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101.
Sakya SM Bertinato P Pratt B Suarez-Contreras M Lundy KM Minich ML Cheng H Ziegler CB Kamicker BJ Hayashi SF Santoro SL George DM Bertsche CD 《Bioorganic & medicinal chemistry letters》2003,13(7):1373-1375
Aryl and hetero aryl substituted 3,6-ketals of 15-membered azalide analogues were synthesized and were found to have potent in vitro antibacterial activity against veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida. 相似文献
102.
103.
Buhlmann JE Elkin SK Sharpe AH 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(11):5421-5428
Although costimulation plays an important role in activating naive T cells, its role in negative selection is controversial. By following thymocyte deletion induced by endogenous superantigens in mice lacking B7-1 and/or B7-2, we have identified a role for both B7-1 and B7-2 in negative selection. Studies using CD28-deficient and CD28/CTLA-4-double-deficient mice have revealed that either CD28 or another as yet undefined coreceptor can mediate these B7-dependent signals that promote negative selection. Finally, CTLA-4 delivers signals that inhibit selection, suggesting that CTLA-4 and CD28 have opposing functions in thymic development. Combined, the data demonstrate that B7-1/B7-2-dependent signals help shape the T cell repertoire. 相似文献
104.
Effect of non-heparin thrombin antagonists on thrombin generation, platelet function, and clot structure in whole blood 总被引:4,自引:0,他引:4
Platelet contractile force (PCF), which is absent in blood obtained during cardiopulmonary bypass, significantly recovers after protamine sulfate administration. In vitro studies reveal this effect to be primarily caused by heparin. Because many of heparin's effects are mediated by suppression of thrombin generation and activity, this study assessed the influence of thrombin inhibition on PCF. The effects of natural and synthetic antithrombins were measured. Clots were formed by the addition of batroxobin (0.21 microg/mL) to whole blood (platelet count 200,000/microL). Force development was measured from the moment of batroxobin addition. After 1200 s of clotting, purified antithrombin III (22 microM) reduced PCF by 74%. Thrombomodulin (0.014 microM) reduced PCF by 60%. At 0.040 microM, PCF was reduced by 82% (6.5-1.2 Kdynes). Hirudin decreased PCF in a dose-dependent fashion, with complete suppression at concentrations > or = 0.30 microM. At concentrations between 0.04 and 0.29 microM, Lepirudin (Refludan, a recombinant therapeutic hirudin) produced dose-dependent delay and suppression of PCF. Above 0.29 microM Lepirudin, PCF was totally suppressed. At 1.60 microM, bivalirudin (a synthetic, 20 amino acid peptide) delayed and reduced PCF by 50%. At 6.40 micro;M, PCF was completely suppressed. Although 20 microM of P-PACK II (d-Phenylalanyl-L-Phenylalanylarginine- chloro-methyl ketone 2 HCl) had little effect, 40 microM delayed onset of force development from 300 to 600 s and reduced PCF at 1200 s from 5.2 to 3.3 Kdynes. At 120 microM, force development was totally suppressed. Four micromol Thromstop (BNas-Gly-(pAM)Phe-Pip) delayed force development by greater than 800 s and PCF at 1200 s was reduced by 70%. At 0.20 microM, Argatroban (a synthetic polypeptide direct thrombin antagonist) delayed onset of PCF from 300 to 540 s and decreased PCF by 40%. At a concentration of 0.40 microM and above, Argatroban totally suppressed PCF. These results indicate that some of the antiplatelet effects of heparin are the result of thrombin inhibition and that low-level thrombin generation is essential for clot retraction. The sensitivity of PCF to the presence of thrombin may permit monitoring of antithrombin agents via this assay. 相似文献
105.
BCL-2 in prostate cancer: a minireview 总被引:10,自引:0,他引:10
Prostate cancer progression and the development of androgen-independent prostate cancer have been largely related to a number of genetic abnormality that affect not only the androgen receptor but also crucial molecules involved in the regulation of survival or apoptotic pathways. One of these molecules, the pro-survival protein BCL-2, has been associated with the development of androgen-independent prostate cancer due to its high levels of expression in androgen-independent tumors in advanced stages of the pathology. The upregulation of BCL-2 after androgen ablation in prostate carcinoma cell lines and in a castrated-male rat model further established a connection between BCL-2 expression and prostate cancer progression. This review focuses on the experimental evidence that associates BCL-2 expression with prostate carcinogenesis and cancer progression, and analyzes the evidence that links the phosphatidylinositol 3-kinase (PI 3-kinase)/nuclear factor kappa B (NF-B) survival pathway with the upregulation of BCL-2. The way in which hormone ablation influences this survival pathway and the potential application of novel therapeutic strategies to overcome this anti-apoptotic mechanism is examined. 相似文献
106.
Dong H Rothmel R Onstott TC Fuller ME DeFlaun MF Streger SH Dunlap R Fletcher M 《Applied and environmental microbiology》2002,68(5):2120-2132
The transport characteristics of two adhesion-deficient, indigenous groundwater strains, Comamonas sp. strain DA001 and Erwinia herbicola OYS2-A, were studied by using intact sediment cores (7 by 50 cm) from Oyster, Va. Both strains are gram-negative rods (1.10 by 0.56 and 1.56 by 0.46 microm, respectively) with strongly hydrophilic membranes and a slightly negative surface charge. The two strains exhibited markedly different behaviors when they were transported through granular porous sediment. To eliminate any effects of physical and chemical heterogeneity on bacterial transport and thus isolate the biological effect, the two strains were simultaneously injected into the same core. DA001 cells were metabolically labeled with (35)S and tagged with a vital fluorescent stain, while OYS2-A cells were metabolically labeled with (14)C. The fast decay of (35)S allowed deconvolution of the two isotopes (and therefore the two strains). Dramatic differences in the transport behaviors were observed. The breakthrough of DA001 and the breakthrough of OYS2-A both occurred before the breakthrough of a conservative tracer (termed differential advection), with effluent recoveries of 55 and 30%, respectively. The retained bacterial concentration of OYS2-A in the sediment was twofold higher than that of DA001. Among the cell properties analyzed, the statistically significant differences between the two strains were cell length and diameter. The shorter, larger-diameter DA001 cells displayed a higher effluent recovery than the longer, smaller-diameter OYS2-A cells. CXTFIT modeling results indicated that compared to the DA001 cells, the OYS2-A cells experienced lower pore velocity, higher porosity, a higher attachment rate, and a lower detachment rate. All these factors may contribute to the observed differences in transport. 相似文献
107.
Smith SS 《Steroids》2002,67(6):519-528
Early work in the field established that the 5 alpha-reduced metabolite of progesterone 3 alpha-OH-5 alpha-pregnan-20-one (allopregnanolone or 3 alpha,5 alpha-THP) is a potent positive modulator of the GABA(A) receptor (GABAR), the receptor mediating the effects of the primary inhibitory transmitter in the brain. This steroid acts in a manner similar to sedative drugs, such as the barbiturates, both in terms of potentiating GABA-induced inhibition in vitro and in behavioral assays, by reducing anxiety and seizure susceptibility. Because sedative compounds exhibit withdrawal properties that result in behavioral hyperexcitability, our laboratory has more recently investigated the effect of prolonged application and rapid removal (i.e. 'withdrawal') of this steroid, administered in vivo to female rats. Withdrawal from 3 alpha,5 alpha-THP produces a state of increased anxiety and lowered seizure threshold, similar to withdrawal from other GABA-modulatory drugs such as the benzodiazepines and alcohol. Hormone withdrawal also produced increases in the alpha 4-containing GABAR, an effect correlated with insensitivity of the GABAR to modulation by the benzodiazepine class of tranquilizers, as would normally occur under control conditions. In addition, changes in intrinsic channel properties, including a marked acceleration in the decay rate was also observed as a result of declining levels of 3 alpha,5 alpha-THP. Such a change would result in less inhibitory total current, and the resulting increase in neuronal excitability could then underlie the observed behavioral excitability following hormone withdrawal. These results suggest that actions of this steroid on a traditional transmitter receptor in the brain lead to alterations in GABAR subunit composition that result in changes in the intrinsic channel properties of the receptor and behavioral excitability. These results may have implications for endogenous fluctuations in this hormone which may accompany premenstrual dysphoric disorder. 相似文献
108.
The evolution of sociality in insects holds a central place in evolutionary theory. By examining the phylogenetic patterns of solitary and social behavior and how they correlate with ecological variables, we may identify factors important in the evolution of sociality. In this study, we investigated historical and biogeographical patterns of sociality in a socially polymorphic bee species (one that demonstrates both social and solitary nesting behavior). This unique system allows for a more powerful examination of evolutionary transitions in sociality than interspecific studies of obligately social and solitary species. We conducted a phylogenetic analysis among populations of the halictine bee Halictus rubicundus and then identified relationships among mitochondrial DNA sequence data, sociality, environmental conditions at the nesting site, and geographic location of populations of this species. Within North America, populations of H. rubicundus expressing social and solitary behavior belong to different genetic lineages. Sociality is also correlated with at least one environmental variable used in this study. Taken together, the results support the predictions for genetic control of sociality, but they are still consistent with social behavior at some level being determined by the environmental conditions at the nesting site. 相似文献
109.
Serikov V Bodi I Koch SE Muth JN Mikala G Martinov SG Haase H Schwartz A 《Biochemical and biophysical research communications》2002,293(5):1405-1411
The beta subunit of the L-type voltage-dependent calcium channel modifies the properties of the channel complex by both allosteric modulation of the alpha1 subunit function and by chaperoning the translocation of the alpha1 subunit to the plasma membrane. The goal of this study was to investigate the functional effect of changing the in vivo stoichiometry between the alpha1 and beta subunits by creating a dominant negative expression system in a transgenic mouse model. The high affinity beta subunit-binding domain of the alpha1 subunit was overexpressed in a cardiac-specific manner to act as a beta subunit trap. We found that the predominant beta isoform was located primarily in the membrane bound fraction of heart protein, whereas the beta1 and beta3 were mostly cytosolic. There was a significant diminution of the amount of beta2 in the membrane fraction of the transgenic animals, resulting in a decrease in contractility of the heart and a decrease in L-type calcium current density in the myocyte. However, there were no distinguishable differences in beta1 and beta3 protein expression levels in the membrane bound fraction between transgenic and non-transgenic animals. Since the beta1 and beta3 isoforms only make up a small portion of the total beta subunit in the heart, slight changes in this fraction are not detectable using Western analysis. In contrast, beta1 and beta3 in skeletal muscle and brain, the predominant isoforms in these tissues, respectively, are membrane bound. 相似文献
110.
Zhu QY Holt RR Lazarus SA Orozco TJ Keen CL 《Experimental biology and medicine (Maywood, N.J.)》2002,227(5):321-329
Excessive peroxidation of biomembranes is thought to contribute to the initiation and progression of numerous degenerative diseases. The present study examined the inhibitory effects of a cocoa extract, individual cocoa flavanols (-)-epicatechin and (+)-catechin, and procyanidin oligomers (dimer to decamer) isolated from cocoa on rat erythrocyte hemolysis. In vitro, the flavanols and the procyanidin oligomers exhibited dose-dependent protection against 2,2'-azo-bis (2-amidinopropane) dihydrochloride (AAPH)-induced erythrocyte hemolysis between concentrations of 2.5 and 40 microM. Dimer, trimer, and tetramer showed the strongest inhibitory effects at 10 microM, 59.4%, 66.2%, 70.9%; 20 microM, 84.1%, 87.6%, 81.0%; and 40 microM, 90.2%, 88.9%, 78.6%, respectively. In a subsequent experiment, male Sprague-Dawley rats (approximately 200 g; n = 5-6) were given a 100-mg intragastric dose of a cocoa extract. Blood was collected over a 4-hr time period. Epicatechin and catechin, and the dimers (-)-epicatechin-(4beta>8)-epicatechin (Dimer B2) and (-)-epicatechin-(4beta>6)-epicatechin (Dimer B5) were detected in the plasma with concentrations of 6.4 microM, and 217.6, 248.2, and 55.4 nM, respectively. Plasma antioxidant capacity (as measured by the total antioxidant potential [TRAP] assay) was elevated (P < 0.05) between 30 and 240 min following the cocoa extract feeding. Erythrocytes obtained from the cocoa extract-fed animals showed an enhanced resistance to hemolysis (P < 0.05). This enhanced resistance was also observed when erythrocytes from animals fed the cocoa extract were mixed with plasma obtained from animals given water only. Conversely, plasma obtained from rats given the cocoa extract improved the resistance of erythrocytes obtained from rats given water only. These results show cocoa flavanols and procyanidins can provide membrane protective effects. 相似文献