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11.
Lafontaine JA Day RF Dibrino J Hadcock JR Hargrove DM Linhares M Martin KA Maurer TS Nardone NA Tess DA Dasilva-Jardine P 《Bioorganic & medicinal chemistry letters》2007,17(18):5245-5250
A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human beta(3)-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the beta(3)-AR, functional selectivity against beta(1)- and beta(2)-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an ED(20%) of 2mg/kg. 相似文献
12.
Tess Shideler Daniel P. Nickerson Alexey J. Merz Greg Odorizzi 《Molecular biology of the cell》2015,26(7):1345-1356
Vps9 and Muk1 are guanine nucleotide exchange factors (GEFs) in Saccharomyces cerevisiae that regulate membrane trafficking in the endolysosomal pathway by activating Rab5 GTPases. We show that Vps9 is the primary Rab5 GEF required for biogenesis of late endosomal multivesicular bodies (MVBs). However, only Vps9 (but not Muk1) is required for the formation of aberrant class E compartments that arise upon dysfunction of endosomal sorting complexes required for transport (ESCRTs). ESCRT dysfunction causes ubiquitinated transmembrane proteins to accumulate at endosomes, and we demonstrate that endosomal recruitment of Vps9 is promoted by its ubiquitin-binding CUE domain. Muk1 lacks ubiquitin-binding motifs, but its fusion to the Vps9 CUE domain allows Muk1 to rescue endosome morphology, cargo trafficking, and cellular stress-tolerance phenotypes that result from loss of Vps9 function. These results indicate that ubiquitin binding by the CUE domain promotes Vps9 function in endolysosomal membrane trafficking via promotion of localization. 相似文献
13.
Robinson RP Bartlett JA Bertinato P Bessire AJ Cosgrove J Foley PM Manion TB Minich ML Ramos B Reese MR Schmahai TJ Swick AG Tess DA Vaz A Wolford A 《Bioorganic & medicinal chemistry letters》2011,21(14):4150-4154
Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4′-alkyl and 4′-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies. 相似文献
14.
Sucrose and light effects on in vitro cultures of potato,chokecherry and saskatoon berry during low temperature storage 总被引:1,自引:0,他引:1
Pruski Kris Kozai Toyoki Lewis Tina Astatkie Tess Nowak Jerzy 《Plant Cell, Tissue and Organ Culture》2000,63(3):215-221
Cultures of potato (Solanum tuberosum) cv. Atlantic, chokecherry (Prunus virginiana L.) cv. Garrington and saskatoon berry (Amelancher alnifolia Nutt.) cv. Northline grown in vitro for 3 weeks at 24/22 °C, 16-h photoperiod, 150 μmol m−2 s−1 photosynthetic photon flux density (PPFD) mixed fluorescent/incandescent light were stored for 6, 9 and 12 weeks at 4 °C
under 0 (darkness) and 3 μmol m−2 s−1 PPFD (690 nm red light continuous illumination). Growth regulators free MSMO medium either with or without 30 g l−1 sucrose was used to store the cultures. All cultures retained capacity to re-grow after storage. Tested factors, sucrose,
light and the length of the storage period had an impact on shoot quality and re-growth capacity of the cultures. For either
light treatment sucrose was essential for the low temperature maintenance of vigorous stock plants of potato, if stored for
over 6 weeks. Chokecherry and saskatoon cultures stored well without sucrose; although chokecherry benefited from sucrose
in the storage medium when the stock cultures were kept at the low temperature for 12 weeks. Low light significantly improved
quality of the stored potato cultures, but had very little effect on both chokecherry and saskatoon berry cultures. The woody
plant cultures grew during storage, and the longer the stock plants were stored, the more vigorous cultures they generated.
The results indicate that growers can successfully use their existing facilities, small refrigerators and coolers with low
light intensity, set at 4 °C, for short term storage of potato, chokecherry and saskatoon berry cultures. The potato cultures,
which are known to be sensitive to prolonged low temperature storage, should be frequently monitored and subcultured as required.
On the other hand, the woody plant stock cultures do not require any special attention when kept at 4 °C and re-grow the most
vigorous shoots if stored for at least 12 weeks.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
15.
Moran FM Hendrickx AG Shideler S Overstreet JW Watkins SM Lasley BL 《Birth defects research. Part B, Developmental and reproductive toxicology》2004,71(1):37-46
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to alter carbohydrate utilization and specific steps in lipid metabolism. TCDD interacts with estradiol in mobilizing specific fatty acids in chickens that may be a cause of cranial/beak malformations in this species. This study was designed to test the hypothesis that TCDD simultaneously alters critical fatty acid mobilization during early pregnancy and determine if those changes correlate to morphological defects of the developing neural tube in the nonhuman primate. Cynomolgus macaques were treated with a single dose of 4 microg/kg body weight (BW) TCDD on gestational day 15 or 20. Pregnancies were terminated by hysterectomy on gestational day 24-26 and embryos were examined to determine morphology of the developing neural tube. Maternal blood samples were used for fatty acid quantification. Embryos exhibited cellular changes, mainly increased cell death, and intercellular spaces in the neural tube, suggestive of an adverse effect on the developing nervous system. Significant decreases on fatty acid composition were found on some of the eight classes of lipids analyzed. Particularly, a decrease was observed in the n-3 (40-60%) and n-6 (47-75%) essential fatty acids in treated pregnancies compared to untreated controls. These data demonstrate the effect of TCDD in decreasing maternal levels of n-3 and n-6 fatty acids that are considered necessary for normal development in mammals. Since neural tube development is dependent, in part, on n-3 and n-6 fatty acids, it is possible that the limitation of these essential fatty acids in plasma resulted in the observed detrimental effects on early brain development. 相似文献
16.
Notch EG Chapline C Flynn E Lameyer T Lowell A Sato D Shaw JR Stanton BA 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2012,162(4):443-448
The Atlantic killifish (Fundulus heteroclitus) is an environmental sentinel organism used extensively for studies of environmental toxicants and osmoregulation. Previous research in our laboratory has shown that acute acclimation to seawater is mediated by an increase in SGK1. SGK1 promotes the trafficking of CFTR chloride channels from intracellular vesicles to the plasma membrane of the gill within the first hour in seawater resulting in increased chloride secretion. Although we have shown that the increase in gill SGK1 does not require activation of the glucocorticoid receptor, the mechanisms that mediate the rise SGK1 during acute acclimation is unknown. To test the hypothesis that mitogen activated protein kinase (MAPK14) is responsible for the rise in SGK1 we identified the coding sequence of killifish MAPK14-1 and designed a translational blocking vivo-morpholino targeting MAPK14-1. Injection of the MAPK14-1 vivo-morpholino resulted in a 30% reduction of MAPK14-1 and a 45% reduction in phosphorylated-MAPK14-1 protein in the gill of killifish transitioned from freshwater to seawater. Knock down of phosphorlyated-MAPK14-1 completely blocked the rise in SGK1 mRNA and protein in the killifish gill, providing the first direct and in vivo evidence that MAPK14-1 is necessary for acute seawater acclimation. 相似文献
17.
18.
Although estradiol-17 beta (E2) induces premature regression of the corpus luteum (CL), its role in spontaneous luteolysis which occurs at the end of the nonfertile cycle has not been demonstrated. We compared the effects of an estrogen antagonist on E2-induced and spontaneous luteolysis by administering clomiphene (10 mg/day) to cynomolgus macaques during the luteal phase in the presence and absence of exogenous E2 (supplied by subcutaneous Silastic implants). Other animals received either vehicle or E2 implants. Luteal function was assessed by progesterone concentrations and luteal phase length. Clomiphene maintained normal luteal function in the presence of luteolytic levels of E2 in five of six monkeys. However, clomiphene alone did not prolong luteal function beyond that observed in monkeys receiving vehicle. To assess the direct effect of clomiphene on the CL, we incubated monkey luteal cells with human chorionic gonadotropin and clomiphene, E2, or clomiphene plus E2. Clomiphene (1500 ng/ml) alone and E2 (1000 ng/ml) alone significantly (P less than 0.05) inhibited progestin production. Clomiphene and E2 together depressed progestin production to an even greater extent. The data suggest that the mechanisms involved in E2-induced and spontaneous luteolysis differ. 相似文献
19.
P F Daels S Shideler B L Lasley J P Hughes G H Stabenfeldt 《Journal of reproduction and fertility》1990,90(1):55-61
Oestrogen secretion was determined by oestrogen conjugate (EC) analysis of urine in three groups of pregnant mares: Group I (N = 6), animals ovariectomized on Day 18-19 of gestation with pregnancy maintained by daily administration of an oral progestagen, altrenogest; Group II (N = 9), untreated, pregnant mares; Group III (N = 5) intact, pregnant mares treated daily with altrenogest. The mean EC concentrations in the ovariectomized mares in Group I increased in a constant linear manner from 17 ng/mg Cr on Day 20 to 291 ng/mg Cr on Day 70, with no apparent surge in oestrogen secretion around Day 39. Mean EC concentrations on Days 33, 39 and 44 were respectively 41, 48, and 73 ng/mg Cr. In the intact mares in Groups II and III (shown in parentheses), the mean urinary EC concentrations were 201 (171) ng/mg Cr between Days 20 and 33 of gestation, increased rapidly from 172 (77) ng/mg Cr on Day 33 to a peak of 1066 (895) ng/mg Cr on Day 39, followed by a decline to 637 (719) ng/mg Cr on Day 44. After Day 44, EC concentrations continued to increase in a linear manner to 1191 (842) ng/mg Cr on Day 70. The mean EC concentrations between Days 20 and 70 in Group I were significantly (P less than 0.05) lower than in mares in Groups II and III. EC concentrations in Group III mares were significantly lower (P less than 0.05) than in Group II mares between Days 28 and 34.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
20.
Erdinc Sezgin Fatma Betul Can Falk Schneider Mathias P. Clausen Silvia Galiani Tess A. Stanly Dominic Waithe Alexandria Colaco Alf Honigmann Daniel Wüstner Frances Platt Christian Eggeling 《Journal of lipid research》2016,57(2):299-309
Cholesterol (Chol) is a crucial component of cellular membranes, but knowledge of its intracellular dynamics is scarce. Thus, it is of utmost interest to develop tools for visualization of Chol organization and dynamics in cells and tissues. For this purpose, many studies make use of fluorescently labeled Chol analogs. Unfortunately, the introduction of the label may influence the characteristics of the analog, such as its localization, interaction, and trafficking in cells; hence, it is important to get knowledge of such bias. In this report, we compared different fluorescent lipid analogs for their performance in cellular assays: 1) plasma membrane incorporation, specifically the preference for more ordered membrane environments in phase-separated giant unilamellar vesicles and giant plasma membrane vesicles; 2) cellular trafficking, specifically subcellular localization in Niemann-Pick type C disease cells; and 3) applicability in fluorescence correlation spectroscopy (FCS)-based and super-resolution stimulated emission depletion-FCS-based measurements of membrane diffusion dynamics. The analogs exhibited strong differences, with some indicating positive performance in the membrane-based experiments and others in the intracellular trafficking assay. However, none showed positive performance in all assays. Our results constitute a concise guide for the careful use of fluorescent Chol analogs in visualizing cellular Chol dynamics. 相似文献