全文获取类型
收费全文 | 423篇 |
免费 | 42篇 |
出版年
2023年 | 2篇 |
2022年 | 8篇 |
2021年 | 13篇 |
2020年 | 6篇 |
2019年 | 5篇 |
2018年 | 6篇 |
2017年 | 6篇 |
2016年 | 14篇 |
2015年 | 16篇 |
2014年 | 22篇 |
2013年 | 32篇 |
2012年 | 28篇 |
2011年 | 36篇 |
2010年 | 23篇 |
2009年 | 18篇 |
2008年 | 18篇 |
2007年 | 20篇 |
2006年 | 15篇 |
2005年 | 21篇 |
2004年 | 19篇 |
2003年 | 16篇 |
2002年 | 16篇 |
2001年 | 8篇 |
2000年 | 9篇 |
1999年 | 4篇 |
1998年 | 5篇 |
1997年 | 6篇 |
1996年 | 4篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1992年 | 3篇 |
1991年 | 10篇 |
1990年 | 4篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1981年 | 2篇 |
1979年 | 6篇 |
1978年 | 3篇 |
1977年 | 1篇 |
1976年 | 9篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1972年 | 5篇 |
1971年 | 2篇 |
1967年 | 1篇 |
排序方式: 共有465条查询结果,搜索用时 31 毫秒
71.
Images of human erythrocytes from a healthy donor were recorded under differential interference contrast (DIC) microscopy;
they were acquired rapidly (~336 Hz) and the intensity of the centermost pixel of each cell was recorded for ~60 s (20,000
values). Various techniques were used to analyze the data, including detrended fluctuation analysis (DFA) and multiscale entropy
(MSE); however, power spectrum analysis was deemed the most appropriate for metrifying and comparing results. This analysis
was used to compare cells from young and old populations, and after perturbing normal conditions, with changes in temperature,
adenosine triphosphate (ATP) concentration (using NaF, an inhibitor of glycolysis, and α-toxin, a pore-forming molecule used
to permeabilize red cells to ATP), and water transport rates [using glycerol, and p-chloromercuriphenylsulfonic acid (pCMBS) to inhibit aquaporins, AQPs]. There were measurable differences in the membrane
fluctuation characteristics in populations of young and old cells, but there was no significant change in the flickering time
series on changing the temperature of an individual cell, by depleting it of ATP, or by competing with the minor water exchange
pathway via AQP3 using glycerol. However, pCMBS, which inhibits AQP1, the major water exchange pathway, inhibited flickering
in all cells, and yet it was restored by the membrane intercalating species dibutyl phthalate (DBP). We developed a computer
model to simulate acquired displacement spectral time courses and to evaluate various methods of data analysis, and showed
how the flexibility of the membrane, as defined in the model, affects the flickering time course. 相似文献
72.
Thomson JG Yau YY Blanvillain R Nunes WM Chiniquy D Thilmony R Ow DW 《Transgenic research》2009,18(2):237-248
The small serine resolvase ParA from bacterial plasmids RK2 and RP4 catalyzes the recombination of two identical 133 bp recombination
sites known as MRS. Previously, we reported that ParA is active in the fission yeast Schizosaccharomyces pombe. In this work, the parA recombinase gene was placed under the control of the Arabidopsis
OXS3 promoter and introduced into Arabidopsis lines harboring a chromosomally integrated MRS-flanked target. The ParA recombinase excised the MRS-flanked DNA and the excision event was detected in subsequent generations in the absence of ParA, indicating germinal transmission
of the excision event. The precise site-specific deletion by the ParA recombination system in planta demonstrates that the
ParA recombinase can be used to remove transgenic DNA, such as selectable markers or other introduced transgenes that are
no longer desired in the final product. 相似文献
73.
Owing to the complex nature of V1VO ATPases, identification of neighboring subunits is essential for mechanistic understanding of this enzyme. Here, we describe the links between the V1 headpiece and the VO-domain of the yeast V1VO ATPase via subunit A and d as well as the VO subunits a and d using surface plasmon resonance and fluorescence correlation spectroscopy. Binding constants of about 60 and 200 nM have been determined for the a-d and d-A assembly, respectively. The data are discussed in light of subunit a and d forming a peripheral stalk, connecting the catalytic A3B3 hexamer with VO.
Structured summary
MINT-7012054: d (uniprotkb:P32366) binds (MI:0407) to A (uniprotkb:P17255) by fluorescence correlation spectroscopy (MI:0052)MINT-7012041: d (uniprotkb:P32366) binds (MI:0407) to A (uniprotkb:P17255) by surface plasmon resonance (MI:0107)MINT-7012028: d (uniprotkb:P32366) binds (MI:0407) to a (uniprotkb:P32563) by surface plasmon resonance (MI:0107) 相似文献74.
Ming-hon Yau Yu Wang Karen S. L. Lam Jialiang Zhang Donghai Wu Aimin Xu 《The Journal of biological chemistry》2009,284(18):11942-11952
Lipoprotein lipase (LPL) is a principal enzyme responsible for the
clearance of chylomicrons and very low density lipoproteins from the
bloodstream. Two members of the Angptl (angiopoietin-like protein) family,
namely Angptl3 and Angptl4, have been shown to inhibit LPL activity in
vitro and in vivo. Here, we further investigated the structural
basis underlying the LPL inhibition by Angptl3 and Angptl4. By multiple
sequence alignment analysis, we have identified a highly conserved 12-amino
acid consensus motif that is present within the coiled-coil domain (CCD) of
both Angptl3 and Angptl4, but not other members of the Angptl family.
Substitution of the three polar amino acid residues (His46,
Gln50, and Gln53) within this motif with alanine
abolishes the inhibitory effect of Angptl4 on LPL in vitro and also
abrogates the ability of Angptl4 to elevate plasma triglyceride levels in
mice. The CCD of Angptl4 interacts with LPL and converts the catalytically
active dimers of LPL to its inactive monomers, whereas the mutant protein with
the three polar amino acids being replaced by alanine loses such a property.
Furthermore, a synthetic peptide consisting of the 12-amino acid consensus
motif is sufficient to inhibit LPL activity, although the potency is
much lower than the recombinant CCD of Angptl4. In summary, our data suggest
that the 12-amino acid consensus motif within the CCD of Angptl4, especially
the three polar residues within this motif, is responsible for its interaction
with and inhibition of LPL by blocking the enzyme dimerization.Lipoprotein lipase
(LPL)3 is an
endothelium-bound enzyme that catalyzes the hydrolysis of plasma triglyceride
(TG) associated with chylomicrons and very low density lipoproteins
(1,
2). This enzyme plays a major
role in maintaining lipid homeostasis by promoting the clearance of TG-rich
lipoproteins from the bloodstream. Abnormality in LPL functions has been
associated with a number of pathological conditions, including
atherosclerosis, dyslipidemia associated with diabetes, and Alzheimer disease
(1).LPL is expressed in a wide variety of cell types, particularly in
adipocytes and myocytes (2). As
a rate-limiting enzyme for clearance of TG-rich lipoproteins, the activity of
LPL is tightly modulated by multiple mechanisms in a tissue-specific manner in
response to nutritional changes
(3,
4). The enzymatic activity of
LPL in adipose tissue is enhanced after feeding to facilitate the storage of
TG, whereas it is down-regulated during fasting to increase the utilization of
TG by other tissues (5). The
active form of LPL is a noncovalent homodimer with the subunits associated in
a head-to-tail manner, and the dissociation of its dimeric form leads to the
formation of a stable inactive monomeric conformation and irreversible enzyme
inactivation (6). At the
post-translational level, the LPL activity is regulated by numerous
apolipoprotein co-factors. For instance, apoCII, a small apolipoprotein
consisting of 79 amino acid residues in human, activates LPL by directly
binding to the enzyme (7,
8). By contrast, several other
apolipoproteins such as apoCI, apo-CIII, and apoE have been shown to inhibit
the LPL activity in vitro
(3).Angiopoietin-like proteins (Angptl) are a family of secreted proteins
consisting of seven members, Angptl1 to Angptl7
(9,
10). All the members of the
Angptl family share a similar domain organization to those of angiopoietins,
with an NH2-terminal coiled-coil domain (CCD) and a COOH-terminal
fibrinogen-like domain. Among the seven family members, only Angptl3 and
Angptl4 have been shown to be involved in regulating triglyceride metabolism
(10,
11). The biological functions
of Angptl3 in lipid metabolism were first discovered by Koishi et al.
(12) in their positional
cloning of the recessive mutation gene responsible for the hypolipidemia
phenotype in a strain of obese mouse KK/snk. Subsequent studies have
demonstrated that Angptl3 increases plasma TG levels by inhibiting the LPL
enzymatic activity
(13–15).
Angptl4, also known as fasting-induced adipocyte factor, hepatic
fibrinogen/angiopoietin-related protein, or peroxisome proliferator-activated
receptor-γ angiopoietin-related, is a secreted glycoprotein abundantly
expressed in adipocyte, liver, and placenta
(16–18).
In addition to its role in regulating angiogenesis, a growing body of evidence
demonstrated that Angptl4 is an important player of lipid metabolism
(10,
11). Elevation of circulating
Angptl4 by transgenic or adenoviral overexpression, or by direct
supplementation of recombinant protein, leads to a marked elevation in the
levels of plasma TG and low density lipoprotein cholesterol in mice
(19–22).
By contrast, Angptl4 knock-out mice exhibit much lower plasma TG and
cholesterol levels compared with the wild type littermates
(19,
20). Notably, treatment of
several mouse models (such as C57BL/6J, ApoE–/–,
LDLR–/–, and db/db obese/diabetic mice) with a
neutralizing antibody against Angptl4 recapitulate the lipid phenotype found
in Angptl4 knock-out mice
(19). The role of Angptl4 as a
physiological inhibitor of LPL is also supported by the finding that its
expression levels in adipose tissue change rapidly during the fed-to-fasting
transitions and correlate inversely with LPL activity
(23). In humans, a genetic
variant of the ANGPTL4 gene (E40K) has been found to be associated
with significantly lower plasma TG levels and higher high density lipoprotein
cholesterol concentrations in several ethnic groups
(24–26).Angptl3 and Angptl4 share many common biochemical and functional properties
(10). In both humans and
rodents, Angptl3 and Angptl4 are proteolytically cleaved at the linker region
and circulate in plasma as two truncated fragments, including
NH2-terminal CCD and COOH-terminal fibrinogen-like domain
(14,
27–29).
The effects of both Angptl3 and Angptl4 on elevating plasma TG levels are
mediated exclusively by their NH2-terminal CCDs
(15,
22,
23,
27,
30). The CCDs of Angptl3 and
Angptl4 have been shown to inhibit the LPL activity in vitro as well
as in mice
(23,30,31).
Angptl4 inhibits LPL by promoting the conversion of the catalytically active
LPL dimers into catalytically inactive LPL monomers, thereby leading to the
inactivation of LPL (23,
31). However, the detailed
structural and molecular basis underlying the LPL inhibition by Angptl3 and
Angptl4 remain poorly characterized at this stage.In this study, we analyzed all known amino acid sequences of Angptl3 and
Angptl4 from various species and found a short motif,
LAXGLLXLGXGL (where X represents polar
amino acid residues), which corresponds to amino acid residues 46–57 and
44–55 of human Angptl3 and Angptl4, respectively, is highly conserved
despite the low degree of their overall homology (∼30%). Using both in
vitro and in vivo approaches, we demonstrated that this 12-amino
acid sequence motif, in particular the three polar amino acid residue within
this motif, is essential for mediating the interactions between LPL and
Angpt4, which in turn disrupts the dimerization of the enzyme. 相似文献
75.
Tai On Yau Thomas Ho Yin Leung Sandra Lam Oi Fung Cheung Edmund Kwok Kwan Tung Pek Lan Khong Amy Lam Sookja Chung Irene Oi Lin Ng 《PloS one》2009,4(8)
DLC2 (deleted in liver cancer 2), a Rho GTPase-activating protein, was previously shown to be underexpressed in human hepatocellular carcinoma and has tumor suppressor functions in cell culture models. We generated DLC2-deficient mice to investigate the tumor suppressor role of DLC2 in hepatocarcinogenesis and the function of DLC2 in vivo. In this study, we found that, unlike homologous DLC1, which is essential for embryonic development, DLC2 was dispensable for embryonic development and DLC2-deficient mice could survive to adulthood. We also did not observe a higher incidence of liver tumor formation or diethylnitrosamine (DEN)-induced hepatocarcinogenesis in DLC2-deficient mice. However, we observed that DLC2-deficient mice were smaller and had less adipose tissue than the wild type mice. These phenotypes were not due to reduction of cell size or defect in adipogenesis, as observed in the 190B RhoGAP-deficient mouse model. Together, these results suggest that deficiency in DLC2 alone does not enhance hepatocarcinogenesis. 相似文献
76.
We propose a feature vector approach to characterize the variation in large data sets of biological sequences. Each candidate sequence produces a single feature vector constructed with the number and location of amino acids or nucleic acids in the sequence. The feature vector characterizes the distance between the actual sequence and a model of a theoretical sequence based on the binomial and uniform distributions. This method is distinctive in that it does not rely on sequence alignment for determining protein relatedness, allowing the user to visualize the relationships within a set of proteins without making a priori assumptions about those proteins. We apply our method to two large families of proteins: protein kinase C, and globins, including hemoglobins and myoglobins. We interpret the high-dimensional feature vectors using principal components analysis and agglomerative hierarchical clustering. We find that the feature vector retains much of the information about the original sequence. By using principal component analysis to extract information from collections of feature vectors, we are able to quickly identify the nature of variation in a collection of proteins. Where collections are phylogenetically or functionally related, this is easily detected. Hierarchical agglomerative clustering provides a means of constructing cladograms from the feature vector output. 相似文献
77.
Stringer LD Suckling DM Baird D Vander Meer RK Christian SJ Lester PJ 《Environmental entomology》2011,40(5):1276-1284
Cost-effective detection of invasive ant colonies before establishment in new ranges is imperative for the protection of national borders and reducing their global impact. We examined the sampling efficiency of food-baits and pitfall traps (baited and nonbaited) in detecting isolated red imported fire ant (Solenopsis invicta Buren) nests in multiple environments in Gainesville, FL. Fire ants demonstrated a significantly higher preference for a mixed protein food type (hotdog or ground meat combined with sweet peanut butter) than for the sugar or water baits offered. Foraging distance success was a function of colony size, detection trap used, and surveillance duration. Colony gyne number did not influence detection success. Workers from small nests (0- to 15-cm mound diameter) traveled no >3 m to a food source, whereas large colonies (>30-cm mound diameter) traveled up to 17 m. Baited pitfall traps performed best at detecting incipient ant colonies followed by nonbaited pitfall traps then food baits, whereas food baits performed well when trying to detect large colonies. These results were used to create an interactive model in Microsoft Excel, whereby surveillance managers can alter trap type, density, and duration parameters to estimate the probability of detecting specified or unknown S. invicta colony sizes. This model will support decision makers who need to balance the sampling cost and risk of failure to detect fire ant colonies. 相似文献
78.
The use of recombinases for genomic engineering is no longer a new technology. In fact, this technology has entered its third
decade since the initial discovery that recombinases function in heterologous systems (Sauer in Mol Cell Biol 7(6):2087–2096,
1987). The random insertion of a transgene into a plant genome by traditional methods generates unpredictable expression patterns.
This feature of transgenesis makes screening for functional lines with predictable expression labor intensive and time consuming.
Furthermore, an antibiotic resistance gene is often left in the final product and the potential escape of such resistance
markers into the environment and their potential consumption raises consumer concern. The use of site-specific recombination
technology in plant genome manipulation has been demonstrated to effectively resolve complex transgene insertions to single
copy, remove unwanted DNA, and precisely insert DNA into known genomic target sites. Recombinases have also been demonstrated
capable of site-specific recombination within non-nuclear targets, such as the plastid genome of tobacco. Here, we review
multiple uses of site-specific recombination and their application toward plant genomic engineering. We also provide alternative
strategies for the combined use of multiple site-specific recombinase systems for genome engineering to precisely insert transgenes
into a pre-determined locus, and removal of unwanted selectable marker genes. 相似文献
79.
Catherine Chojenta Sheree Harris Nicole Reilly Peta Forder Marie-Paule Austin Deborah Loxton 《PloS one》2014,9(4)
While grief, emotional distress and other mental health conditions have been associated with pregnancy loss, less is known about the mental health impact of these events during subsequent pregnancies and births. This paper examined the impact of any type of pregnancy loss on mental health in a subsequent pregnancy and postpartum. Data were obtained from a sub-sample (N = 584) of the 1973-78 cohort of the Australian Longitudinal Study on Women''s Health, a prospective cohort study that has been collecting data since 1996. Pregnancy loss was defined as miscarriage, termination due to medical reasons, ectopic pregnancy and stillbirth. Mental health outcomes included depression, anxiety, stress or distress, sadness or low mood, excessive worry, lack of enjoyment, and feelings of guilt. Demographic factors and mental health history were controlled for in the analysis. Women with a previous pregnancy loss were more likely to experience sadness or low mood (AOR = 1.75, 95% CI: 1.11 to 2.76, p = 0.0162), and excessive worry (AOR = 2.01, 95% CI: 1.24 to 3.24, p = 0.0043) during a subsequent pregnancy, but not during the postpartum phase following a subsequent birth. These results indicate that while women who have experienced a pregnancy loss are a more vulnerable population during a subsequent pregnancy, these deficits are not evident in the postpartum. 相似文献
80.
Tan To Cheung Ronnie T. P. Poon Kenneth S. H. Chok Albert C. Y. Chan Simon H. Y. Tsang Wing Chiu Dai Thomas C. C. Yau See Ching Chan Sheung Tat Fan Chung Mau Lo 《PloS one》2014,9(4)