全文获取类型
收费全文 | 822篇 |
免费 | 114篇 |
出版年
2022年 | 9篇 |
2021年 | 11篇 |
2020年 | 8篇 |
2019年 | 9篇 |
2017年 | 6篇 |
2016年 | 18篇 |
2015年 | 26篇 |
2014年 | 34篇 |
2013年 | 33篇 |
2012年 | 48篇 |
2011年 | 38篇 |
2010年 | 30篇 |
2009年 | 24篇 |
2008年 | 55篇 |
2007年 | 47篇 |
2006年 | 45篇 |
2005年 | 58篇 |
2004年 | 45篇 |
2003年 | 63篇 |
2002年 | 56篇 |
2001年 | 14篇 |
2000年 | 6篇 |
1999年 | 13篇 |
1998年 | 15篇 |
1997年 | 14篇 |
1996年 | 10篇 |
1995年 | 8篇 |
1994年 | 12篇 |
1993年 | 12篇 |
1992年 | 12篇 |
1991年 | 10篇 |
1989年 | 5篇 |
1988年 | 6篇 |
1987年 | 11篇 |
1986年 | 9篇 |
1985年 | 4篇 |
1984年 | 7篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1981年 | 16篇 |
1980年 | 5篇 |
1978年 | 5篇 |
1977年 | 6篇 |
1974年 | 4篇 |
1973年 | 5篇 |
1972年 | 5篇 |
1970年 | 4篇 |
1969年 | 7篇 |
1968年 | 5篇 |
1964年 | 4篇 |
排序方式: 共有936条查询结果,搜索用时 15 毫秒
161.
Epsin is part of a protein complex that performs endocytosis in eukaryotes. Drosophila epsin, Liquid facets (Lqf), was identified because it is essential for patterning the eye and other imaginal disc derivatives [2]. Previous work has provided only indirect evidence that Lqf is required for endocytosis in Drosophila [2, 3]. Epsins are modular and have an N-terminal ENTH (epsin N-terminal homology) domain that binds PIP(2) at the cell membrane and four different classes of protein-protein interaction motifs. The current model for epsin function in higher eukaryotes is that epsin bridges the cell membrane, a transmembrane protein to be internalized, and the core endocytic complex. Here, we show directly that Drosophila epsin (Lqf) is required for endocytosis. Specifically, we find that Lqf is essential for internalization of the Delta (Dl) transmembrane ligand in the developing eye. Using this endocytic defect in lqf mutants, we develop a transgene rescue assay and perform a structure/function analysis of Lqf. We find that when we divide Lqf into two pieces, an ENTH domain and an ENTH-less protein, each part retains significant ability to function in Dl internalization and eye patterning. These results challenge the model for epsin function that requires an intact protein. 相似文献
162.
Beverly Agtuca Elisabeth Rieger Katharina Hilger Lihui Song Christelle A. M. Robert Matthias Erb Abhijit Karve Richard A. Ferrieri 《Journal of Plant Growth Regulation》2014,33(2):328-339
Auxin (IAA) is an important regulator of plant development and root differentiation. Although recent studies indicate that salicylic acid (SA) may also be important in this context by interfering with IAA signaling, comparatively little is known about its impact on the plant’s physiology, metabolism, and growth characteristics. Using carbon-11, a short-lived radioisotope (t 1/2 = 20.4 min) administered as 11CO2 to maize plants (B73), we measured changes in these functions using SA and IAA treatments. IAA application decreased total root biomass, though it increased lateral root growth at the expense of primary root elongation. IAA-mediated inhibition of root growth was correlated with decreased 11CO2 fixation, photosystem II (PSII) efficiency, and total leaf carbon export of 11C-photoassimilates and their allocation belowground. Furthermore, IAA application increased leaf starch content. On the other hand, SA application increased total root biomass, 11CO2 fixation, PSII efficiency, and leaf carbon export of 11C-photoassimilates, but it decreased leaf starch content. IAA and SA induction patterns were also examined after root-herbivore attack by Diabrotica virgifera to place possible hormone crosstalk into a realistic environmental context. We found that 4 days after infestation, IAA was induced in the midzone and root tip, whereas SA was induced only in the upper proximal zone of damaged roots. We conclude that antagonistic crosstalk exists between IAA and SA which can affect the development of maize plants, particularly through alteration of the root system’s architecture, and we propose that the integration of both signals may shape the plant’s response to environmental stress. 相似文献
163.
Sarcomas represent a diverse group of malignancies with distinct molecular and pathological features. A better understanding of the alterations associated with specific sarcoma subtypes is critically important to improve sarcoma treatment. Renewed interest in the metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a therapeutic strategy. In this study, we have characterized key bioenergetic properties of human sarcoma cells in order to identify metabolic vulnerabilities between sarcoma subtypes. We have also investigated the effects of compounds that inhibit glycolysis or mitochondrial respiration, either alone or in combination, and examined relationships between bioenergetic parameters and sensitivity to metabolic inhibitors. Using 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glycolysis, oligomycin, an inhibitor of mitochondrial ATP synthase, and metformin, a widely used anti-diabetes drug and inhibitor of complex I of the mitochondrial respiratory chain, we evaluated the effects of metabolic inhibition on sarcoma cell growth and bioenergetic function. Inhibition of glycolysis by 2-DG effectively reduced the viability of alveolar rhabdomyosarcoma cells vs. embryonal rhabdomyosarcoma, osteosarcoma, and normal cells. Interestingly, inhibitors of mitochondrial respiration did not significantly affect viability, but were able to increase sensitivity of sarcomas to inhibition of glycolysis. Additionally, inhibition of glycolysis significantly reduced intracellular ATP levels, and sensitivity to 2-DG-induced growth inhibition was related to respiratory rates and glycolytic dependency. Our findings demonstrate novel relationships between sarcoma bioenergetics and sensitivity to metabolic inhibitors, and suggest that inhibition of metabolic pathways in sarcomas should be further investigated as a potential therapeutic strategy. 相似文献
164.
Melissa J. Morine Jacqueline Pontes Monteiro Carolyn Wise Candee Teitel Lisa Pence Anna Williams Baitang Ning Beverly McCabe-Sellers Catherine Champagne Jerome Turner Beatrice Shelby Margaret Bogle Richard D. Beger Corrado Priami Jim Kaput 《Genes & nutrition》2014,9(4)
The discovery of vitamins and clarification of their role in preventing frank essential nutrient deficiencies occurred in the early 1900s. Much vitamin research has understandably focused on public health and the effects of single nutrients to alleviate acute conditions. The physiological processes for maintaining health, however, are complex systems that depend upon interactions between multiple nutrients, environmental factors, and genetic makeup. To analyze the relationship between these factors and nutritional health, data were obtained from an observational, community-based participatory research program of children and teens (age 6–14) enrolled in a summer day camp in the Delta region of Arkansas. Assessments of erythrocyte S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), plasma homocysteine (Hcy) and 6 organic micronutrients (retinol, 25-hydroxy vitamin D3, pyridoxal, thiamin, riboflavin, and vitamin E), and 1,129 plasma proteins were performed at 3 time points in each of 2 years. Genetic makeup was analyzed with 1 M SNP genotyping arrays, and nutrient status was assessed with 24-h dietary intake questionnaires. A pattern of metabolites (met_PC1) that included the ratio of erythrocyte SAM/SAH, Hcy, and 5 vitamins were identified by principal component analysis. Met_PC1 levels were significantly associated with (1) single-nucleotide polymorphisms, (2) levels of plasma proteins, and (3) multilocus genotypes coding for gastrointestinal and immune functions, as identified in a global network of metabolic/protein–protein interactions. Subsequent mining of data from curated pathway, network, and genome-wide association studies identified genetic and functional relationships that may be explained by gene–nutrient interactions. The systems nutrition strategy described here has thus associated a multivariate metabolite pattern in blood with genes involved in immune and gastrointestinal functions.
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-014-0408-4) contains supplementary material, which is available to authorized users. 相似文献165.
Tomás?Gutiérrez Valentina?Parra Rodrigo?Troncoso Christian?Pennanen Ariel?Contreras-Ferrat César?Vasquez-Trincado Pablo?E?Morales Camila?Lopez-Crisosto Cristian?Sotomayor-Flores Mario?Chiong Beverly?A?Rothermel Sergio?LavanderoEmail author 《Cell communication and signaling : CCS》2014,12(1):68
Background
Cardiac hypertrophy is characterized by alterations in both cardiac bioenergetics and insulin sensitivity. Insulin promotes glucose uptake by cardiomyocytes and its use as a substrate for glycolysis and mitochondrial oxidation in order to maintain the high cardiac energy demands. Insulin stimulates Ca2+ release from the endoplasmic reticulum, however, how this translates to changes in mitochondrial metabolism in either healthy or hypertrophic cardiomyocytes is not fully understood.Results
In the present study we investigated insulin-dependent mitochondrial Ca2+ signaling in normal and norepinephrine or insulin like growth factor-1-induced hypertrophic cardiomyocytes. Using mitochondrion-selective Ca2+-fluorescent probes we showed that insulin increases mitochondrial Ca2+ levels. This signal was inhibited by the pharmacological blockade of either the inositol 1,4,5-triphosphate receptor or the mitochondrial Ca2+ uniporter, as well as by siRNA-dependent mitochondrial Ca2+ uniporter knockdown. Norepinephrine-stimulated cardiomyocytes showed a significant decrease in endoplasmic reticulum-mitochondrial contacts compared to either control or insulin like growth factor-1-stimulated cells. This resulted in a reduction in mitochondrial Ca2+ uptake, Akt activation, glucose uptake and oxygen consumption in response to insulin. Blocking mitochondrial Ca2+ uptake was sufficient to mimic the effect of norepinephrine-induced cardiomyocyte hypertrophy on insulin signaling.Conclusions
Mitochondrial Ca2+ uptake is a key event in insulin signaling and metabolism in cardiomyocytes.166.
167.
Pam Factor-Litvak Beverly Insel Antonia M. Calafat Xinhua Liu Frederica Perera Virginia A. Rauh Robin M. Whyatt 《PloS one》2014,9(12)
Background
Prior research reports inverse associations between maternal prenatal urinary phthalate metabolite concentrations and mental and motor development in preschoolers. No study evaluated whether these associations persist into school age.Methods
In a follow up of 328 inner-city mothers and their children, we measured prenatal urinary metabolites of di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP), di-isobutyl phthalate (DiBP), di-2-ethylhexyl phthalate and diethyl phthalate in late pregnancy. The Wechsler Intelligence Scale for Children, 4th edition was administered at child age 7 years and evaluates four areas of cognitive function associated with overall intelligence quotient (IQ).Results
Child full-scale IQ was inversely associated with prenatal urinary metabolite concentrations of DnBP and DiBP: b = −2.69 (95% confidence interval [CI] = −4.33, −1.05) and b = −2.69 (95% CI = −4.22, −1.16) per log unit increase. Among children of mothers with the highest versus lowest quartile DnBP and DiBP metabolite concentrations, IQ was 6.7 (95% CI = 1.9, 11.4) and 7.6 (95% CI = 3.2, 12.1) points lower, respectively. Associations were unchanged after control for cognition at age 3 years. Significant inverse associations were also seen between maternal prenatal metabolite concentrations of DnBP and DiBP and child processing speed, perceptual reasoning and working memory; DiBP and child verbal comprehension; and BBzP and child perceptual reasoning.Conclusion
Maternal prenatal urinary metabolite concentrations measured in late pregnancy of DnBP and DiBP are associated with deficits in children’s intellectual development at age 7 years. Because phthalate exposures are ubiquitous and concentrations seen here within the range previously observed among general populations, results are of public health significance. 相似文献168.
169.
Suttichai Krisanaprakornkit Janet R Kimball Beverly A Dale 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(1):316-324
Stratified epithelia of the oral cavity are continually exposed to bacterial challenge that is initially resisted by neutrophils and epithelial factors, including antimicrobial peptides of the beta-defensin family. Previous work has shown that multiple signaling pathways are involved in human beta-defensin (hBD)-2 mRNA regulation in human gingival epithelial cells stimulated with a periodontal bacterium, Fusobacterium nucleatum, and other stimulants. The goal of this study was to further characterize these pathways. The role of NF-kappaB in hBD-2 regulation was investigated initially due to its importance in inflammation and infection. Nuclear translocation of p65 and NF-kappaB activation was seen in human gingival epithelial cells stimulated with F. nucleatum cell wall extract, indicating possible involvement of NF-kappaB in hBD-2 regulation. However, hBD-2 induction by F. nucleatum was not blocked by pretreatment with two NF-kappaB inhibitors, pyrrolidine dithiocarbamate and the proteasome inhibitor, MG132. To investigate alternative modes of hBD-2 regulation, we explored involvement of mitogen-activated protein kinase pathways. F. nucleatum activated p38 and c-Jun NH(2)-terminal kinase (JNK) pathways, whereas it had little effect on p44/42. Furthermore, inhibition of p38 and JNK partially blocked hBD-2 mRNA induction by F. nucleatum, and the combination of two inhibitors completely blocked expression. Our results suggest that NF-kappaB is neither essential nor sufficient for hBD-2 induction, and that hBD-2 regulation by F. nucleatum is via p38 and JNK, while phorbol ester induces hBD-2 via the p44/42 extracellular signal-regulated kinase pathway. Studies of hBD-2 regulation provide insight into how its expression may be enhanced to control infection locally within the mucosa and thereby reduce microbial invasion into the underlying tissue. 相似文献
170.
Shelley A. Phelan David R. Beier David C. Higgins Beverly Paigen 《Mammalian genome》2002,13(10):548-553
Previously, we demonstrated that Ath1 is a quantitative trait locus for aortic fatty streak formation, located on Chromosome
(chr) 1, with susceptibility in C57BL/6J mice and resistance in C3H/HeJ and BALB/cJ mice fed an atherogenic diet. In this
study, we find an atherosclerosis susceptibility locus in the same region of Chr 1 by constructing two congenic strains with
the resistance phenotype transferred from different resistant strains, PERA/EiJ or SPRETUS/EiJ. By backcrossing one congenic
strain to C57BL/6J and testing recombinant animals, we reduced the distance of the atherosclerosis susceptibility region to
2.3 cM between D1Mit14 and D1Mit10. Further testing of nine recombinant animals showed that eight of the nine were consistent
with a further narrowing between D1Mit159 and D1Mit398 a distance of 0.66 cM. This region encompasses a number of potential
candidate genes including the thiol-specific antioxidant gene Aop2, also known as peroxiredoxin 5 (Prdx5). AOP2 is capable
of reducing hydroperoxides and lipid peroxides in the cell. To investigate Aop2 as a potential candidate, we mapped Aop2 in
our backcross and localized it to the atherosclerosis susceptibility interval. We determined that Aop2 is highly expressed
in atherosclerosis-related tissues including liver and heart. We also found an inverse correlation between Aop2 mRNA in liver
and atherosclerosis phenotype for strains C57BL/6 and the resistant congenic derived from SPRETUS/EiJ. Since LDL oxidation
has been implicated in the pathogenesis of this disease, and AOP2 possesses antioxidant activity, we suggest the role of Aop2
in atherosclerosis susceptibility needs to be further explored. 相似文献