全文获取类型
收费全文 | 254篇 |
免费 | 18篇 |
出版年
2022年 | 1篇 |
2021年 | 1篇 |
2019年 | 1篇 |
2018年 | 2篇 |
2017年 | 4篇 |
2016年 | 4篇 |
2015年 | 14篇 |
2014年 | 10篇 |
2013年 | 6篇 |
2012年 | 14篇 |
2011年 | 9篇 |
2010年 | 11篇 |
2009年 | 7篇 |
2008年 | 6篇 |
2007年 | 10篇 |
2006年 | 13篇 |
2005年 | 10篇 |
2004年 | 8篇 |
2003年 | 12篇 |
2002年 | 11篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 9篇 |
1998年 | 10篇 |
1997年 | 8篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1994年 | 1篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1990年 | 5篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1987年 | 1篇 |
1985年 | 7篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 7篇 |
1976年 | 6篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1972年 | 2篇 |
1971年 | 1篇 |
排序方式: 共有272条查询结果,搜索用时 427 毫秒
221.
222.
Andrew J. Perry Lakshmi C. Wijeyewickrema Pascal G. Wilmann Menachem J. Gunzburg Laura D'Andrea James A. Irving Siew Siew Pang Renee C. Duncan Jacqueline A. Wilce James C. Whisstock Robert N. Pike 《The Journal of biological chemistry》2013,288(22):15821-15829
The complement system is an ancient innate immune defense pathway that plays a front line role in eliminating microbial pathogens. Recognition of foreign targets by antibodies drives sequential activation of two serine proteases, C1r and C1s, which reside within the complement Component 1 (C1) complex. Active C1s propagates the immune response through its ability to bind and cleave the effector molecule complement Component 4 (C4). Currently, the precise structural and biochemical basis for the control of the interaction between C1s and C4 is unclear. Here, using surface plasmon resonance, we show that the transition of the C1s zymogen to the active form is essential for C1s binding to C4. To understand this, we determined the crystal structure of a zymogen C1s construct (comprising two complement control protein (CCP) domains and the serine protease (SP) domain). These data reveal that two loops (492–499 and 573–580) in the zymogen serine protease domain adopt a conformation that would be predicted to sterically abrogate C4 binding. The transition from zymogen to active C1s repositions both loops such that they would be able to interact with sulfotyrosine residues on C4. The structure also shows the junction of the CCP1 and CCP2 domains of C1s for the first time, yielding valuable information about the exosite for C4 binding located at this position. Together, these data provide a structural explanation for the control of the interaction with C1s and C4 and, furthermore, point to alternative strategies for developing therapeutic approaches for controlling activation of the complement cascade. 相似文献
223.
Tang Yongqing Pascal G. Wilmann Shane B. Reeve Theresa H. Coetzer A. Ian Smith James C. Whisstock Robert N. Pike Lakshmi C. Wijeyewickrema 《The Journal of biological chemistry》2013,288(31):22399-22407
The mannose-binding lectin associated-protease-3 (MASP-3) is a member of the lectin pathway of the complement system, a key component of human innate and active immunity. Mutations in MASP-3 have recently been found to be associated with Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome, a severe developmental disorder manifested by cleft palate, intellectual disability, and skeletal abnormalities. However, the molecular basis for MASP-3 function remains to be understood. Here we characterize the substrate specificity of MASP-3 by screening against a combinatorial peptide substrate library. Through this approach, we successfully identified a peptide substrate that was 20-fold more efficiently cleaved than any other identified to date. Furthermore, we demonstrated that mutant forms of the enzyme associated with 3MC syndrome were completely inactive against this substrate. To address the structural basis for this defect, we determined the 2.6-Å structure of the zymogen form of the G666E mutant of MASP-3. These data reveal that the mutation disrupts the active site and perturbs the position of the catalytic serine residue. Together, these insights into the function of MASP-3 reveal how a mutation in this enzyme causes it to be inactive and thus contribute to the 3MC syndrome. 相似文献
224.
Lopez JV; Culver M; Stephens JC; Johnson WE; O'Brien SJ 《Molecular biology and evolution》1997,14(3):277-286
Differential rates of nucleotide substitution among different gene segments
and between distinct evolutionary lineages is well documented among
mitochondrial genes and is likely a consequence of locus-specific selective
constraints that delimit mutational divergence over evolutionary time. We
compared sequence variation of 18 homologous loci (15 coding genes and 3
parts of the control region) among 10 mammalian mitochondrial DNA genomes
which allowed us to describe different mitochondrial evolutionary patterns
and to produce an estimation of the relative order of gene divergence. The
relative rates of divergence of mitochondrial DNA genes in the family
Felidae were estimated by comparing their divergence from homologous
counterpart genes included in nuclear mitochondrial DNA (Numt, pronounced
"new might"), a genomic fossil that represents an ancient transfer of 7.9
kb of mitochondrial DNA to the nuclear genome of an ancestral species of
the domestic cat (Felis catus). Phylogenetic analyses of mitochondrial
(mtDNA) sequences with multiple outgroup species were conducted to date the
ancestral node common to the Numt and the cytoplasmic (Cymt) mtDNA genes
and to calibrate the rate of sequence divergence of mitochondrial genes
relative to nuclear homologous counterparts. By setting the fastest
substitution rate as strictly mutational, an empirical "selective
retardation index" is computed to quantify the sum of all constraints,
selective and otherwise, that limit sequence divergence of mitochondrial
gene sequences over time.
相似文献
225.
Camarodont sea urchins possess a rapidly evolving actin gene family whose
members are expressed in distinct cell lineages in a developmentally
regulated fashion. Evolutionary changes in the actin gene family of
echinoids include alterations in number of family members, site of
expression, and gene linkage, and a dichotomy between rapidly and slowly
evolving isoform-specific 3' untranslated regions. We present sequence
comparisons and an analysis of the actin gene family in two congeneric sea
urchins that develop in radically different modes, Heliocidaris
erythrogramma and H. tuberculata. The sequences of several actin genes from
the related species Lytechinus variegatus are also presented. We compare
the features of the Heliocidaris and Lytechinus actin genes to those of the
the actin gene families of other closely related sea urchins and discuss
the nature of the evolutionary changes among sea urchin actins and their
relationship to developmental mode.
相似文献
226.
The purpose of this paper is to assess the extent of gene identity and
differentiation at 33 dinucleotide repeat loci (377 total alleles) within
and among three European and three Native American populations. In order to
do this, we show that a maximum-likelihood method proposed for phylogenetic
trees (Cavalli-Sforza and Piazza 1975) can be used to estimate gene
identity (Nei 1987) with respect to any hierarchical structure. This method
allows gene differentiation to be evaluated with respect to any internal
node of a hierarchy. It also allows a generalization of F- and G-statistics
to situations with unequal expected levels of differentiation. Our
principal finding is that levels of genetic differentiation are unique to
specific populations and levels of nesting. The populations of European
origin show very little internal differentiation; moreover, their
continental average is close to the total population defined by the
aggregate of Europeans and Native Americans. By contrast, the Native
American populations show moderate levels of internal differentiation, and
a great distance between their continental average and the total. The
results of analyses of subsets of loci that were selected to have high gene
diversities in either Europeans or Native Americans closely parallel those
from the total set of loci. This suggests that the principal results are
unlikely to be caused by a European ascertainment bias in locus selection.
In summary, our findings demonstrate that partitions of gene diversity into
within- and between-populations components are heavily biased by the
populations analyzed and the models fitted. Optimistically, however, more
information is available to analyze population history and evolution by
quantifying, as we have done, the uniqueness of patterns of
differentiation.
相似文献
227.
Fish populations in Albasini and Nandoni dams are negatively affected by extensive netting practices. This observation was made by the authors following a number of fish health assessment surveys related to aquatic pollution in the Luvuvhu River catchment. A comparison between the number and size of fish collected over a period of ten years indicated decreases in the average size and a consistent low number of fish, despite similar extensive sampling efforts. Unregulated netting is a common practice in both dams. This may become a serious problem as fish from these two dams are an important source of protein for the local communities. The purpose of this note is to report that gillnets are illegally used in the system and on the effect this could have on the fish population. The authors suggest educational and awareness initiatives to inform local communities about the importance of utilising fish in a sustainable manner to ensure the livelihood of generations to come. 相似文献
228.
Daniel JC Kronauer Caspar Schöning Lars B Vilhelmsen Jacobus J Boomsma 《BMC evolutionary biology》2007,7(1):56
Background
Army ants are the prime arthropod predators in tropical forests, with huge colonies and an evolutionary derived nomadic life style. Five of the six recognized subgenera of Old World Dorylus army ants forage in the soil, whereas some species of the sixth subgenus (Anomma) forage in the leaf-litter and some as conspicuous swarm raiders on the forest floor and in the lower vegetation (the infamous driver ants). Here we use a combination of nuclear and mitochondrial DNA sequences to reconstruct the phylogeny of the Dorylus s.l. army ants and to infer the evolutionary transitions in foraging niche and associated morphological adaptations. 相似文献229.
SerpinB6 is an inhibitor of kallikrein-8 in keratinocytes 总被引:1,自引:0,他引:1
SerpinB6 (Proteinase inhibitor 6/PI-6) is an intracellular serpin produced by leukocytes, platelets, endothelial cells, keratinocytes and other epithelial cells. It is a potent cathepsin G inhibitor thought to protect monocytes, neutrophils and bystander cells from ectopic cathepsin G during inflammation. Here we show that serpinB6 also inhibits the human serine protease kallikrein-8 (hK8) and that in human and mouse skin, serpinB6 and kallikrein-8 co-localize in differentiated keratinocytes. SerpinB6 inhibits hK8 with an association rate constant (kass) of 1.8 +/- 0.2 x 10(5) M(-1)s(-1) compared to 3.4 +/- 0.2 x 10(6) M(-1) s(-1) for the interaction between the mouse orthologue of serpinB6 (SPI3/serpinb6a) and mouse kallikrein-8 (mK8). Molecular modelling suggested that the lower efficiency of the serpinB6/hK8 interaction is partly due to the bulkier P2 methionine residue of serpinB6 compared to the smaller P2 valine in SPI3. Taken together, these results suggest that serpinB6 is a physiologically relevant inhibitor of hK8 in skin. We postulate that serpinB6 protects the intracellular compartment of keratinocytes from ectopic hK8. 相似文献
230.
Askew DJ Cataltepe S Kumar V Edwards C Pace SM Howarth RN Pak SC Askew YS Brömme D Luke CJ Whisstock JC Silverman GA 《The Journal of biological chemistry》2007,282(34):24948-24960
SERPINB11, the last of 13 human clade B serpins to be described, gave rise to seven different isoforms. One cDNA contained a premature termination codon, two contained splice variants, and four contained full-length open reading frames punctuated by eight single nucleotide polymorphisms (SNPs). The SNPs encoded amino acid variants located within the serpin scaffold but not the reactive site loop (RSL). Although the mouse orthologue, Serpinb11, could inhibit trypsin-like peptidases, SERPINB11 showed no inhibitory activity. To determine whether the human RSL targeted a different class of peptidases or the serpin scaffold was unable to support inhibitory activity, we synthesized chimeric human and mouse proteins, in which the RSLs had been swapped. The human RSL served as a trypsin inhibitor when supported by mouse scaffold sequences. Conversely, the mouse RSL on the human scaffold showed no inhibitory activity. These findings suggested that variant residues in the SERPINB11 scaffold impaired serpin function. SDS-PAGE analysis supported this notion as RSL-cleaved SERPINB11 was unable to undergo the stressed-to-relaxed transition typical of inhibitory type serpins. Mutagenesis studies supported this hypothesis, since the reversion of amino acid sequences in helices D and I to those conserved in other clade B serpins partially restored the ability of SERPINB11 to form covalent complexes with trypsin. Taken together, these findings suggested that SERPINB11 SNPs encoded amino acids in the scaffold that impaired RSL mobility, and HapMap data showed that the majority of genomes in different human populations harbored these noninhibitory SERPINB11 alleles. Like several other serpin superfamily members, SERPINB11 has lost inhibitory activity and may have evolved a noninhibitory function. 相似文献