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81.
PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect 总被引:11,自引:0,他引:11
Tunaru S Kero J Schaub A Wufka C Blaukat A Pfeffer K Offermanns S 《Nature medicine》2003,9(3):352-355
Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia. 相似文献
82.
Evrard DA Zhou P Yi SY Zhou D Smith DL Sullivan KM Hornby GA Schechter LE Andree TH Mewshaw RE 《Bioorganic & medicinal chemistry letters》2005,15(4):911-914
Derivatives of the serotonin reuptake inhibitor 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine, in which serotonin 1A (5-HT(1A)) receptor pharmacophoric elements are incorporated, are reported. Analogs exhibiting affinity for both the serotonin transporter and the 5-HT(1A) receptor are described. Compounds containing 1-(4-indolyl)piperazine and 2-(1H-indol-4-yloxy)ethylamine are promising leads for further SAR studies. 相似文献
83.
Initial characteristics of koi herpesvirus and development of a polymerase chain reaction assay to detect the virus in koi,Cyprinus carpio koi 总被引:4,自引:0,他引:4
Gilad O Yun S Andree KB Adkison MA Zlotkin A Bercovier H Eldar A Hedrick RP 《Diseases of aquatic organisms》2002,48(2):101-108
Since 1998, episodes of mass mortality have occurred in populations of common carp Cyprinus carpio carpio in Israel and in populations of koi Cyprinus carpio koi in Israel and the USA. A herpesvirus isolated from infected fish has been shown in experimental studies to induce disease and mortality similar to those observed in outbreaks at infected farms. Initial characteristics of the virus show that it is clearly different from Herpesvirus cyprini (CHV), the most commonly known herpesvirus from cyprinid fish. The koi herpesvirus (KHV) has 31 virion polypeptides. Twelve of the virion polypeptides of KHV have similar molecular weights to those of CHV and 10 are similar to those of channel catfish virus (CCV). Both virion polypeptide and restriction fragment length polymorphism analyses of genomic DNA showed that the first KHV isolates from Israel and the USA were identical. In contrast, the genomic DNA restriction fragments clearly distinguish KHV from CHV and CCV. A polymerase chain reaction (PCR) assay to detect the virus in koi tissues was developed with sequences obtained from 1 restriction fragment of KHV DNA. The PCR assay effectively detected a 484 base pair sequence from KHV but did not amplify genomic DNA from either CHV or CCV. The PCR assay detected as little as 1 pg of KHV DNA mixed with 100 ng of host DNA. Viral sequences were amplified from koi obtained from field collections and from koi that were experimentally exposed to 10(2) TCID50 ml(-1) of KHV via the waterborne route. All KHV exposed fish dying of infection between 8 and 10 d post exposure or surviving to 14 d post exposure were found to be positive by PCR, while unexposed control koi were all negative. The assay also showed the presence of KHV DNA in tissues of koi obtained from farms in Israel. The PCR assay should assist virus isolation procedures and histologic and electron microscopic analyses now commonly used to detect KHV infection. Current studies are examining the possibility of using the PCR to detect KHV DNA in live fish and the relative sensitivity and specificity of the KHV PCR assay compared with other diagnostic tests. 相似文献
84.
Grindle S Garganta C Sheehan S Gile J Lapierre A Whitmore H Paigen B DiPetrillo K 《Comparative medicine》2006,56(6):482-486
Chronic kidney disease is a substantial medical and economic burden. Animal models, including mice, are a crucial component of kidney disease research; however, recent studies disprove the ability of autoanalyzer methods to accurately quantify plasma creatinine levels, an established marker of kidney disease, in mice. Therefore, we validated autoanalyzer methods for measuring blood urea nitrogen (BUN) and urinary albumin concentrations, 2 common markers of kidney disease, in samples from mice. We used high-performance liquid chromatography to validate BUN concentrations measured using an autoanalyzer, and we utilized mouse albumin standards to determine the accuracy of the autoanalyzer over a wide range of albumin concentrations. We observed a significant, linear correlation between BUN concentrations measured by autoanalyzer and high-performance liquid chromatography. We also found a linear relationship between known and measured albumin concentrations, although the autoanalyzer method underestimated the known amount of albumin by 3.5- to 4-fold. We confirmed that plasma and urine constituents do not interfere with the autoanalyzer methods for measuring BUN and urinary albumin concentrations. In addition, we verified BUN and albuminuria as useful markers to detect kidney disease in aged mice and mice with 5/6-nephrectomy. We conclude that autoanalyzer methods are suitable for high-throughput analysis of BUN and albumin concentrations in mice. The autoanalyzer accurately quantifies BUN concentrations in mouse plasma samples and is useful for measuring urinary albumin concentrations when used with mouse albumin standards. 相似文献
85.
Hedrick RP McDowell TS Marty GD Mukkatira K Antonio DB Andree KB Bukhari Z Clancy T 《Diseases of aquatic organisms》2000,42(1):53-59
The effects of ultraviolet (UV) irradiation on the viability of the waterborne triactinomyxon stages of Myxobolus cerebralis were evaluated by vital staining and the infectivity for juvenile rainbow trout Oncorhynchus mykiss. A dose of 1300 mWs cm-2 was required to inactivate 100% of the triactinomyxons held under a static collimated beam of UV as determined by vital staining. Juvenile rainbow trout were protected from infections with M. cerebralis when exposed to 14,000 or 1400 triactinomyxon spores per fish that had been treated with the collimating beam apparatus (1300 mWs cm-2). Among all fish receiving UV-treated triactinomyxons, none had clinical signs of whirling disease, or evidence of microscopic lesions or spores of M. cerebralis after 5 mo at water temperatures of 15 degrees C. In contrast, 100% of the fish receiving the higher dose of untreated triactinomyxons developed clinical signs of whirling disease and both microscopic signs of infection and spores were detected in all of the high and low dose trout receiving untreated triactinomyxon exposures. Two additional trials evaluated the Cryptosporidium Inactivation Device (CID) for its ability to treat flow-through 15 degrees C well water to which triactinomyxons were added over a 2 wk period. CID treatments of a cumulative dose exceeding 64,000 triactinomyxons per fish protected juvenile rainbow from infections with M. cerebralis. Rainbow trout controls receiving the same number of untreated triactinomyxons developed both microscopic lesions and cranial spore concentrations up to 10(4.6) per 1/2 head, although no signs of clinical whirling disease were observed. UV (126 mWs cm-2, collimated beam apparatus) was also effective in killing Flavobacterium psychrophilum, the agent causing salmonid bacterial coldwater disease, as demonstrated by the inability of bacterial cells to grow on artificial media following UV treatment. 相似文献
86.
Phosphorylation by casein kinase 2 induces PACS-1 binding of nephrocystin and targeting to cilia 下载免费PDF全文
Schermer B Höpker K Omran H Ghenoiu C Fliegauf M Fekete A Horvath J Köttgen M Hackl M Zschiedrich S Huber TB Kramer-Zucker A Zentgraf H Blaukat A Walz G Benzing T 《The EMBO journal》2005,24(24):4415-4424
Mutations in proteins localized to cilia and basal bodies have been implicated in a growing number of human diseases. Access of these proteins to the ciliary compartment requires targeting to the base of the cilia. However, the mechanisms involved in transport of cilia proteins to this transitional zone are elusive. Here we show that nephrocystin, a ciliary protein mutated in the most prevalent form of cystic kidney disease in childhood, is expressed in respiratory epithelial cells and accumulates at the base of cilia, overlapping with markers of the basal body area and the transition zone. Nephrocystin interacts with the phosphofurin acidic cluster sorting protein (PACS)-1. Casein kinase 2 (CK2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates PACS-1 binding, and is essential for colocalization of nephrocystin with PACS-1 at the base of cilia. Inhibition of CK2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. These data suggest that CK2-dependent transport processes represent a novel pathway of targeting proteins to the cilia. 相似文献
87.
2‐phenylethynesulphonamide (PFT‐μ) enhances the anticancer effect of the novel hsp90 inhibitor NVP‐AUY922 in melanoma,by reducing GSH levels 下载免费PDF全文
Andree Yeramian Alvar Vea Sandra Benítez Joan Ribera Mónica Domingo Maria Santacana Montserrat Martinez Oscar Maiques Joan Valls Xavier Dolcet Ramón Vilella Elisa Cabiscol Xavier Matias‐Guiu Rosa M. Marti 《Pigment cell & melanoma research》2016,29(3):352-371
Heat shock proteins (HSPs), are molecular chaperones that assist the proper folding of nascent proteins. This study aims to evaluate the antitumour effects of the hsp90 inhibitor NVP‐AUY922 in melanoma, both in vitro and in vivo. Our results show that NVP‐AUY922 inhibits melanoma cell growth in vitro, with down regulation of multiple signalling pathways involved in melanoma progression such as NF‐?B and MAPK/ERK. However, NVP‐AUY922 was unable to limit tumour growth in vivo. Cotreatment of A375M xenografts with NVP‐AUY922 and PFT‐μ, a dual inhibitor of both hsp70 and autophagy, induced a synergistic increase of cell death in vitro, and delayed tumour formation in A375M xenografts. PFT‐μ depleted cells from the reduced form of glutathione (GSH) and increased oxidative stress. The oxidative stress induced by PFT‐μ further enhanced NVP‐AUY922‐induced cytotoxic effects. These data suggest a potential therapeutic role for NVP‐AUY922 used in combination with PFT‐μ, in melanoma. 相似文献
88.
Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with 5-HT transporter and 5-HT1A affinity 总被引:1,自引:0,他引:1
Gilbert AM Coleman T Kodah J Mewshaw RE Scerni R Schechter LE Smith DL Andree TH 《Bioorganic & medicinal chemistry letters》2004,14(21):5281-5284
Joining aryl 8-azabicyclo[3.2.1]oct-3-enes with aryloxyethanes and aryloxypropanes produces novel series of compounds 11 and 12 with potent 5-HT-T affinity and moderately potent 5-HT(1A) affinity. Moreover, several of these compounds possess functional 5-HT(1A) antagonism. Optimal compounds are, 4-indolyloxyethane 21, 4-indolyloxypropanes 25, and 27, which possess potent 5-HT-T affinity (5-HT-T K(i): 21: 1.2nM, 25: 0.54nM, 27: 0.38nM) and good 5-HT(1A) affinity/antagonism (5-HT(1A)K(i), [(35)S]GTPgammaS: E(max) (%): 21: 111.1nM, 0%; 25: 173.2nM, 0%; 27: 107nM, 0%). 相似文献
89.
Mewshaw RE Meagher KL Zhou P Zhou D Shi X Scerni R Smith D Schechter LE Andree TH 《Bioorganic & medicinal chemistry letters》2002,12(3):307-310
The design and synthesis of a novel series of indole derivatives (9) having dual 5-HT transporter reuptake and 5-HT(1A) antagonist activity are described. 相似文献
90.
Sabb AL Vogel RL Kelly MG Palmer Y Smith DL Andree TH Schechter LE 《Bioorganic & medicinal chemistry letters》2001,11(8):1069-1071
Amino acid derivatives of 1,2,5-thiadiazol-3-yl-piperazine related to (+)-WAY-100135 and WAY-100635 are potent 5-HT1A receptor agonists and antagonists, which have selective affinity for 5-HT1A receptors versus alpha1 and dopamine (D2, D3, and D4) receptors. 相似文献