全文获取类型
收费全文 | 638篇 |
免费 | 63篇 |
国内免费 | 1篇 |
专业分类
702篇 |
出版年
2022年 | 3篇 |
2021年 | 4篇 |
2020年 | 2篇 |
2018年 | 13篇 |
2017年 | 7篇 |
2016年 | 15篇 |
2015年 | 18篇 |
2014年 | 20篇 |
2013年 | 34篇 |
2012年 | 30篇 |
2011年 | 23篇 |
2010年 | 26篇 |
2009年 | 18篇 |
2008年 | 30篇 |
2007年 | 29篇 |
2006年 | 39篇 |
2005年 | 39篇 |
2004年 | 31篇 |
2003年 | 41篇 |
2002年 | 33篇 |
2001年 | 16篇 |
2000年 | 4篇 |
1999年 | 13篇 |
1998年 | 8篇 |
1997年 | 3篇 |
1996年 | 7篇 |
1995年 | 3篇 |
1994年 | 5篇 |
1993年 | 2篇 |
1992年 | 6篇 |
1991年 | 11篇 |
1990年 | 9篇 |
1989年 | 4篇 |
1988年 | 9篇 |
1987年 | 16篇 |
1986年 | 11篇 |
1985年 | 11篇 |
1984年 | 8篇 |
1983年 | 8篇 |
1982年 | 14篇 |
1981年 | 8篇 |
1980年 | 8篇 |
1979年 | 4篇 |
1978年 | 8篇 |
1977年 | 5篇 |
1976年 | 7篇 |
1974年 | 10篇 |
1973年 | 7篇 |
1972年 | 10篇 |
1970年 | 2篇 |
排序方式: 共有702条查询结果,搜索用时 15 毫秒
101.
Irestedt M Fuchs J Jønsson KA Ohlson JI Pasquet E Ericson PG 《Molecular phylogenetics and evolution》2008,48(3):1218-1222
102.
Chemical–Genetic Profiling of Imidazo[1,2-a]pyridines and -Pyrimidines Reveals Target Pathways Conserved between Yeast and Human Cells 下载免费PDF全文
Lisa Yu Andres Lopez Abderrahmane Anaflous Brahim El Bali Abdellah Hamal Elke Ericson Lawrence E. Heisler Angus McQuibban Guri Giaever Corey Nislow Charles Boone Grant W. Brown Mohammed Bellaoui 《PLoS genetics》2008,4(11)
Small molecules have been shown to be potent and selective probes to understand cell physiology. Here, we show that imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines compose a class of compounds that target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharomyces cerevisiae, we discovered that two closely related compounds, an imidazo[1,2-a]pyridine and -pyrimidine that differ by a single atom, have distinctly different mechanisms of action in vivo. 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine was toxic to yeast strains with defects in electron transport and mitochondrial functions and caused mitochondrial fragmentation, suggesting that compound 13 acts by disrupting mitochondria. By contrast, 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine acted as a DNA poison, causing damage to the nuclear DNA and inducing mutagenesis. We compared compound 15 to known chemotherapeutics and found resistance required intact DNA repair pathways. Thus, subtle changes in the structure of imidazo-pyridines and -pyrimidines dramatically alter both the intracellular targeting of these compounds and their effects in vivo. Of particular interest, these different modes of action were evident in experiments on human cells, suggesting that chemical–genetic profiles obtained in yeast are recapitulated in cultured cells, indicating that our observations in yeast can: (1) be leveraged to determine mechanism of action in mammalian cells and (2) suggest novel structure–activity relationships. 相似文献
103.
Ingemar Björkhem Angel Cedazo-Minguez Valerio Leoni Steve Meaney 《Molecular aspects of medicine》2009,30(3):171-179
In contrast to their parent molecule cholesterol, two of its side-chain oxidized metabolites are able to cross the blood–brain barrier. There is a concentration-driven flux of 24S-hydroxycholesterol (24S-OHC) from the brain into the circulation, which is of major importance for elimination of excess cholesterol from the brain. The opposite flux of 27-hydroxycholesterol (27-OHC) from the circulation into the brain may regulate a number of key enzymes within the brain. In vitro experiments suggest that the balance between the levels of these two molecules may be of importance for the generation of β-amyloid peptides. In primary cultures of rat hippocampal cells 27-OHC is able to suppress expression of the activity regulated cytoskeleton-associated protein (Arc), a protein important in memory consolidation which is reduced in patients with Alzheimer’s disease (AD). In the present work we explore the possibility that the flux of 27-OHC from the circulation into the brain represents the missing link between AD and hypercholesterolemia, and discuss the possibility that modification of this flux may be a therapeutic strategy. Lastly, we discuss the use of oxysterols as diagnostic markers in neurodegenerative disease. 相似文献
104.
Cancer attractors: A systems view of tumors from a gene network dynamics and developmental perspective 总被引:1,自引:0,他引:1
Sui Huang Ingemar Ernberg Stuart Kauffman 《Seminars in cell & developmental biology》2009,20(7):869-876
Cell lineage commitment and differentiation are governed by a complex gene regulatory network. Disruption of these processes by inappropriate regulatory signals and by mutational rewiring of the network can lead to tumorigenesis. Cancer cells often exhibit immature or embryonic traits and dysregulated developmental genes can act as oncogenes. However, the prevailing paradigm of somatic evolution and multi-step tumorigenesis, while useful in many instances, offers no logically coherent reason for why oncogenesis recapitulates ontogenesis. The formal concept of “cancer attractors”, derived from an integrative, complex systems approach to gene regulatory network may provide a natural explanation. Here we present the theory of attractors in gene network dynamics and review the concept of cell types as attractors. We argue that cancer cells are trapped in abnormal attractors and discuss this concept in the light of recent ideas in cancer biology, including cancer genomics and cancer stem cells, as well as the implications for differentiation therapy. 相似文献
105.
Systematic analysis of genome-wide fitness data in yeast reveals novel gene function and drug action
Maureen E Hillenmeyer Elke Ericson Ronald W Davis Corey Nislow Daphne Koller Guri Giaever 《Genome biology》2010,11(3):R30
We systematically analyzed the relationships between gene fitness profiles (co-fitness) and drug inhibition profiles (co-inhibition)
from several hundred chemogenomic screens in yeast. Co-fitness predicted gene functions distinct from those derived from other
assays and identified conditionally dependent protein complexes. Co-inhibitory compounds were weakly correlated by structure
and therapeutic class. We developed an algorithm predicting protein targets of chemical compounds and verified its accuracy
with experimental testing. Fitness data provide a novel, systems-level perspective on the cell. 相似文献
106.
Hanessian S Therrien E van Otterlo WA Bayrakdarian M Nilsson I Fjellström O Xue Y 《Bioorganic & medicinal chemistry letters》2006,16(4):1032-1036
Prototypical thrombin inhibitors were synthesized based on a trisubstituted phenol as a core motif. A naphthylsulfonamide analogue showed excellent antithrombin activity. An X-ray co-crystal structure showed the expected interactions. 相似文献
107.
Shafaati M Marutle A Pettersson H Lövgren-Sandblom A Olin M Pikuleva I Winblad B Nordberg A Björkhem I 《Journal of lipid research》2011,52(5):1004-1010
There is a significant flux of the neurotoxic oxysterol 27-hydroxycholesterol (27OHC) from the circulation across the blood-brain barrier. Because there is a correlation between 27OHC and cholesterol in the circulation and lipoprotein-bound cholesterol does not pass the blood-brain barrier, we have suggested that 27OHC may mediate the effects of hypercholesterolemia on the brain. We previously demonstrated a modest accumulation of 27OHC in brains of patients with sporadic Alzheimer's disease (AD), consistent with a role of 27OHC as a primary pathogenetic factor. We show here that there is a 4-fold accumulation of 27OHC in different regions of the cortexes of patients carrying the Swedish amyloid precursor protein (APPswe) 670/671 mutation. The brain levels of sitosterol and campesterol were not significantly different in the AD patients compared with the controls, suggesting that the blood-brain barrier was intact in the AD patients. We conclude that accumulation of 27OHC is likely to be secondary to neurodegeneration, possibly a result of reduced activity of CYP7B1, the neuronal enzyme responsible for metabolism of 27OHC. We discuss the possibility of a vicious circle in the brains of the patients with familial AD whereby neurodegenerative changes cause an accumulation of 27OHC that further accelerates neurodegeneration. 相似文献
108.
109.
Responses are quicker to predictable stimuli than if the time and place of appearance is uncertain. Studies that manipulate target predictability often involve overt cues to speed up response times. However, less is known about whether individuals will exhibit faster response times when target predictability is embedded within the inter-trial relationships. The current research examined the combined effects of spatial and temporal target predictability on reaction time (RT) and allocation of overt attention in a sustained attention task. Participants responded as quickly as possible to stimuli while their RT and eye movements were measured. Target temporal and spatial predictability were manipulated by altering the number of: 1) different time intervals between a response and the next target; and 2) possible spatial locations of the target. The effects of target predictability on target detection (Experiment 1) and target discrimination (Experiment 2) were tested. For both experiments, shorter RTs as target predictability increased across both space and time were found. In addition, the influences of spatial and temporal target predictability on RT and the overt allocation of attention were task dependent; suggesting that effective orienting of attention relies on both spatial and temporal predictability. These results indicate that stimulus predictability can be increased without overt cues and detected purely through inter-trial relationships over the course of repeated stimulus presentations. 相似文献
110.
Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain 总被引:1,自引:0,他引:1
Mast N Norcross R Andersson U Shou M Nakayama K Bjorkhem I Pikuleva IA 《Biochemistry》2003,42(48):14284-14292
The known activity of cytochrome P450 46A1 (P450 46A1) is 24(S)-hydroxylation of cholesterol. This reaction produces biologically active oxysterol, 24(S)-hydroxycholesterol, and is also the first step in enzymatic degradation of cholesterol in the brain. We report here that P450 46A1 can further metabolize 24(S)-hydroxycholesterol, giving 24,25- and 24,27-dihydroxycholesterols in both the cell cultures transfected with P450 46A1 cDNA and the in vitro reconstituted system with recombinant enzyme. In addition, P450 46A1 was able to carry out side chain hydroxylations of two endogenous C27-steroids with and without a double bond between C5-C6 (7alpha-hydroxycholesterol and cholestanol, respectively) and introduce a hydroxyl group on the steroid nucleus of the C21-steroid hormones with the C4-C5 double bond (progesterone and testosterone). Also, P450 46A1 was found to metabolize xenobiotics carrying out dextromethorphan O- and N-demethylations, diclofenac 4'-hydroxylation, and phenacetin O-deethylation. Thus, substrate specificities of P450 46A1 are not limited to cholesterol and include a number of structurally diverse compounds. Activities of P450 46A1 suggest that, in addition to the involvement in cholesterol homeostasis in the brain, this enzyme may participate in metabolism of neurosteroids and drugs that can cross the blood-brain barrier and are targeted to the central nervous system. 相似文献