全文获取类型
收费全文 | 2696篇 |
免费 | 259篇 |
出版年
2022年 | 27篇 |
2021年 | 48篇 |
2020年 | 22篇 |
2019年 | 37篇 |
2018年 | 45篇 |
2017年 | 31篇 |
2016年 | 67篇 |
2015年 | 121篇 |
2014年 | 124篇 |
2013年 | 165篇 |
2012年 | 156篇 |
2011年 | 197篇 |
2010年 | 118篇 |
2009年 | 105篇 |
2008年 | 138篇 |
2007年 | 198篇 |
2006年 | 176篇 |
2005年 | 159篇 |
2004年 | 131篇 |
2003年 | 131篇 |
2002年 | 156篇 |
2001年 | 27篇 |
2000年 | 17篇 |
1999年 | 28篇 |
1998年 | 37篇 |
1997年 | 27篇 |
1996年 | 24篇 |
1995年 | 26篇 |
1994年 | 21篇 |
1993年 | 32篇 |
1992年 | 19篇 |
1991年 | 20篇 |
1990年 | 17篇 |
1989年 | 17篇 |
1988年 | 23篇 |
1987年 | 21篇 |
1986年 | 22篇 |
1985年 | 17篇 |
1984年 | 15篇 |
1983年 | 8篇 |
1982年 | 9篇 |
1981年 | 16篇 |
1980年 | 23篇 |
1979年 | 10篇 |
1978年 | 15篇 |
1975年 | 14篇 |
1973年 | 13篇 |
1972年 | 10篇 |
1971年 | 12篇 |
1969年 | 8篇 |
排序方式: 共有2955条查询结果,搜索用时 31 毫秒
121.
Satriano Joseph; Ishizuka Shunji; Archer D. Clay; Blantz Roland C.; Kelly Carolyn J. 《American journal of physiology. Cell physiology》1999,276(4):C892
Nitric oxide (NO)has been described to exert cytostatic effects on cellularproliferation; however the mechanisms responsible for these effectshave yet to be fully resolved. Polyamines, conversely, are requiredcomponents of cellular proliferation. In experimental models ofinflammation, a relationship between these two pathways has beensuggested by the temporal regulation of a common precursor, arginine.This study was undertaken to determine the effects NO and the NOsynthase (NOS)-inducing cytokines, tumor necrosis factor- (TNF-)and interferon- (IFN-), exert on polyamine regulation. Thetransformed kidney proximal tubule cell line, MCT, maintains highconstitutive levels of the first polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). NO donors markedly suppressed ODC activity in MCT and all other cell lines examined. TNF- and IFN- induction of NO generation resulted in suppressed ODC activity, aneffect prevented by the inducible NOS inhibitorL-N6-(1-iminoethyl)lysine(L-NIL). Dithiothreitol reversalof NO-mediated ODC suppression supports nitrosylation as the mechanismof inactivation. We also evaluated polyamine uptake, inasmuch asinhibition of ODC can result in a compensatory induction of polyaminetransporters. Administration of NO donors, or TNF- and IFN-,suppressed[3H]putrescine uptake,thereby preventing transport-mediated reestablishment of intracellularpolyamine levels. This study demonstrates the capacity of NO andinflammatory cytokines to regulate both polyamine biosynthesis and transport. 相似文献
122.
Tracey WR Treadway JL Magee WP Sutt JC McPherson RK Levy CB Wilder DE Yu LJ Chen Y Shanker RM Mutchler AK Smith AH Flynn DM Knight DR 《American journal of physiology. Heart and circulatory physiology》2004,286(3):H1177-H1184
Interventions such as glycogen depletion, which limit myocardial anaerobic glycolysis and the associated proton production, can reduce myocardial ischemic injury; thus it follows that inhibition of glycogenolysis should also be cardioprotective. Therefore, we examined whether the novel glycogen phosphorylase inhibitor 5-Chloro-N-[(1S,2R)-3-[(3R,4S)-3,4-dihydroxy-1-pyrrolidinyl)]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (ingliforib; CP-368,296) could reduce infarct size in both in vitro and in vivo rabbit models of ischemia-reperfusion injury (30 min of regional ischemia, followed by 120 min of reperfusion). In Langendorff-perfused hearts, constant perfusion of ingliforib started 30 min before regional ischemia and elicited a concentration-dependent reduction in infarct size; infarct size was reduced by 69% with 10 microM ingliforib. No significant drug-induced changes were observed in either cardiac function (heart rate, left ventricular developed pressure) or coronary flow. In open-chest anesthetized rabbits, a dose of ingliforib (15 mg/kg loading dose; 23 mg.kg(-1).h(-1) infusion) selected to achieve a free plasma concentration equivalent to an estimated EC(50) in the isolated hearts (1.2 microM, 0.55 microg/ml) significantly reduced infarct size by 52%, and reduced plasma glucose and lactate concentrations. Furthermore, myocardial glycogen phosphorylase a and total glycogen phosphorylase activity were reduced by 65% and 40%, respectively, and glycogen stores were preserved in ingliforib-treated hearts. No significant change was observed in mean arterial pressure or rate-pressure product in the ingliforib group, although heart rate was modestly decreased postischemia. In conclusion, glycogen phosphorylase inhibition with ingliforib markedly reduces myocardial ischemic injury in vitro and in vivo; this may represent a viable approach for both achieving clinical cardioprotection and treating diabetic patients at increased risk of cardiovascular disease. 相似文献
123.
Rouse CM 《Culture, medicine and psychiatry》2004,28(3):369-399
The emergence of two different sickle cell disease and disease/treatment paradigms in two clinics, Children's Hospital West (CHW) and Children's Hospital East (CHE), demonstrates how physicians can influence institutional regimes of truth to improve patient access. Physicians at both clinics, far from simply acquiescing to dominant biomedical paradigms, recognize that their paradigms are in part rhetorical strategies designed to subvert problematic staff biases and perceptions, and to encourage a particular "self-efficacy" ethic in the patients. This paper positions physicians as struggling within the discursive regimes of biomedicine to create an institutional space where the disease and the sickle cell patient matter, and where patients comply with the performative rules of that space. This paper explores how physicians, patients, and institutions collaborate in the construction of sickle cell disease in such a way that biomedicine becomes a plural, as opposed to a singular and oppressive, discursive regime. 相似文献
124.
Dinsmore CJ Zartman CB Bergman JM Abrams MT Buser CA Culberson JC Davide JP Ellis-Hutchings M Fernandes C Graham SL Hartman GD Huber HE Lobell RB Mosser SD Robinson RG Williams TM 《Bioorganic & medicinal chemistry letters》2004,14(3):639-643
A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed. 相似文献
125.
Dyatkin AB Hoekstra WJ Kinney WA Kontoyianni M Santulli RJ Kimball ES Fisher MC Carolyn Fisher M Prouty SM Abraham WM de Garavilla L Andrade-Gordon P Hlasta DJ He W Hornby PJ Damiano BP Maryanoff BE 《Bioorganic & medicinal chemistry letters》2004,14(3):591-596
The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma. 相似文献
126.
Tan Q Birzin ET Chan W Yang YT Pai LY Hayes EC DaSilva CA DiNinno F Rohrer SP Schaeffer JM Hammond ML 《Bioorganic & medicinal chemistry letters》2004,14(14):3753-3755
Dihydrobenzodithiin compounds (1-6) were prepared to explore the expansion of the dihydrobenzoxathiin lead compounds I-III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, however, they lacked the in vivo antagonism/agonism activity exhibited by the lead class in an immature rat uterine growth model. 相似文献
127.
Li J DeMello KM Cheng H Sakya SM Bronk BS Rafka RJ Jaynes BH Ziegler CB Kilroy C Mann DW Nimz EL Lynch MP Haven ML Kolosko NL Minich ML Li C Dutra JK Rast B Crosson RM Morton BJ Kirk GW Callaghan KM Koss DA Shavnya A Lund LA Seibel SB Petras CF Silvia A 《Bioorganic & medicinal chemistry letters》2004,14(1):95-98
Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted. 相似文献
128.
Niu C Smith D Zask A Loganzo F Discafani C Beyer C Greenberger L Ayral-Kaloustian S 《Bioorganic & medicinal chemistry letters》2004,14(16):4329-4332
Modifications of the B-segment of HTI-286 (2) produced a class of analogs incorporating heteroatom-substituents. The structure-activity relationship was studied. Analogs bearing methylsulfide and fluoride groups exhibited potency comparable to that of the parent compound HTI-286 and to paclitaxel in cytotoxicity assays against KB-3-1 cell lines. These analogs were more potent than paclitaxel against P-glycoprotein expressing KB-8-5 and KB-V1 cell lines. Several analogs showed strong inhibition of tubulin polymerization. 相似文献
129.
SUMMARY: LumberJack is a phylogenetic tool intended to serve two purposes: to facilitate sampling treespace to find likely tree topologies quickly, and to map phylogenetic signal onto regions of an alignment in a revealing way. LumberJack creates non-random jackknifed alignments by progressively sliding a window of omission along the alignment. A neighbor-joining tree is built from the full alignment and from each jackknifed alignment, and then the likelihood for each topology (given the original full alignment) is calculated. To determine whether any of the topologies generated is significantly more likely than the others, Kishino-Hasegawa, Shimodaira-Hasegawa and ELW tests are implemented. Availability and SUPPLEMENTARY INFORMATION: http://www.plantbio.uga.edu/~russell/software.html 相似文献
130.
Dietary Ethanol Mediates Selection on Aldehyde Dehydrogenase Activity in Drosophila melanogaster 总被引:1,自引:0,他引:1
Fry JD Bahnck CM Mikucki M Phadnis N Slattery WC 《Integrative and comparative biology》2004,44(4):275-283
Ethanol is an important environmental variable for fruit-breedingDrosophila species, serving as a resource at low levels anda toxin at high levels. The first step of ethanol metabolism,the conversion of ethanol to acetaldehyde, is catalyzed primarilyby the enzyme alcohol dehydrogenase (ADH). The second step,the oxidation of acetaldehyde to acetate, has been a sourceof controversy, with some authors arguing that it is carriedout primarily by ADH itself, rather than a separate aldehydedehydrogenase (ALDH) as in mammals. We review recent evidencethat ALDH plays an important role in ethanol metabolism in Drosophila.In support of this view, we report that D. melanogaster populationsmaintained on ethanol-supplemented media evolved higher activityof ALDH, as well as of ADH. We have also tentatively identifiedthe structural gene responsible for the majority of ALDH activityin D. melanogaster. We hypothesize that variation in ALDH activitymay make an important contribution to the observed wide variationin ethanol tolerance within and among Drosophila species. 相似文献