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排序方式: 共有119条查询结果,搜索用时 15 毫秒
101.
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103.
Choi SH Veeraraghavalu K Lazarov O Marler S Ransohoff RM Ramirez JM Sisodia SS 《Neuron》2008,59(4):568-580
Presenilin 1 (PS1) regulates environmental enrichment (EE)-mediated neural progenitor cell (NPC) proliferation and neurogenesis in the adult hippocampus. We now report that transgenic mice that ubiquitously express human PS1 variants linked to early-onset familial Alzheimer's disease (FAD) neither exhibit EE-induced proliferation, nor neuronal lineage commitment of NPCs. Remarkably, the proliferation and differentiation of cultured NPCs from standard-housed mice expressing wild-type PS1 or PS1 variants are indistinguishable. On the other hand, wild-type NPCs cocultured with primary microglia from mice expressing PS1 variants exhibit impaired proliferation and neuronal lineage commitment, phenotypes that are recapitulated with mutant microglia conditioned media in which we detect altered levels of selected soluble signaling factors. These findings lead us to conclude that factors secreted from microglia play a central role in modulating hippocampal neurogenesis, and argue for non-cell-autonomous mechanisms that govern FAD-linked PS1-mediated impairments in adult hippocampal neurogenesis. 相似文献
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105.
The analysis of genetic behaviour within and between species provides important clues about the forces shaping the evolution
of behavioural genes. Genes can affect natural behavioural variation in different ways. Allelic variation causes alternative
behavioural phenotypes, whereas changes in gene expression can influence the initiation of behaviour at different ages. Identifying
the genes involved in polygenic traits has been difficult. Chromosomal analysis has been widely used as a first step in elucidating
the genetic architecture of several behaviours ofDrosophila. Behavioural genetic and molecular studies helped to reveal the genetic basis of circadian time keeping and rhythmic behaviours.
InDrosophila, a number of key processes such as emergence from the pupal case, locomotor activity, feeding, olfaction and aspects of mating
behaviour are under circadian regulation. Evolutionary biology considers migration behaviour as central in genetic structure
of populations and speciation. Genetic loci that influence behaviour are often difficult to identify and localise in part
due to the quantitative nature of behavioural phenotypes. Diapause is a hormonally mediated delayed response to future adverse
conditions and can occur at any stage of development in an insect. Diapauseassociated gene expression was studied inDrosophila using subtractive hybridisation. Several approaches have been made to unravel the genetic complexity of the behaviour, which
have provided information that may be useful in different ways. There is evidence that species do differ in genetic architecture
of photoresponse and this may be related to their natural environment. The classical experiments by Jerry Hirsh and Th. Dobzhansky
to know the nature of genetic basis for extreme selected geotactic behaviour in fruit flies constituted the first attempt
at the genetic dissection of a complex, polygenic behaviour. Understanding the genetic differences between these selected
lines would provide an important point of entry into the study of genetic mechanisms of sensing and responding to gravity,
as well as clues to the origins of genetic flexibility and plasticity in an organism’s response. 相似文献
106.
Yu C Kim SH Ikeuchi T Xu H Gasparini L Wang R Sisodia SS 《The Journal of biological chemistry》2001,276(47):43756-43760
A variety of investigations have led to the conclusion that presenilins (PS) play a critical role in intramembranous, gamma-secretase proteolysis of selected type I membrane proteins, including Notch1 and amyloid precursor protein (APP). We now show that the generation of the S3/Notch intracellular domain and APP-carboxyl-terminal fragment gamma (CTFgamma) derivatives are dependent on PS expression and inhibited by a highly selective and potent gamma-secretase inhibitor. Unexpectedly, the APP-CTFgamma derivative is generated by processing between Leu-645 and Val-646 (of APP(695)), several amino acids carboxyl-terminal to the scissile bonds for production of amyloid beta protein peptides. Although the relationship of APP-CTFgamma to the production of amyloid beta protein peptides is not known, we conclude that in contrast to the highly selective PS-dependent processing of Notch, the PS-dependent gamma-secretase processing of APP is largely nonselective and occurs at multiple sites within the APP transmembrane domain. 相似文献
107.
A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome 总被引:5,自引:24,他引:5
A model of DNA sequence evolution applicable to coding regions is
presented. This represents the first evolutionary model that accounts for
dependencies among nucleotides within a codon. The model uses the codon, as
opposed to the nucleotide, as the unit of evolution, and is parameterized
in terms of synonymous and nonsynonymous nucleotide substitution rates. One
of the model's advantages over those used in methods for estimating
synonymous and nonsynonymous substitution rates is that it completely
corrects for multiple hits at a codon, rather than taking a parsimony
approach and considering only pathways of minimum change between homologous
codons. Likelihood-ratio versions of the relative-rate test are constructed
and applied to data from the complete chloroplast DNA sequences of Oryza
sativa, Nicotiana tabacum, and Marchantia polymorpha. Results of these
tests confirm previous findings that substitution rates in the chloroplast
genome are subject to both lineage-specific and locus-specific effects.
Additionally, the new tests suggest tha the rate heterogeneity is due
primarily to differences in nonsynonymous substitution rates. Simulations
help confirm previous suggestions that silent sites are saturated, leaving
no evidence of heterogeneity in synonymous substitution rates.
相似文献
108.
Benjannet S Elagoz A Wickham L Mamarbachi M Munzer JS Basak A Lazure C Cromlish JA Sisodia S Checler F Chrétien M Seidah NG 《The Journal of biological chemistry》2001,276(14):10879-10887
Processing of the beta-amyloid precursor protein (betaAPP) by beta- and gamma-secretases generates the amyloidogenic peptide Abeta, a major factor in the etiology of Alzheimer's disease. Following the recent identification of the beta-secretase beta-amyloid-converting enzyme (BACE), we herein investigate its zymogen processing, molecular properties, and cellular trafficking. Our data show that among the proprotein convertase family members, furin is the major converting enzyme of pro-BACE into BACE within the trans-Golgi network of HK293 cells. While we demonstrate that the 24-amino acid prosegment is required for the efficient exit of pro-BACE from the endoplasmic reticulum, it may not play a strong inhibitory role since we observe that pro-BACE can produce significant quantities of the Swedish mutant betaAPP(sw) beta-secretase product C99. BACE is palmitoylated at three Cys residues within its transmembrane/cytosolic tail and is sulfated at mature N-glycosylated moieties. Data with three different antibodies show that a small fraction of membrane-bound BACE is shed into the medium and that the extent of ectodomain shedding is palmitoylation-dependent. Overexpression of full-length BACE causes a significant increase in the production of C99 and a decrease in the alpha-secretase product APPsalpha. Although there is little increase in the generation of Abeta by full-length BACE, overexpression of either a soluble form of BACE (equivalent to the shed form) or one lacking the prosegment leads to enhanced Abeta levels. These findings suggest that the shedding of BACE may play a role in the amyloidogenic processing of betaAPP. 相似文献
109.
110.
Lysosomal enzymes are important mediators of acute and chronic inflammatory diseases. The release of lysosomal enzymes into cytoplasm stimulate the inflammatory mediators like oxygen radicals, prostaglandins etc. Enfenamic acid, a fenamate, along with other antiinflammatory drugs, did not stabilize lysosomal membrane isolated from normal and activated phagocytic polymorphonuclear leucocytes of different species. 相似文献