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排序方式: 共有209条查询结果,搜索用时 15 毫秒
91.
J. Mark Brown Jenna L. Betters Caleb Lord Yinyan Ma Xianlin Han Kui Yang Heather M. Alger John Melchior Janet Sawyer Ramesh Shah Martha D. Wilson Xiuli Liu Mark J. Graham Richard Lee Rosanne Crooke Gerald I. Shulman Bingzhong Xue Hang Shi Liqing Yu 《Journal of lipid research》2010,51(11):3306-3315
Mutations of Comparative Gene Identification-58 (CGI-58) in humans cause triglyceride (TG) accumulation in multiple tissues. Mice genetically lacking CGI-58 die shortly after birth due to a skin barrier defect. To study the role of CGI-58 in integrated lipid and energy metabolism, we utilized antisense oligonucleotides (ASOs) to inhibit CGI-58 expression in adult mice. Treatment with two distinct CGI-58-targeting ASOs resulted in ∼80–95% knockdown of CGI-58 protein expression in both liver and white adipose tissue. In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels ∼4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive. Collectively, this work demonstrates that CGI-58 plays a critical role in limiting hepatic steatosis and maintaining hepatic glycerophospholipid homeostasis and has unmasked an unexpected role for CGI-58 in promoting HFD-induced obesity and insulin resistance. 相似文献
92.
Zhang YL Hernandez-Ono A Siri P Weisberg S Conlon D Graham MJ Crooke RM Huang LS Ginsberg HN 《The Journal of biological chemistry》2006,281(49):37603-37615
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11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) converts inactive 11-keto derivatives to active glucocorticoids within tissues and may play a role in the metabolic syndrome (MS). We used an antisense oligonucleotide (ASO) to knock down 11β-HSD1 in livers of C57BL/6J mice consuming a Western-type diet (WTD). 11β-HSD1 ASO-treated mice consumed less food, so we compared them to ad libitum-fed mice and to food-matched mice receiving control ASO. Knockdown of 11β-HSD1 directly protected mice from WTD-induced steatosis and dyslipidemia by reducing synthesis and secretion of triglyceride (TG) and increasing hepatic fatty acid oxidation. These changes in hepatic and plasma lipids were not associated with reductions in genes involved in de novo lipogenesis. However, protein levels of both sterol regulatory element-binding protein (SREBP) 1 and fatty acid synthase were significantly reduced in mice treated with 11β-HSD1 ASO. There was no change in hepatic secretion of apolipoprotein (apo)B, indicating assembly and secretion of smaller apoB-containing lipoproteins by the liver in the 11β-HSD1-treated mice. Our results indicate that inhibition of 11β-HSD1 by ASO treatment of WTD-fed mice resulted in improved plasma and hepatic lipid levels, reduced lipogenesis by posttranslational regulation, and secretion of similar numbers of apoB-containing lipoproteins containing less TG per particle. 相似文献
96.
Willemijn van den Ancker Marvin M. van Luijn Jurjen M. Ruben Theresia M. Westers Hetty J. Bontkes Gert J. Ossenkoppele Tanja D. de Gruijl Arjan A. van de Loosdrecht 《Cancer immunology, immunotherapy : CII》2011,60(1):37-47
Therapeutic vaccination with dendritic cells (DC) is an emerging investigational therapy for eradication of minimal residual
disease in acute myeloid leukemia. Various strategies are being explored in manufacturing DC vaccines ex vivo, e.g., monocyte-derived
DC (MoDC) loaded with leukemia-associated antigens (LAA). However, the optimal source of LAA and the choice of DC-activating
stimuli are still not well defined. Here, loading with leukemic cell preparations (harboring both unknown and known LAA) was
explored in combination with a DC maturation-inducing cytokine cocktail (CC; IL-1β, IL-6, TNF-α, and PGE2) and Toll-like receptor ligands (TLR-L) to optimize uptake. Since heat shock induced apoptotic blasts were more efficiently
taken up than lysates, we focused on uptake of apoptotic leukemic cells. Uptake of apoptotic blast was further enhanced by
the TLR7/8-L R848 (20–30%); in contrast, CC-induced maturation inhibited uptake. CC, and to a lesser extent R848, enhanced
the ability of MoDC to migrate and stimulate T cells. Furthermore, class II-associated invariant chain peptide expression
was down-modulated after R848- or CC-induced maturation, indicating enhanced processing and presentation of antigenic peptides.
To improve both uptake and maturation, leukemic cells and MoDC were co-incubated with R848 for 24 h followed by addition of
CC. However, this approach interfered with CC-mediated MoDC maturation as indicated by diminished migratory and T cell stimulatory
capacity, and the absence of IL-12 production. Taken together, our data demonstrate that even though R848 improved uptake
of apoptotic leukemic cells, the sequential use of R848 and CC is counter-indicated due to its adverse effects on MoDC maturation. 相似文献
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Sandhya Vasan Sarah J. Schlesinger Zhiwei Chen Arlene Hurley Angela Lombardo Soe Than Phumla Adesanya Catherine Bunce Mark Boaz Rosanne Boyle Eddy Sayeed Lorna Clark Daniel Dugin Mar Boente-Carrera Claudia Schmidt Qing Fang Lei Yaoxing Huang Gerasimos J. Zaharatos David F. Gardiner Marina Caskey Laura Seamons Martin Ho Len Dally Carol Smith Josephine Cox Dilbinder Gill Jill Gilmour Michael C. Keefer Patricia Fast David D. Ho 《PloS one》2010,5(1)
Background
We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B''/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers.Methodology/Principal Findings
ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1×107 (low), 5×107 (mid), or 2.5×108 pfu (high)] volunteers were randomized in a 3∶1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNγ ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA.ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNγ ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.Conclusions/Significance
ADMVA was well-tolerated and elicited durable humoral and cellular immune responses.Trial Registration
Clinicaltrials.gov NCT00252148相似文献99.
Linked gene networks involved in nitrogen and carbon metabolism and levels of water-soluble carbohydrate accumulation in wheat stems 总被引:1,自引:0,他引:1
McIntyre CL Casu RE Rattey A Dreccer MF Kam JW van Herwaarden AF Shorter R Xue GP 《Functional & integrative genomics》2011,11(4):585-597
High levels of water-soluble carbohydrates (WSC) provide an important source of stored assimilate for grain filling in wheat.
To better understand the interaction between carbohydrate metabolism and other metabolic processes associated with the WSC
trait, a genome-wide expression analysis was performed using eight field-grown lines from the high and low phenotypic tails
of a wheat population segregating for WSC and the Affymetrix wheat genome array. The 259 differentially expressed probe sets
could be assigned to 26 functional category bins, as defined using MapMan software. There were major differences in the categories
to which the differentially expressed probe sets were assigned; for example, probe sets upregulated in high relative to low
WSC lines were assigned to category bins such as amino acid metabolism, protein degradation and transport and to be involved
in starch synthesis-related processes (carbohydrate metabolism bin), whereas downregulated probe sets were assigned to cell
wall-related bins, amino acid synthesis and stress and were involved in sucrose breakdown. Using the set of differentially
expressed genes as input, chemical–protein network analyses demonstrated a linkage between starch and N metabolism via pyridoxal
phosphate. Twelve C and N metabolism-related genes were selected for analysis of their expression response to varying N and
water treatments in the field in the four high and four low WSC progeny lines; the two nitrogen/amino acid metabolism genes
demonstrated a consistent negative association between their level of expression and level of WSC. Our results suggest that
the assimilation of nitrogen into amino acids is an important factor that influences the levels of WSC in the stems of field-grown
wheat. 相似文献
100.
Stephanie M. Marshall Kathryn L. Kelley Matthew A. Davis Martha D. Wilson Allison L. McDaniel Richard G. Lee Rosanne M. Crooke Mark J. Graham Lawrence L. Rudel J. Mark Brown Ryan E. Temel 《PloS one》2014,9(1)
An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE) is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL) support TICE, antisense oligonucleotides (ASO) were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP), which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg) mice, which predominantly excrete cholesterol via TICE, and wild type (WT) littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG) and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE. 相似文献