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231.
Butcher AJ Prihandoko R Kong KC McWilliams P Edwards JM Bottrill A Mistry S Tobin AB 《The Journal of biological chemistry》2011,286(13):11506-11518
G-protein-coupled receptors are hyper-phosphorylated in a process that controls receptor coupling to downstream signaling pathways. The pattern of receptor phosphorylation has been proposed to generate a "bar code" that can be varied in a tissue-specific manner to direct physiologically relevant receptor signaling. If such a mechanism existed, receptors would be expected to be phosphorylated in a cell/tissue-specific manner. Using tryptic phosphopeptide maps, mass spectrometry, and phospho-specific antibodies, it was determined here that the prototypical G(q/11)-coupled M(3)-muscarinic receptor was indeed differentially phosphorylated in various cell and tissue types supporting a role for differential receptor phosphorylation in directing tissue-specific signaling. Furthermore, the phosphorylation profile of the M(3)-muscarinic receptor was also dependent on the stimulus. Full and partial agonists to the M(3)-muscarinic receptor were observed to direct phosphorylation preferentially to specific sites. This hitherto unappreciated property of ligands raises the possibility that one mechanism underlying ligand bias/functional selectivity, a process where ligands direct receptors to preferred signaling pathways, may be centered on the capacity of ligands to promote receptor phosphorylation at specific sites. 相似文献
232.
Rakhee J. Mistry Fbio Klamt David B. Ramsden Richard B. Parsons 《Journal of biochemical and molecular toxicology》2020,34(3)
Nicotinamide N‐methyltransferase (NNMT) plays a central role in cellular metabolism, regulating pathways including epigenetic regulation, cell signalling, and energy production. Our previous studies have shown that the expression of NNMT in the human neuroblastoma cell line SH‐SY5Y increased complex I activity and subsequent ATP synthesis. This increase in ATP synthesis was lower than the increase in complex I activity, suggesting uncoupling of the mitochondrial respiratory chain. We, therefore, hypothesised that pathways that reduce oxidative stress are also increased in NNMT‐expressing SH‐Y5Y cells. The expression of uncoupling protein‐2 messenger RNA and protein were significantly increased in NNMT‐expressing cells (57% ± 5.2% and 20.1% ± 1.5%, respectively; P = .001 for both). Total GSH (22 ± 0.3 vs 35.6 ± 1.1 nmol/mg protein), free GSH (21.9 ± 0.2 vs 33.5 ± 1 nmol/mg protein), and GSSG (0.6 ± 0.02 vs 1 ± 0.05 nmol/mg protein; P = .001 for all) concentrations were significantly increased in NNMT‐expressing cells, whereas the GSH:GSSG ratio was decreased (39.4 ± 1.8 vs 32.3 ± 2.5; P = .02). Finally, reactive oxygen species (ROS) content was decreased in NNMT‐expressing cells (0.3 ± 0.08 vs 0.12 ± 0.03; P = .039), as was the concentration of 8‐isoprostane F2α (200 ± 11.5 vs 45 ± 2.6 pg/mg protein; P = .0012). Taken together, these results suggest that NNMT expression reduced ROS generation and subsequent lipid peroxidation by uncoupling the mitochondrial membrane potential and increasing GSH buffering capacity, most likely to compensate for increased complex I activity and ATP production. 相似文献
233.
Dewi W. Lewis A. Rabdel Ruiz-Salvador Neyvis Almora-Barrios Ariel Gómez Manisha Mistry 《Molecular simulation》2013,39(6-7):649-661
The successful modelling of the structure of two hydrated calcium-rich natural zeolites is described, showing how modelling can reproduce their complex structure, in excellent agreement with experiment. Furthermore, we demonstrate how such methods are able to determine the preferred Al ordering in the mineral Goosecreekite. The dehydration behaviour of Goosecreekite is also predicted. The interatomic potentials for water, evaluated here, are found to be robust and transferable to zeolitic materials. 相似文献
234.
Nalini Mistry Marcus S. Cooke Mark D. Evans Eugene P. Halligan Damon A. Lowes 《Free radical research》2013,47(4):344-353
Polyunsaturated fats have been linked to occurrences of sporadic colon cancer. One possible cause may be degradation of polyunsaturated fats during cooking, resulting in multiple reactive carbonyl species (RCS) that can damage nuclear DNA and proteins, particularly in rapidly dividing colon crypt cells. This study describes a novel antiserum against RCS-modified DNA, with apparent order of reactivity to DNA modified with 4-hydroxy-trans-2-nonenal > glyoxal > acrolein > crotonaldehyde > malondialdehyde; some reactivity was also observed against conjugated Schiff base-type structures. Anti-(RCS-DNA) antiserum was successfully utilised to demonstrate formation of RCS-DNA in a human colon cell model, exposed to RCS insult derived from endogenous and exogenous lipid peroxidation sources. Further utilisation of the antiserum for immunohistochemical analysis confirmed RCS-modified DNA in crypt areas of ‘normal’ colon tissue. These results fully support a potential role for dietary lipid peroxidation products in the development of sporadic colon cancer. 相似文献
235.
236.
Laura E. Jennings Matthias Schiedel David S. Hewings Sarah Picaud Corentine M.C. Laurin Paul A. Bruno Joseph P. Bluck Amy R. Scorah Larissa See Jessica K. Reynolds Mustafa Moroglu Ishna N. Mistry Amy Hicks Pavel Guzanov James Clayton Charles N.G. Evans Giulia Stazi Philip C. Biggin Stuart J. Conway 《Bioorganic & medicinal chemistry》2018,26(11):2937-2957
Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t½?=?39.8?min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC50?=?166?nM), optimised physicochemical properties (LE?=?0.43; LLE?=?5.74; SFI?=?5.96), and greater metabolic stability (t½?=?388?min). 相似文献
237.
Mistry AM Swick AG Romsos DR 《Experimental biology and medicine (Maywood, N.J.)》2004,229(10):1033-1037
Leptin inhibits food intake and lowers plasma insulin concentrations. This study was designed to determine whether leptin acts independent of food-intake regulation to affect meal-induced increases in plasma insulin concentrations. Leptin-deficient, Lep(ob)/Lep(ob) mice were administered 1 microg leptin intracerebroventricularly (ICV) or intraperitoneally. Food intake and plasma insulin concentrations of mice administered leptin ICV before a meal were lower, as expected, than were intakes and plasma insulin concentrations of mice administered vehicle ICV. However when food intake was controlled, meal-induced increases in plasma insulin were unaffected by ICV administration of leptin. Intraperitoneal administration of 1 microg leptin before a meal lowered meal-induced increases in plasma insulin concentrations without influencing the size of the meal. We conclude that plasma leptin concentrations can affect meal-induced insulin secretion independent of the central nervous system actions of leptin associated with food-intake regulation. 相似文献
238.
Amy Beumer Dawn King Maura Donohue Jatin Mistry Terry Covert Stacy Pfaller 《Applied and environmental microbiology》2010,76(21):7367-7370
It has been suggested that Mycobacterium avium subspecies paratuberculosis has a role in Crohn''s disease. The organism may be acquired but is difficult to culture from the environment. We describe a quantitative PCR (qPCR) method to detect M. avium subsp. paratuberculosis in drinking water and the results of its application to drinking water and faucet biofilm samples collected in the United States.Mycobacterium avium subspecies paratuberculosis is a member of the Mycobacterium avium complex. M. avium subsp. paratuberculosis causes Johne''s disease in bovine and ovine animals and has been hypothetically linked to Crohn''s disease in humans. Several review articles have been written describing the association between M. avium subsp. paratuberculosis and Crohn''s disease (1, 2, 10, 11, 16, 23). Most mycobacterial infections are acquired from the environment; however, M. avium subsp. paratuberculosis can elude laboratory culture from environmental samples (28). M. avium subsp. paratuberculosis has been cultured only once from drinking water in the United States; therefore, its occurrence in drinking water is unknown (17). There are several reasons one could expect to find M. avium subsp. paratuberculosis in drinking water. The bacterium has been isolated from surface water used as a source of drinking water (19, 20, 24, 26). It is resistant to chlorine disinfection (25). Also, other subspecies of M. avium have been detected in biofilms obtained from drinking water pipes in the United States (8, 22, 27).Due to the potential for waterborne transmission of mycobacteria and the association of M. avium subsp. paratuberculosis with human illness, the focus of this study was to estimate the organism''s occurrence in drinking water in the United States using quantitative PCR (qPCR) (15). A comprehensive method was developed for detection of M. avium subsp. paratuberculosis in drinking water and biofilms that includes the concentration of microorganisms from samples using membrane filtration, total DNA extraction and purification, and detection of two targets unique to this bacterium: IS900 and target 251. IS900 is a common target used to identify M. avium subsp. paratuberculosis, and the average number of copies per genome is 14 to 18 (13). Target 251 qPCR analysis, which corresponds to the M. avium subsp. paratuberculosis gene 2765c (David Alexander, personal communication), was developed by Rajeev et al. (21). Samples positive for both targets are considered positive for M. avium subsp. paratuberculosis. TaqMan primer and probe sequences and qPCR assay characteristics are described in Table Table1.1. The complete method is described in Fig. S1 in the supplemental material.
Open in a separate windowaFAM, 6-carboxyfluorescein; TAMRA, 6-carboxytetramethylrhodamine; ND, not determined.bThe limit of detection (LOD) of the IS900 qPCR assay was defined as the lowest copy number resulting in a CT of <40, determined from six independent dilution series.cThe limit of quantification (LOQ) was defined as the lowest copy number per assay yielding a coefficient of variation (CV) of less than 25% (33).A master standard curve was generated from six series of 10-fold dilutions of genomic DNA from M. avium subsp. paratuberculosis strain 49164 for quantification of IS900 target copies (see Fig. S2A in the supplemental material). Each dilution series contained eight standards run in triplicate for a total of 18 threshold cycle (CT) measurements per standard. A linear regression was performed on CT versus log IS900 copy number and R2 was 0.997. The standard error of y was used to create two equations to estimate the upper and lower concentration, or range, of M. avium subsp. paratuberculosis IS900 copy number.The specificities of the IS900 and target 251 primer/probe sets were evaluated by Rajeev et al. (21) on 211 M. avium subsp. paratuberculosis and 38 non-M. avium subsp. paratuberculosis isolates, and each assay was 100% specific for M. avium subsp. paratuberculosis. We further evaluated specificity using 22 M. avium subsp. paratuberculosis isolates from animals and 10 non-M. avium subsp. paratuberculosis ATCC reference strains (see Table S1 in the supplemental material) (18). Target 251 was 100% specific; however, one M. avium subsp. paratuberculosis isolate (3063) repeatedly produced a negative result by IS900 qPCR. Results suggest that a small subset of M. avium subsp. paratuberculosis isolates may not contain the IS900 element or may have a sequence that differs from that of the IS900 primer/probe set.The sensitivity of the method for detection of M. avium subsp. paratuberculosis in different drinking water matrices was evaluated by spiking serial dilutions of strain 1112 cells, ranging from 104 cells to no addition of cells, into 1-liter tap water samples obtained from five locations in the United States. The number of M. avium subsp. paratuberculosis cell equivalents was estimated by dividing the IS900 copy number obtained from the master standard curve by 18 (mean, 18 IS900 copies/M. avium subsp. paratuberculosis genome). The method provided consistent detection (5/5 samples) in a spiked sample of 100 cells/liter. In a spiked sample of 10 cells/liter, the IS900 target was detected 40% (2/5 samples) of the time, and at 1 cell/liter we did not detect the target in any spiked sample. Percent recovery was variable and decreased as the number of spiked cells decreased (Fig. (Fig.1).1). At a spike level of 1 × 104 cells/liter, the average percent recovery was 64%; this decreased to 9.2% at 1 × 102 cells/liter. Cell surface hydrophobicity, a property of mycobacteria, may have influenced clumping of the spiked sample or partitioning of M. avium subsp. paratuberculosis onto the sample bottle or filtration unit, affecting recovery of the bacterium (3).Open in a separate windowFIG. 1.Average percent recovery of M. avium subsp. paratuberculosis spiked into drinking water collected from five sites in the United States. Error bars denote standard deviation. MAP, M. avium subsp. paratuberculosis. 相似文献
TABLE 1.
qPCR assay primers, probes, DNA targets, and assay characteristicsaDNA target | Primer or probe (sequence, 5′→3′) | Product (bp) | Reference | ||
---|---|---|---|---|---|
LODb | LOQc | ||||
IS900 | IS900F (CCGCTAATTGAGAGATGCGATTGG) | 230 | 1.8 | 1.8 | 13 |
IS900R (ATTCAACTCCAGCAGCGCGGCCTC) | |||||
IS900P (6-FAM-TCCACGCCCGCCCAGACAGG-TAMRA) | |||||
Target 251 | 251F (GCAAGACGTTCATGGGAACT) | 200 | ND | ND | 21 |
251R (GCGTAACTCAGCGAACAACA) | |||||
251P (6-FAM-CTGACTTCACGATGCGGTTCTTC-TAMRA) |
239.
240.
BACKGROUND: Human MCF-7 cells have been studied extensively as a model for breast cancer cell growth. Many reports have established that serum-starved MCF-7 cells can be induced to proliferate upon the sole addition of 17beta-estradiol (E2). However, the extent of the mitogenic response to E2 varies in different MCF-7 strains and may even be absent. In this study we compared the E2-sensitivity of three MCF-7 laboratory strains. RESULTS: The MCF-7S line is non-responsive to E2, the MCF-7 ATCC has an intermediate response to E2, while the MCF-7 NKI is highly E2-sensitive, although the levels and activities of the estrogen receptor (ER) are not significantly different. Both suramin and IGF type I receptor blocking antibodies are able to inhibit the mitogenic response to E2-treatment in MCF-7 ATCC and MCF-7 NKI cells. From this we conclude that E2-induced proliferation is dependent on IGF type I receptor activation in all three MCF-7 strains. CONCLUSIONS: The results presented in this article suggest that E2-responsiveness of MCF-7 cells is dependent on the secretion of an autocrine factor activating the IGF-IR. All three strains of MCF-7 breast cancer cells investigated do not respond to E2 if the IGF-RI-pathway is blocked. Generally, breast cancer therapy is targeted at inhibiting estrogen action. This study suggests that inhibition of IGF-action in combination with anti-estrogen-treatment may provide a more effective way in treatment or even prevention of breast cancer. 相似文献