全文获取类型
收费全文 | 646篇 |
免费 | 87篇 |
国内免费 | 2篇 |
出版年
2022年 | 9篇 |
2021年 | 17篇 |
2020年 | 7篇 |
2019年 | 9篇 |
2018年 | 13篇 |
2017年 | 12篇 |
2016年 | 17篇 |
2015年 | 31篇 |
2014年 | 35篇 |
2013年 | 26篇 |
2012年 | 53篇 |
2011年 | 35篇 |
2010年 | 27篇 |
2009年 | 22篇 |
2008年 | 38篇 |
2007年 | 34篇 |
2006年 | 34篇 |
2005年 | 30篇 |
2004年 | 20篇 |
2003年 | 15篇 |
2002年 | 23篇 |
2001年 | 18篇 |
2000年 | 24篇 |
1999年 | 20篇 |
1998年 | 7篇 |
1997年 | 8篇 |
1996年 | 9篇 |
1994年 | 4篇 |
1993年 | 8篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 4篇 |
1989年 | 6篇 |
1988年 | 7篇 |
1987年 | 8篇 |
1986年 | 4篇 |
1985年 | 5篇 |
1984年 | 10篇 |
1983年 | 7篇 |
1982年 | 6篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1978年 | 5篇 |
1976年 | 5篇 |
1975年 | 5篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1971年 | 7篇 |
1969年 | 4篇 |
1966年 | 4篇 |
排序方式: 共有735条查询结果,搜索用时 250 毫秒
81.
Lin L Park M Hulver M York DA 《American journal of physiology. Regulatory, integrative and comparative physiology》2006,290(4):R909-R915
Enterostatin, a pentapeptide cleaved from procolipase, suppresses fat intake after peripheral and central administration. Chronic treatment of rats with enterostatin decreases body weight and body fat. The effect was greater than could be accounted by the reduction in food intake alone. Hence, we have investigated the effect of enterostatin on energy metabolism. Male Sprague-Dawley rats adapted to a high-fat diet were implanted with lateral cerebral ventricular or amygdala cannulas. The metabolic effects were determined by indirect calorimetry. After habituation to the test cages, fasted rats were injected with either saline vehicle or enterostatin given either intraperitoneally (100 nmol) or intracerebroventricularly (1 nmol) or into specific brain regions [amygdala (0.01 nmol) or paraventricular nucleus (PVN) (0.1 nmol)]. Respiratory quotient (RQ) and energy expenditure were monitored over 2 h. Intraperitoneal enterostatin reduced RQ (saline: 0.81 +/- 0.02 vs. enterostatin: 0.76 +/- 0.01) and increased energy expenditure by 44%. Intracerebroventricular enterostatin increased the energy expenditure without any effects on RQ, whereas PVN enterostatin increased metabolic rate, while preventing the increase in RQ observed in the control animals. In contrast, neither RQ nor energy expenditure was altered after enterostatin was injected into the amygdala. Enterostatin activated AMP-activated protein kinase in primary cultures of human myocytes in a dose- and time-dependent manner and increased the rate of fatty acid beta-oxidation. These findings suggest that enterostatin regulates energy expenditure and substrate partitioning through both peripheral and central effects. 相似文献
82.
A deletion at the mouse Xist gene exposes trans-effects that alter the heterochromatin of the inactive X chromosome and the replication time and DNA stability of both X chromosomes 下载免费PDF全文
Diaz-Perez SV Ferguson DO Wang C Csankovszki G Wang C Tsai SC Dutta D Perez V Kim S Eller CD Salstrom J Ouyang Y Teitell MA Kaltenboeck B Chess A Huang S Marahrens Y 《Genetics》2006,174(3):1115-1133
The inactive X chromosome of female mammals displays several properties of heterochromatin including late replication, histone H4 hypoacetylation, histone H3 hypomethylation at lysine-4, and methylated CpG islands. We show that cre-Lox-mediated excision of 21 kb from both Xist alleles in female mouse fibroblasts led to the appearance of two histone modifications throughout the inactive X chromosome usually associated with euchromatin: histone H4 acetylation and histone H3 lysine-4 methylation. Despite these euchromatic properties, the inactive X chromosome was replicated even later in S phase than in wild-type female cells. Homozygosity for the deletion also caused regions of the active X chromosome that are associated with very high concentrations of LINE-1 elements to be replicated very late in S phase. Extreme late replication is a property of fragile sites and the 21-kb deletions destabilized the DNA of both X chromosomes, leading to deletions and translocations. This was accompanied by the phosphorylation of p53 at serine-15, an event that occurs in response to DNA damage, and the accumulation of gamma-H2AX, a histone involved in DNA repair, on the X chromosome. The Xist locus therefore maintains the DNA stability of both X chromosomes. 相似文献
83.
We investigated how epiphytic species and subfamilies of Bromeliaceae change along the extent of the Atlantic Rain Forest, to answer the questions: (i) How do the epiphytic genera and subfamilies of Bromeliaceae change along the domain? (ii) How similar are the different regions of the Atlantic Rain Forest in relation to the epiphytic species of bromeliads? (iii) Which environmental variables are the most important factors in determining species composition along the domain? We found 114 species of Bromelioideae and 73 of Tillandsioideae. The predominance of Bromelioideae was unexpected, because they are not wind-dispersed as would be expected for most epiphytes. The smaller number of species of Tillandsioideae, and the high frequency of species of Vriesea with limited geographic distributions indicated that epiphytes with rather limited geographic distributions predominate in this domain. Species similarity was divided into one block of south–southeastern localities, and a second block of northeastern–southeastern localities. These results suggest that the distribution of epiphytic bromeliad species resembles that of the phorophyte trees, more than a previous pattern suggested for all epiphytes in the domain. Latitude, temperature and altitude were important factors affecting the species composition along the domain. In general, our results differ from those of other studies in Latin America, and we suggest that historical and evolutionary events generated these differences. 相似文献
84.
L1 ligase (L1L) molecular switch is an in vitro optimized synthetic allosteric ribozyme that catalyzes the regioselective formation of a 5′-to-3′ phosphodiester bond, a reaction for which there is no known naturally occurring RNA catalyst. L1L serves as a proof of principle that RNA can catalyze a critical reaction for prebiotic RNA self-replication according to the RNA world hypothesis. L1L crystal structure captures two distinct conformations that differ by a reorientation of one of the stems by around 80 Å and are presumed to correspond to the active and inactive state, respectively. It is of great interest to understand the nature of these two states in solution and the pathway for their interconversion. In this study, we use explicit solvent molecular simulation together with a novel enhanced sampling method that utilizes concepts from network theory to map out the conformational transition between active and inactive states of L1L. We find that the overall switching mechanism can be described as a three‐state/two‐step process. The first step involves a large-amplitude swing that reorients stem C. The second step involves the allosteric activation of the catalytic site through distant contacts with stem C. Using a conformational space network representation of the L1L switch transition, it is shown that the connection between the three states follows different topographical patterns: the stem C swing step passes through a narrow region of the conformational space network, whereas the allosteric activation step covers a much wider region and a more diverse set of pathways through the network. 相似文献
85.
Kulkarni AR Peña MJ Avci U Mazumder K Urbanowicz BR Pattathil S Yin Y O'Neill MA Roberts AW Hahn MG Xu Y Darvill AG York WS 《Glycobiology》2012,22(3):439-451
Glucuronoxylans with a backbone of 1,4-linked β-D-xylosyl residues are ubiquitous in the secondary walls of gymnosperms and angiosperms. Xylans have been reported to be present in hornwort cell walls, but their structures have not been determined. In contrast, the presence of xylans in the cell walls of mosses and liverworts remains a subject of debate. Here we present data that unequivocally establishes that the cell walls of leafy tissue and axillary hair cells of the moss Physcomitrella patens contain a glucuronoxylan that is structurally similar to glucuronoxylans in the secondary cell walls of vascular plants. Some of the 1,4-linked β-D-xylopyranosyl residues in the backbone of this glucuronoxylan bear an α-D-glucosyluronic acid (GlcpA) sidechain at O-2. In contrast, the lycopodiophyte Selaginella kraussiana synthesizes a glucuronoxylan substituted with 4-O-Me-α-D-GlcpA sidechains, as do many hardwood species. The monilophyte Equisetum hyemale produces a glucuronoxylan with both 4-O-Me-α-D-GlcpA and α-D-GlcpA sidechains, as does Arabidopsis. The seedless plant glucuronoxylans contain no discernible amounts of the reducing-end sequence that is characteristic of gymnosperm and eudicot xylans. Phylogenetic studies showed that the P. patens genome contains genes with high sequence similarity to Arabidopsis CAZy family GT8, GT43 and GT47 glycosyltransferases that are likely involved in xylan synthesis. We conclude that mosses synthesize glucuronoxylan that is structurally similar to the glucuronoxylans present in the secondary cell walls of lycopodiophytes, monilophytes, and many seed-bearing plants, and that several of the glycosyltransferases required for glucuronoxylan synthesis evolved before the evolution of tracheophytes. 相似文献
86.
Ferreira SM Domingos GP Ferreira Ddos S Rocha TG Serakides R de Faria Rezende CM Cardoso VN Fernandes SO Oliveira MC 《Bioorganic & medicinal chemistry letters》2012,22(14):4605-4608
Osteomyelitis is an infectious disease located in the bone or bone marrow. Long-circulating and pH-sensitive liposomes containing a technetium-99m-labeled antibiotic, ceftizoxime, (SpHL-(99m)Tc-CF) were developed to identify osteomyelitis foci. Biodistribution studies and scintigraphic images of bone infection or non infection-bearing rats that had been treated with these liposomes were performed. A high accumulation in infectious foci and high values in the target-non target ratio could be observed. These results indicate the potential of SpHL-(99m)Tc-CF as a potential agent for the diagnosis of bone infections. 相似文献
87.
88.
Buket Aksu Anant Paradkar Marcel de Matas ?zgen ?zer Tamer Güneri Peter York 《AAPS PharmSciTech》2012,13(4):1138-1146
The publication of the International Conference of Harmonization (ICH) Q8, Q9, and Q10 guidelines paved the way for the standardization of quality after the Food and Drug Administration issued current Good Manufacturing Practices guidelines in 2003. “Quality by Design”, mentioned in the ICH Q8 guideline, offers a better scientific understanding of critical process and product qualities using knowledge obtained during the life cycle of a product. In this scope, the “knowledge space” is a summary of all process knowledge obtained during product development, and the “design space” is the area in which a product can be manufactured within acceptable limits. To create the spaces, artificial neural networks (ANNs) can be used to emphasize the multidimensional interactions of input variables and to closely bind these variables to a design space. This helps guide the experimental design process to include interactions among the input variables, along with modeling and optimization of pharmaceutical formulations. The objective of this study was to develop an integrated multivariate approach to obtain a quality product based on an understanding of the cause–effect relationships between formulation ingredients and product properties with ANNs and genetic programming on the ramipril tablets prepared by the direct compression method. In this study, the data are generated through the systematic application of the design of experiments (DoE) principles and optimization studies using artificial neural networks and neurofuzzy logic programs.KEY WORDS: artificial neural networks (ANNs), gene expression programming (GEP), optimization, quality by design (QbD) 相似文献
89.
Flight is one of the energetically most costly activities in the animal kingdom, suggesting that natural selection should work to optimize flight performance. The similar size and flight speed of birds and bats may therefore suggest convergent aerodynamic performance; alternatively, flight performance could be restricted by phylogenetic constraints. We test which of these scenarios fit to two measures of aerodynamic flight efficiency in two passerine bird species and two New World leaf-nosed bat species. Using time-resolved particle image velocimetry measurements of the wake of the animals flying in a wind tunnel, we derived the span efficiency, a metric for the efficiency of generating lift, and the lift-to-drag ratio, a metric for mechanical energetic flight efficiency. We show that the birds significantly outperform the bats in both metrics, which we ascribe to variation in aerodynamic function of body and wing upstroke: Bird bodies generated relatively more lift than bat bodies, resulting in a more uniform spanwise lift distribution and higher span efficiency. A likely explanation would be that the bat ears and nose leaf, associated with echolocation, disturb the flow over the body. During the upstroke, the birds retract their wings to make them aerodynamically inactive, while the membranous bat wings generate thrust and negative lift. Despite the differences in performance, the wake morphology of both birds and bats resemble the optimal wake for their respective lift-to-drag ratio regimes. This suggests that evolution has optimized performance relative to the respective conditions of birds and bats, but that maximum performance is possibly limited by phylogenetic constraints. Although ecological differences between birds and bats are subjected to many conspiring variables, the different aerodynamic flight efficiency for the bird and bat species studied here may help explain why birds typically fly faster, migrate more frequently and migrate longer distances than bats. 相似文献
90.
Ravi Tandon Maria T. M. Giret Devi SenGupta Vanessa A. York Andrew A. Wiznia Michael G. Rosenberg Esper G. Kallas Lishomwa C. Ndhlovu Douglas F. Nixon 《PloS one》2012,7(9)
As perinatally HIV-1-infected children grow into adolescents and young adults, they are increasingly burdened with the long-term consequences of chronic HIV-1 infection, with long-term morbidity due to inadequate immunity. In progressive HIV-1 infection in horizontally infected adults, inflammation, T cell activation, and perturbed T cell differentiation lead to an “immune exhaustion”, with decline in T cell effector functions. T effector cells develop an increased expression of CD57 and loss of CD28, with an increase in co-inhibitory receptors such as PD-1 and Tim-3. Very little is known about HIV-1 induced T cell dysfunction in vertical infection. In two perinatally antiretroviral drug treated HIV-1-infected groups with median ages of 11.2 yr and 18.5 yr, matched for viral load, we found no difference in the proportion of senescent CD28−CD57+CD8+ T cells between the groups. However, the frequency of Tim-3+CD8+ and Tim-3+CD4+ exhausted T cells, but not PD-1+ T cells, was significantly increased in the adolescents with longer duration of infection compared to the children with shorter duration of HIV-1 infection. PD-1+CD8+ T cells were directly associated with T cell immune activation in children. The frequency of Tim-3+CD8+ T cells positively correlated with HIV-1 plasma viral load in the adolescents but not in the children. These data suggest that Tim-3 upregulation was driven by both HIV-1 viral replication and increased age, whereas PD-1 expression is associated with immune activation. These findings also suggest that the Tim-3 immune exhaustion phenotype rather than PD-1 or senescent cells plays an important role in age-related T cell dysfunction in perinatal HIV-1 infection. Targeting Tim-3 may serve as a novel therapeutic approach to improve immune control of virus replication and mitigate age related T cell exhaustion. 相似文献