全文获取类型
收费全文 | 306篇 |
免费 | 10篇 |
出版年
2022年 | 2篇 |
2021年 | 4篇 |
2019年 | 3篇 |
2016年 | 3篇 |
2015年 | 10篇 |
2014年 | 10篇 |
2013年 | 11篇 |
2012年 | 13篇 |
2011年 | 11篇 |
2010年 | 5篇 |
2009年 | 9篇 |
2008年 | 12篇 |
2007年 | 11篇 |
2006年 | 16篇 |
2005年 | 10篇 |
2004年 | 9篇 |
2003年 | 13篇 |
2002年 | 11篇 |
2001年 | 13篇 |
2000年 | 8篇 |
1999年 | 6篇 |
1998年 | 5篇 |
1996年 | 10篇 |
1995年 | 7篇 |
1994年 | 6篇 |
1993年 | 5篇 |
1992年 | 4篇 |
1991年 | 5篇 |
1989年 | 5篇 |
1988年 | 9篇 |
1987年 | 2篇 |
1986年 | 5篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1981年 | 2篇 |
1978年 | 6篇 |
1977年 | 2篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1972年 | 2篇 |
1966年 | 3篇 |
1961年 | 4篇 |
1959年 | 2篇 |
1957年 | 3篇 |
1951年 | 2篇 |
1949年 | 1篇 |
1948年 | 1篇 |
1947年 | 2篇 |
1939年 | 1篇 |
排序方式: 共有316条查询结果,搜索用时 15 毫秒
151.
Faig M Bianchet MA Winski S Hargreaves R Moody CJ Hudnott AR Ross D Amzel LM 《Structure (London, England : 1993)》2001,9(8):659-667
BACKGROUND: NAD(P)H:quinone acceptor oxidoreductase (QR1) protects animal cells from the deleterious and carcinogenic effects of quinones and other electrophiles. Remarkably, the same enzyme activates cancer prodrugs that become cytotoxic only after two-electron reduction. QR1's ability to bioactivate quinones and its elevated expression in many human solid tumors makes this protein an excellent target for enzyme-directed drug development. Until now, structural analysis of the mode of binding of chemotherapeutic compounds to QR1 was based on model building using the structures of complexes with simple substrates; no structure of complexes of QR1 with chemotherapeutic prodrugs had been reported. RESULTS: Here we report the high-resolution crystal structures of complexes of QR1 with three chemotherapeutic prodrugs: RH1, a water-soluble homolog of dimethylaziridinylbenzoquinone; EO9, an aziridinylindolequinone; and ARH019, another aziridinylindolequinone. The structures, determined to resolutions of 2.0 A, 2.5 A, and 1.86 A, respectively, were refined to R values below 21% with excellent geometry. CONCLUSIONS: The structures show that compounds can bind to QR1 in more than one orientation. Surprisingly, the two aziridinylindolequinones bind to the enzyme in different orientations. The results presented here reveal two new factors that must be taken into account in the design of prodrugs targeted for activation by QR1: the enzyme binding site is highly plastic and changes to accommodate binding of different substrates, and homologous drugs with different substituents may bind to QR1 in different orientations. These structural insights provide important clues for the optimization of chemotherapeutic compounds that utilize this reductive bioactivation pathway. 相似文献
152.
Gaining information on global gene function in fungal plant pathogens through analysis of expressed sequences is a valuable step towards understanding the overall metabolism and biology underlying the pathogenic habit. Such large-scale gene-finding exercises are poised to provide many useful leads for discovering key events that contribute to the processes of infection and colonisation of host plants. 相似文献
153.
Stellingwerff T Spriet LL Watt MJ Kimber NE Hargreaves M Hawley JA Burke LM 《American journal of physiology. Endocrinology and metabolism》2006,290(2):E380-E388
Five days of a high-fat diet while training, followed by 1 day of carbohydrate (CHO) restoration, increases rates of whole body fat oxidation and decreases CHO oxidation during aerobic cycling. The mechanisms responsible for these shifts in fuel oxidation are unknown but involve up- and downregulation of key regulatory enzymes in the pathways of skeletal muscle fat and CHO metabolism, respectively. This study measured muscle PDH and HSL activities before and after 20 min of cycling at 70% VO2peak and 1 min of sprinting at 150% peak power output (PPO). Estimations of muscle glycogenolysis were made during the initial minute of exercise at 70% VO2peak and during the 1-min sprint. Seven male cyclists undertook this exercise protocol on two occasions. For 5 days, subjects consumed in random order either a high-CHO (HCHO) diet (10.3 g x kg(-1) x day(-1) CHO, or approximately 70% of total energy intake) or an isoenergetic high-fat (FAT-adapt) diet (4.6 g x kg(-1) x day(-1) FAT, or 67% of total energy) while undertaking supervised aerobic endurance training. On day 6 for both treatments, subjects ingested an HCHO diet and rested before their experimental trials on day 7. This CHO restoration resulted in similar resting glycogen contents (FAT-adapt 873 +/- 121 vs. HCHO 868 +/- 120 micromol glucosyl units/g dry wt). However, the respiratory exchange ratio was lower during cycling at 70% VO2peak in the FAT-adapt trial, which resulted in an approximately 45% increase and an approximately 30% decrease in fat and CHO oxidation, respectively. PDH activity was lower at rest and throughout exercise at 70% VO2peak (1.69 +/- 0.25 vs. 2.39 +/- 0.19 mmol x kg wet wt(-1) x min(-1)) and the 1-min sprint in the FAT-adapt vs. the HCHO trial. Estimates of glycogenolysis during the 1st min of exercise at 70% VO2peak and the 1-min sprint were also lower after FAT-adapt (9.1 +/- 1.1 vs. 13.4 +/- 2.1 and 37.3 +/- 5.1 vs. 50.5 +/- 2.7 glucosyl units x kg dry wt(-1) x min(-1)). HSL activity was approximately 20% higher (P = 0.12) during exercise at 70% VO2peak after FAT-adapt. Results indicate that previously reported decreases in whole body CHO oxidation and increases in fat oxidation after the FAT-adapt protocol are a function of metabolic changes within skeletal muscle. The metabolic signals responsible for the shift in muscle substrate use during cycling at 70% VO2peak remain unclear, but lower accumulation of free ADP and AMP after the FAT-adapt trial may be responsible for the decreased glycogenolysis and PDH activation during sprinting. 相似文献
154.
Wilson C Hargreaves M Howlett KF 《American journal of physiology. Endocrinology and metabolism》2006,290(2):E341-E346
The subcellular localization of insulin signaling proteins is altered by various stimuli such as insulin, insulin-like growth factor I, and oxidative stress and is thought to be an important mechanism that can influence intracellular signal transduction and cellular function. This study examined the possibility that exercise may also alter the subcellular localization of insulin signaling proteins in human skeletal muscle. Nine untrained males performed 60 min of cycling exercise (approximately 67% peak pulmonary O2 uptake). Muscle biopsies were sampled at rest, immediately after exercise, and 3 h postexercise. Muscle was fractionated by centrifugation into the following crude fractions: cytosolic, nuclear, and a high-speed pellet containing membrane and cytoskeletal components. Fractions were analyzed for protein content of insulin receptor, insulin receptor substrate (IRS)-1 and -2, p85 subunit of phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3 (GSK-3). There was no significant change in the protein content of the insulin signaling proteins in any of the crude fractions after exercise or 3 h postexercise. Exercise had no significant effect on the phosphorylation of IRS-1 Tyr612 in any of the fractions. In contrast, exercise increased (P < 0.05) the phosphorylation of Akt Ser473 and GSK-3alpha/beta Ser9/21 in the cytosolic fraction only. In conclusion, exercise can increase phosphorylation of downstream insulin signaling proteins specifically in the cytosolic fraction but does not result in changes in the subcellular localization of insulin signaling proteins in human skeletal muscle. Change in the subcellular protein localization is therefore an unlikely mechanism to influence signal transduction pathways and cellular function in skeletal muscle after exercise. 相似文献
155.
Beneficial and detrimental interactive effects of dissolved organic matter and ultraviolet radiation on Zooplankton in a transparent lake 总被引:2,自引:2,他引:0
Sandra L. Cooke Craig E. Williamson Bruce R. Hargreaves Donald P. Morris 《Hydrobiologia》2006,568(1):15-28
While changes in dissolved organic matter (DOM) concentrations are expected to affect zooplankton species through attenuation
of potentially damaging ultraviolet (UV) radiation, generation of potentially beneficial or harmful photoproducts, pH alteration,
and microbial food web stimulation, the combined effects of such changes on zooplankton community structure have not been
studied previously. Our purpose was to determine how an increase in allochthonous DOM and associated changes in pH in an initially
transparent lake may affect zooplankton community structure, and how exposure to solar UV may alter these DOM and pH effects.
We ran microcosm experiments manipulating UV, DOM, and pH near the surface of Lake Giles in northeastern Pennsylvania. We
found that when DOM was added in the presence of ambient UV, Daphnia and copepod UV-mortality was reduced by approximately three and two times compared to UV exposure without extra DOM. When
DOM was added in the absence of UV, adult Daphnia and copepods were reduced compared to no DOM addition in the absence of UV. Daphnia and cyclopoid egg production and rotifer abundance were generally higher in the presence of DOM, regardless of UV treatment.
The lower abundance yet high egg production in the presence of DOM and absence of UV may be explained by higher abundance
of egg-bearing adults compared to non-egg-bearers. We conclude that allochthonous DOM benefits some zooplankton in a high-UV
environment, but may be detrimental under low-UV conditions. Overall, Daphnia abundance and egg production were higher than that of calanoid copepods in the DOM additions, indicating that in some lakes
an increase in allochthonous DOM may lead to a zooplankton community shift favoring Daphnia over calanoid copepods. 相似文献
156.
I. A. Montalbán A. Setién-Olarra C. L. Hargreaves P. Moncaleán 《Trees - Structure and Function》2013,27(5):1339-1351
Pinus halepensis Mill. is a common forest species in the Mediterranean area and it is important for environmental conservation. This study established a method of regenerating Pinus halepensis Mill. through somatic embryogenesis. The effect of culture medium (mineral salts, nitrogen source and plant growth regulators), collection date and seed family on embryogenic tissue initiation and proliferation in Pinus halepensis was analysed during the first steps of embryogenesis process. This study showed a marked effect of the culture medium tested as well as some significant differences among collection dates. Furthermore, the embryogenic tissue initiation was affected by the amino acid mixture in the culture medium and the proliferation stage was significantly affected by the combination of plant growth regulators. At the end of the maturation phase the presence of activated charcoal was also evaluated. Finally, maturation of embryogenic tissue was affected by the nitrogen source in the culture medium and these results were different for high and low mature embryo producing cell lines. To the best of our knowledge, this is the first report on Aleppo pine somatic embryogenesis describing a simple and efficient procedure for large-scale somatic embryo production. 相似文献
157.
Raibatak Das Robert B. Nachbar Leah Edelstein-Keshet Jeffrey S. Saltzman Matthew C. Wiener Ansuman Bagchi James Bailey Daniel Coombs Adam J. Simon Richard J. Hargreaves Jacquelynn J. Cook 《Bulletin of mathematical biology》2011,73(1):230-247
Aggregation of the small peptide amyloid beta (A??) into oligomers and fibrils in the brain is believed to be a precursor to Alzheimer??s disease. A?? is produced via multiple proteolytic cleavages of amyloid precursor protein (APP), mediated by the enzymes ??- and ??-secretase. In this study, we examine the temporal dynamics of soluble (unaggregated) A?? in the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys treated with different oral doses of a ??-secretase inhibitor. A dose-dependent reduction of A?? concentration was observed within hours of drug ingestion, for all doses tested. A?? concentration in the CSF returned to its predrug level over the monitoring period. In contrast, A?? concentration in the plasma exhibited an unexpected overshoot to as high as 200% of the predrug concentration, and this overshoot persisted as late as 72 hours post-drug ingestion. To account for these observations, we proposed and analyzed a minimal physiological model for A?? dynamics that could fit the data. Our analysis suggests that the overshoot arises from the attenuation of an A?? clearance mechanism, possibly due to the inhibitor. Our model predicts that the efficacy of A?? clearance recovers to its basal (pretreatment) value with a characteristic time of >48 hours, matching the time-scale of the overshoot. These results point to the need for a more detailed investigation of soluble A?? clearance mechanisms and their interaction with A??-reducing drugs. 相似文献
158.
Erik A Richter Adam Rose J?rgen F P Wojtaszewski Mark Hargreaves 《Journal of applied physiology》2006,101(6):1809; author reply 1810-1809; author reply 1811
159.
Jiqing Guo Serdar Durdagi Mohamed Changalov Laura L. Perissinotti Jason M. Hargreaves Thomas G. Back Sergei Y. Noskov Henry J. Duff 《PloS one》2014,9(9)
One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K+, Ca2+ and Na+ currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on interventions with a drug that may proactively activate hERG1 channels reducing cardiovascular risks. Small molecules-activators have a great potential for co-therapies where the risk of hERG-related QT prolongation is significant and rehabilitation of the drug is impractical. Although a number of hERG1 activators have been identified in the last decade, their binding sites, functional moieties responsible for channel activation and thus mechanism of action, have yet to be established. Here, we present a proof-of-principle study that combines de-novo drug design, molecular modeling, chemical synthesis with whole cell electrophysiology and Action Potential (AP) recordings in fetal mouse ventricular myocytes to establish basic chemical principles required for efficient activator of hERG1 channel. In order to minimize the likelihood that these molecules would also block the hERG1 channel they were computationally engineered to minimize interactions with known intra-cavitary drug binding sites. The combination of experimental and theoretical studies led to identification of functional elements (functional groups, flexibility) underlying efficiency of hERG1 activators targeting binding pocket located in the S4–S5 linker, as well as identified potential side-effects in this promising line of drugs, which was associated with multi-channel targeting of the developed drugs. 相似文献
160.
Boccia D Hargreaves J De Stavola BL Fielding K Schaap A Godfrey-Faussett P Ayles H 《PloS one》2011,6(6):e20824