全文获取类型
收费全文 | 1130篇 |
免费 | 82篇 |
国内免费 | 21篇 |
出版年
2024年 | 3篇 |
2023年 | 19篇 |
2022年 | 21篇 |
2021年 | 47篇 |
2020年 | 30篇 |
2019年 | 45篇 |
2018年 | 41篇 |
2017年 | 29篇 |
2016年 | 25篇 |
2015年 | 39篇 |
2014年 | 65篇 |
2013年 | 102篇 |
2012年 | 45篇 |
2011年 | 32篇 |
2010年 | 26篇 |
2009年 | 46篇 |
2008年 | 56篇 |
2007年 | 52篇 |
2006年 | 50篇 |
2005年 | 45篇 |
2004年 | 41篇 |
2003年 | 35篇 |
2002年 | 38篇 |
2001年 | 16篇 |
2000年 | 23篇 |
1999年 | 26篇 |
1998年 | 21篇 |
1997年 | 12篇 |
1996年 | 11篇 |
1995年 | 18篇 |
1994年 | 17篇 |
1993年 | 18篇 |
1992年 | 22篇 |
1991年 | 17篇 |
1990年 | 13篇 |
1989年 | 16篇 |
1988年 | 14篇 |
1987年 | 11篇 |
1986年 | 7篇 |
1985年 | 8篇 |
1984年 | 8篇 |
1983年 | 2篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
排序方式: 共有1233条查询结果,搜索用时 15 毫秒
91.
92.
In silico two-hybrid system for the selection of physically interacting protein pairs 总被引:1,自引:0,他引:1
Deciphering the interaction links between proteins has become one of the main tasks of experimental and bioinformatic methodologies. Reconstruction of complex networks of interactions in simple cellular systems by integrating predicted interaction networks with available experimental data is becoming one of the most demanding needs in the postgenomic era. On the basis of the study of correlated mutations in multiple sequence alignments, we propose a new method (in silico two-hybrid, i2h) that directly addresses the detection of physically interacting protein pairs and identifies the most likely sequence regions involved in the interactions. We have applied the system to several test sets, showing that it can discriminate between true and false interactions in a significant number of cases. We have also analyzed a large collection of E. coli protein pairs as a first step toward the virtual reconstruction of its complete interaction network. 相似文献
93.
The maintenance of mobile DNA sequences in clonal organisms has been seen as a paradox. If selfish mobile sequences spread through genomes only by overreplication in transposition, then sexuality is necessary for their spread through populations. The persistence of bacterial transposable elements without obvious dominant selectable markers has previously been explained by horizontal transfer. However, advantageous insertions of mobile DNAs are known in bacteria. Here we model maintenance of an otherwise selfish mobile DNA element in a clonal species in which selection for null mutations occurs during one of two temporally alternating environments. Large areas of parameter space permit maintenance of mobile DNAs where, without selection, they would have gone extinct. Horizontal transfer diminishes, rather than enhances, mean copy number. In finite populations, effective population sizes are greatly reduced by selective sweeps, and mean copy number can be increased as the reduced variance in copy number results in reduced selection. 相似文献
94.
In certain cases, predicted by evolutionary theory of sex-allocation and confirmed by empirical evidence, animals adaptively change their progeny sex-ratio according to individual circumstances. Here we argue that a similar response of offspring sex-ratio must exist in relation to genetic variation of mothers' mitochondria, as a consequence of maternal inheritance of these organelles and of their influence on fitness resulting from their crucial role in metabolism. In fact, a mathematical analysis of evolutionary dynamics of sex-allocation mutants demonstrates that natural selection promotes an evolutionarily stable allocation policy where mothers with defective mitochondria generate only sons, while those with optimal mitochondria have female biased progenies. 相似文献
95.
The relationship between probability of survival and the number of deleterious mutations in the genome is investigated using
three different models of highly redundant systems that interact with a threatening environment. Model one is a system that
counters a potentially lethal infection; it has multiple identical components that act in sequence and in parallel. Model
two has many different overlapping components that provide three-fold coverage of a large number of vital functions. The third
model is based on statistical decision theory: an ideal detector, following an optimum decision strategy, makes crucial decisions
in an uncertain world. The probability of a fatal error is reduced by a redundant sampling system, but the chance of error
rises as the system is impaired by deleterious mutations. In all three cases the survival profile shows a synergistic pattern
in that the probability of survival falls slowly and then more rapidly. This is different than the multiplicative or independent
survival profile that is often used in mathematical models. It is suggested that a synergistic profile is a property of redundant
systems.
Model one is then used to study the conservation of redundancy during sexual and asexual reproduction. A unicellular haploid
organism reproducing asexually retains redundancy when the mutation rate is very low (0001 per cell division), but tends to
lose high levels of redundancy if the mutation rate is increased (001 to 01 per cell division). If a similar unicellular haploid
organism has a sexual phase then redundancy is retained for mutation rates between 0001 and 01 per cell division. The sexual
organism outgrows the asexual organism when the above mutation rates apply. If they compete for finite resources the asexual
organism will be extinguished. Variants of the sexual organism with increased redundancy will outgrow those with lower levels
of redundancy and the sexual process facilitates the evolution of more complex forms. There is a limit to the extent that
complexity can be increased by increasing the size of the genome and in asexual organisms this leads to progressive accumulation
of mutations with loss of redundancy and eventual extinction. If complexity is increased by using genes in new combinations,
the asexual form can reach a stable equilibrium, although it is associated with some loss of redundancy. The sexual form,
by comparison, can survive, with retention of redundancy, even if the mutation rate is above one per generation.
The conservation and evolution of redundancy, which is essential for complexity, depends on the sexual process of reproduction. 相似文献
96.
H<Subscript>2</Subscript>O<Subscript>2</Subscript>-induced higher order chromatin degradation: A novel mechanism of oxidative genotoxicity 总被引:2,自引:0,他引:2
Konat GW 《Journal of biosciences》2003,28(1):57-60
The genotoxicity of reactive oxygen species (ROS) is well established. The underlying mechanism involves oxidation of DNA by ROS. However, we have recently shown that hydrogen peroxide (H2O2), the major mediator of oxidative stress, can also cause genomic damage indirectly. Thus, H2O2 at pathologically relevant concentrations rapidly induces higher order chromatin degradation (HOCD), i.e. enzymatic excision of chromatin loops and their oligomers at matrix-attachment regions. The activation of endonuclease that catalyzes HOCD is a signalling event triggered specifically by H2O2. The activation is not mediated by an influx of calcium ions, but resting concentrations of intracellular calcium ions are required for the maintenance of the endonuclease in an active form. Although H2O2-induced HOCD can efficiently dismantle the genome leading to cell death, under sublethal oxidative stress conditions H2O2-induced HOCD may be the major source of somatic mutations. 相似文献
97.
Mutations in the rhodopsin gene are the most common cause of retinitis pigmentosa (RP) among human patients. The nature of
the rhodopsin mutations has critical implications for the design of strategies for gene therapy. Nearly all rhodopsin mutations
are dominant. Although dominance does not arise because of haploinsufficiency, it is unclear whether it is caused by gain-of-function
or dominant-negative mutations. Current strategies for gene therapy have been devised to deal with toxic, gain-of-function
mutations. However, analysis of results of transgenic and targeted expression of various rhodopsin genes in mice suggests
that dominance may arise as a result of dominant-negative mutations. This has important consequences for gene therapy. The
effects of dominant-negative mutations can be alleviated, in principle, by supplementation with additional wild-type rhodopsin.
If added wild-type rhodopsin could slow retinal degeneration in human patients, as it does in mice, it would represent a valuable
new strategy for gene therapy of RP caused by dominant rhodopsin mutations. 相似文献
98.
Towards an understanding of the genetics of human male infertility: lessons from flies 总被引:12,自引:0,他引:12
It has been argued that about 4–5% of male adults suffer from infertility due to a genetic causation. From studies in the fruitfly Drosophila, there is evidence that up to 1500 recessive genes contribute to male fertility in that species. Here we suggest that the control of human male fertility is of at least comparable genetic complexity. However, because of small family size, conventional positional cloning methods for identifying human genes will have little impact on the dissection of male infertility. A critical selection of well-defined infertility phenotypes in model organisms, combined with identification of the genes involved and their orthologues in man, might reveal the genes that contribute to human male infertility. 相似文献
99.
Lehväslaiho H 《Briefings in bioinformatics》2000,1(2):161-166
This paper aims to give an overview of current resources onhuman sequence variations and give an idea about the directionin which these services are moving. 相似文献
100.
The cDNA sequence for the human d-bifunctional protein (D-BP: 17β-hydroxysteroid dehydrogenase IV) was investigated in patients with peroxisomal disorders
belonging to the BP complementation group (CG). In three cases, analysis of polymerase chain reaction products generated from
the patients' cDNA indicated the presence of a deletion within the region corresponding to nucleotides 209–537 of the normal
cDNA sequence. Subsequent sequencing revealed that, in two of the patients, 47 base pairs were missing, with the deletion
corresponding to nucleotides 302/3–349/50 of the normal sequence. In the third patient, a smaller deletion of 22 bp (nucleotides
280/1–302/3) was characterized. Only the mutant sequence was detected in each of these cases, consistent with parental consanguinity.
Both deletions cause a frameshift, and would lead to premature termination of the BP. Available family members were also investigated,
and the findings conformed with expectations for an autosomal recessive disorder. In addition to the deletions, a number of
other base changes have been identified in this series of patients. In particular, one patient, whose parents were also consanguineous,
was homozygous for a base change, which results in a nonconservative substitution of serine 177 with a phenylalanine residue.
The functional significance of this amino acid substitution, as well as the other identified changes, is still to be determined.
Nevertheless, our data provide strong support for the hypothesis that defects in the gene for the D-BP are responsible for
the β-oxidation defect in patients belonging to the BP CG. 相似文献