年 | 12篇 |
1996年 | 8篇 |
1995年 | 9篇 |
1994年 | 12篇 |
1993年 | 7篇 |
1992年 | 6篇 |
1991年 | 13篇 |
1990年 | 5篇 |
1989年 | 7篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 11篇 |
1985年 | 12篇 |
1984年 | 5篇 |
1983年 | 14篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1977年 | 10篇 |
1975年 | 3篇 |
1972年 | 5篇 |
1971年 | 5篇 |
1970年 | 4篇 |
1969年 | 7篇 |
排序方式: 共有1139条查询结果,搜索用时 46 毫秒
71.
72.
Manish Jaiswal Nele A. Haelterman Hector Sandoval Bo Xiong Taraka Donti Auinash Kalsotra Shinya Yamamoto Thomas A. Cooper Brett H. Graham Hugo J. Bellen 《PLoS biology》2015,13(7)
Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration—defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise. 相似文献
73.
Xuejun Tian Upasana Gala Yongping Zhang Weina Shang Sonal Nagarkar Jaiswal Alberto di Ronza Manish Jaiswal Shinya Yamamoto Hector Sandoval Lita Duraine Marco Sardiello Roy V. Sillitoe Kartik Venkatachalam Hengyu Fan Hugo J. Bellen Chao Tong 《PLoS biology》2015,13(3)
Autophagy helps deliver sequestered intracellular cargo to lysosomes for proteolytic degradation and thereby maintains cellular homeostasis by preventing accumulation of toxic substances in cells. In a forward mosaic screen in Drosophila designed to identify genes required for neuronal function and maintenance, we identified multiple cacophony (cac) mutant alleles. They exhibit an age-dependent accumulation of autophagic vacuoles (AVs) in photoreceptor terminals and eventually a degeneration of the terminals and surrounding glia. cac encodes an α1 subunit of a Drosophila voltage-gated calcium channel (VGCC) that is required for synaptic vesicle fusion with the plasma membrane and neurotransmitter release. Here, we show that cac mutant photoreceptor terminals accumulate AV-lysosomal fusion intermediates, suggesting that Cac is necessary for the fusion of AVs with lysosomes, a poorly defined process. Loss of another subunit of the VGCC, α2δ or straightjacket (stj), causes phenotypes very similar to those caused by the loss of cac, indicating that the VGCC is required for AV-lysosomal fusion. The role of VGCC in AV-lysosomal fusion is evolutionarily conserved, as the loss of the mouse homologues, Cacna1a and Cacna2d2, also leads to autophagic defects in mice. Moreover, we find that CACNA1A is localized to the lysosomes and that loss of lysosomal Cacna1a in cerebellar cultured neurons leads to a failure of lysosomes to fuse with endosomes and autophagosomes. Finally, we show that the lysosomal CACNA1A but not the plasma-membrane resident CACNA1A is required for lysosomal fusion. In summary, we present a model in which the VGCC plays a role in autophagy by regulating the fusion of AVs with lysosomes through its calcium channel activity and hence functions in maintaining neuronal homeostasis. 相似文献
74.
The intra-S phase checkpoint kinase of metazoa and yeast, ATR/MEC1, protects chromosomes from DNA damage and replication stress by phosphorylating subunits of the replicative helicase, MCM2-7. Here we describe an unprecedented ATR-dependent pathway in Tetrahymena thermophila in which the essential pre-replicative complex proteins, Orc1p, Orc2p and Mcm6p are degraded in hydroxyurea-treated S phase cells. Chromosomes undergo global changes during HU-arrest, including phosphorylation of histone H2A.X, deacetylation of histone H3, and an apparent diminution in DNA content that can be blocked by the deacetylase inhibitor sodium butyrate. Most remarkably, the cell cycle rapidly resumes upon hydroxyurea removal, and the entire genome is replicated prior to replenishment of ORC and MCMs. While stalled replication forks are elongated under these conditions, DNA fiber imaging revealed that most replicating molecules are produced by new initiation events. Furthermore, the sole origin in the ribosomal DNA minichromosome is inactive and replication appears to initiate near the rRNA promoter. The collective data raise the possibility that replication initiation occurs by an ORC-independent mechanism during the recovery from HU-induced replication stress. 相似文献
75.
76.
77.
78.
Valeria Sabaj Mario Galindo Daniela Silva Lea Sandoval Juan C. Rodríguez 《Molecular biology reports》2010,37(6):2927-2933
Toxoplasma gondii is one of the most successful protozoan parasites given its ability to manipulate the immune system and establish a chronic infection. It is a parasite with a significant impact on human health, mainly in immunocompromised patients. In Europe and North America, only a few clonal genotypes (I, II and III) seem to be responsible for the vast majority of Toxoplasma infections. Surface antigen 2 gene (SAG2) has been extensively used for genotyping T. gondii isolates. The analysis of this locus reveals that in Northern hemisphere, human disease causing isolates are mainly type II, whereas T. gondii isolated from different animals are both type II and III. Since the immune response depends on parasite genotype, it seems relevant to characterize parasites producing human toxoplasmosis in different geographical areas. The growing information about the prevalent T. gondii genotypes in South America mostly refers to domestic animals. This is the first report of genetic characterization of T. gondii isolates from clinical samples in Chile, South America. All the samples analyzed corresponded to SAG2 type I isolates, and they differ from classic SAG2 type I by genetic polymorphisms. This study contributes to the scarce available information on T. gondii at South America, and reinforces an emerging concept suggesting that SAG2 type I, rather than II, parasites are a frequent cause of clinical toxoplasmosis in this continent. 相似文献
79.
80.
Pablo M. Vergara Ingo J. Hahn Horacio Zeballos Juan J. Armesto 《Ecological Research》2010,25(3):683-690
Conservation of forest birds in fragmented landscapes requires not only determining the critical patch characteristics influencing
local population persistence but also identifying patch networks providing connectivity and suitable habitat conditions necessary
to ensure regional persistence. In this study, we assessed the importance of patch attributes, patch connectivity, and network
components (i.e., groups of interconnected patches) in explaining the occupancy pattern of the Thorn-tailed Rayadito (Aphrastura spinicauda), a forest bird species of central Chile. Using a daily movement threshold distance, we identified a total of 16 network
components of sclerophyllous forest within the study area. Among those components, patch area and vegetation structure-composition
were important predictors of patch occupancy. However, the inclusion of patch connectivity and component size (i.e., the area
of a network component) into the models greatly increases the models’ accuracy and parsimony. Using the best-fitted model,
a total of 33 patches were predicted to be occupied by rayaditos within the study area, but such occupied patches were distributed
in only six network components. These results suggest that persistence of rayaditos in central Chile requires the maintenance
of large single patches and patch networks providing habitat and connectivity. 相似文献