全文获取类型
收费全文 | 12565篇 |
免费 | 1104篇 |
国内免费 | 3篇 |
出版年
2023年 | 43篇 |
2022年 | 127篇 |
2021年 | 257篇 |
2020年 | 150篇 |
2019年 | 169篇 |
2018年 | 232篇 |
2017年 | 186篇 |
2016年 | 317篇 |
2015年 | 582篇 |
2014年 | 572篇 |
2013年 | 739篇 |
2012年 | 1003篇 |
2011年 | 1045篇 |
2010年 | 635篇 |
2009年 | 546篇 |
2008年 | 864篇 |
2007年 | 866篇 |
2006年 | 779篇 |
2005年 | 725篇 |
2004年 | 774篇 |
2003年 | 640篇 |
2002年 | 650篇 |
2001年 | 115篇 |
2000年 | 72篇 |
1999年 | 109篇 |
1998年 | 167篇 |
1997年 | 117篇 |
1996年 | 112篇 |
1995年 | 97篇 |
1994年 | 85篇 |
1993年 | 77篇 |
1992年 | 60篇 |
1991年 | 69篇 |
1990年 | 49篇 |
1989年 | 45篇 |
1988年 | 49篇 |
1987年 | 44篇 |
1986年 | 57篇 |
1985年 | 44篇 |
1984年 | 48篇 |
1983年 | 46篇 |
1982年 | 40篇 |
1981年 | 37篇 |
1980年 | 36篇 |
1979年 | 26篇 |
1978年 | 24篇 |
1977年 | 21篇 |
1976年 | 24篇 |
1974年 | 16篇 |
1973年 | 14篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
151.
Mary C. O'Sullivan Qibing Zhou Zhili Li Timothy B. Durham Donna Rattendi Schennella Lane Cyrus J. Bacchi 《Bioorganic & medicinal chemistry》1997,5(12):2145-2155
Trypanothione reductase (TR) occurs exclusively in trypanosomes and leishmania, which are the etiological agents of many diseases. TR plays a vital role in the antioxidant defenses of these parasites and inhibitors of TR have potential as antitrypanosomal agents. We describe the syntheses of several spermine and spermidine derivatives and the inhibiting effects of these compounds on T. cruzi TR. All of the inhibiting compounds displayed competitive inhibition of TR-mediated reduction of trypanothione disulfide. The three most effective compounds studied were N4,N8-bis(3-phenylpropyl)spermine (12), N4,N8-bis(2-naphthylmethyl)spermine (14), and N1,N8-bis(2-naphthylmethyl)spermidine (21), with Ki values of 3.5, 5.5 and 9.5 μM, respectively. Compounds 12, 14, and 21 were found to be potent trypanocides in vitro with IC50 values ranging from 0.19 to 0.83 μM against four T. brucei ssp. strains. However, these compounds did not prolong the lives of mice infected with trypanosomes. This work indicates that certain polyamine derivatives which target a unique pathway in Trypanosomatidae have potential as antitrypanosomal agents. 相似文献
152.
Yarus Sinai Greenberg Norman M. Wei Yongli Whitsett Jeffrey A. Weaver Timothy E. Rosen Jeffrey M. 《Transgenic research》1997,6(1):51-57
Because of the apparent clinical importance of human pulmonary surfactant B (SP-B), the expression of SP-B was directed to the mammary gland of transgenic mice using previously characterized rat whey acidic protein (WAP) regulatory sequences. rWAP/SP-B mRNA was expressed specifically in the mammary gland, and ranged from 1 to 5% of the endogenous WAP mRNA levels. SP-B was detected immunologically in both tissue and milk. The transgene product had an apparent molecular weight of 40--45 kDa, corresponding to the predicted size of the SP-B proprotein. Incubation of an SP-B-enriched fraction of milk with cathepsin D in vitro produced 20--25 kDa species, consistent with cleavage of the amino terminal domain by cathepsin D. This was confirmed using antibodies specific to the carboxy-terminal domain of SP-B. However, the appearance of only the SP-B proprotein in milk suggests that cathepsin D is not involved in the in vivo processing of SP-B. The SP-B proprotein can be expressed in milk of transgenic mice without any observed effects on mammary gland morphology or lactation 相似文献
153.
Timothy S. McClintock Fuqiang Xu Jorge Quintero Anne M. Gress Teresa M. Landers 《Journal of neurochemistry》1997,68(6):2248-2254
Abstract: We have isolated from an American lobster ( Homarus americanus ) olfactory organ cDNA library a clone, hGαq , with >80% identity to mammalian and arthropod Gαq sequences. In brain and olfactory organ, hGαq mRNA was expressed predominantly in neurons, including virtually all the neuronal cell body clusters of the brain. Gαq protein was also expressed broadly, appearing on western blots as a single band of 46 kDa in brain, eyestalk, pereiopod, dactyl, tail muscle, olfactory organ, and aesthetasc hairs. These results suggest that hGαq plays a role in a wide variety of signal transduction events. Its presence in the olfactory aesthetasc hairs, which are almost pure preparations of the outer dendrites of the olfactory receptor neurons, the expression of a single hGαq mRNA species (6 kb) in the olfactory organ, and the localization of hGαq mRNA predominantly in the olfactory receptor neurons of the olfactory organ strongly suggest that one function of hGαq is to mediate olfactory transduction. 相似文献
154.
Pickar Joel G.; Mattson John P.; Lloyd Steve; Musch Timothy I. 《Journal of applied physiology》1997,83(1):323
Pickar, Joel G., John P. Mattson, Steve Lloyd, and TimothyI. Musch. Decreased[3H]ouabainbinding sites in skeletal muscle of rats with chronic heart failure.J. Appl. Physiol. 83(1): 323-329, 1997.Abnormalities intrinsic to skeletal muscle are thought tocontribute to decrements in exercise capacity found in individualswith chronic heart failure (CHF).Na+-K+-adenosinetriphosphatase(the Na+ pump) is essential formaintaining muscle excitability and contractility. Therefore, weinvestigated the possibility that the number and affinity ofNa+ pumps in locomotor muscles ofrats with CHF are decreased. Myocardial infarction (MI) was induced in8 rats, and a sham operation was performed in 12 rats. The degree ofCHF was assessed ~180 days after surgery. Soleus and plantarismuscles were harvested, and Na+pumps were quantified by using a[3H]ouabain bindingassay. At the time of muscle harvest, MI and sham-operated rats weresimilar in age (458 ± 54 vs. 447 ± 34 days old, respectively).Compared with their sham-operated counterparts, MI rats had asignificant amount of heart failure, right ventricular-to-body weightratio was greater (48%), and the presence of pulmonary congestion wassuggested by an elevated lung-to-body weight ratio (29%). Leftventricular end-diastolic pressure was significantly increased in theMI rats (11 ± 1 mmHg) compared with the sham-operated controls (1 ± 1 mmHg). In addition, mean arterial blood pressure was lower inthe MI rats compared with their control counterparts. [3H]ouabain bindingsites were reduced 18% in soleus muscle (136 ± 12 vs. 175 ± 13 pmol/g wet wt, MI vs. sham, respectively) and 22% in plantaris muscle(119 ± 12 vs. 147 ± 8 pmol/g wet wt, MI vs. sham,respectively). The affinity of these[3H]ouabain bindingsites was similar for the two groups. The relationship between thereduction in Na+ pump number andthe reduced exercise capacity in individuals with CHF remains to bedetermined. 相似文献
155.
156.
Ewa Sewerynek Mitsushi Abe Russel J. Reiter Lornell R. Barlow-Walden Lidun Chen Timothy J. McCabe Linda J. Roman Beatriz Diaz-Lopez 《Journal of cellular biochemistry》1995,58(4):436-444
The protective effect of melatonin on lipopolysaccharide (LPS)-induced oxidative damage in phenobarbital-treated rats was measured using the following parameters: changes in total glutathione (tGSH) concentration, levels of oxidized glutathione (GSSG), the activity of the antioxidant enzyme glutathione peroxidase (GSH-PX) in both brain and liver, and the content of cytochrome P450 reductase in liver. Melatonin was injected intraperitoneally (ip, 4mg/kg BW) every hour for 4 h after LPS administration; control animals received 4 injections of diluent. LPS was given (ip, 4 mg/kg) 6 h before the animals were killed. Prior to the LPS injection, animals were pretreated with phenobarbital (PB), a stimulator of cytochrome P450 reductase, at a dose 80 mg/kg BW ip for 3 consecutive days. One group of animals received LPS together with Nw-nitro-L-arginine methyl ester (L-NAME), a blocker of nitric oxide synthase (NOS) (for 4 days given in drinking water at a concentration of 50 mM). In liver, PB, in all groups, increased significantly both the concentration of tGSH and the activity of GSH-PX. When the animals were injected with LPS the levels of tGSH and GSSG were significantly higher compared with other groups while melatonin and L-NAME significantly enhanced tGSH when compared with that in the LPS-treated rats. Melatonin alone reduced GSSG levels and enhanced the activity of GSH-PX in LPS-treated animals. Additionally, LPS diminished the content of cytochrome P450 reductase with this effect being largely prevented by L-NAME administration. Melatonin did not change the content of P450 either in PB- or LPS-treated animals. In brain, melatonin and L-NAME increased both tGSH levels and the activity of GSH-PX in LPS-treated animals. The results suggest that melatonin protects against LPS-induced oxidative toxicity in PB-treated animals in both liver and brain, and the findings are consistent with previously published observations related to the antioxidant activity of the pineal hormone. 相似文献
157.
Michael Hoppert Timothy J. Mahony Frank Mayer David J. Miller 《Archives of microbiology》1995,163(4):300-306
The hydroxylamine oxidoreductase from Nitrosomonas europaea was prepared to apparent electrophoretic homogeneity. Electron microscopy of negatively stained preparations of the sample revealed an overall diameter of about 8.8 nm of the enzyme particle. The native structure was determined as a tetrahedron-like assembly of identical subunits exhibiting four protein masses.Abbreviations
ESI
Electron spectroscopic imaging
-
HAO
Hydroxylamine oxidoreductase 相似文献
158.
Five models have been built by the ICM method for the Comparative Modeling section of the Meeting on the Critical Assessment of Techniques for Protein Structure Prediction. The targets have homologous proteins with known three-dimensional structure with sequence identity ranging from 25 to 77%. After alignment of the target sequence with the related three-dimensional structure, the modeling procedure consists of two subproblems: side-chain prediction and loop prediction. The ICM method approaches these problems with the following steps: (1) a starting model is created based on the homologous structure with the conserved portion fixed and the noncon-served portion having standard covalent geometry and free torsion angles; (2) the Biased Probability Monte Carlo (BPMC) procedure is applied to search the subspaces of either all the nonconservative side-chain torsion angles or torsion angles in a loop backbone and surrounding side chains. A special algorithm was designed to generate low-energy loop deformations. The BPMC procedure globally optimizes the energy function consisting of ECEPP/3 and solvation energy terms. Comparison of the predictions with the NMR or crystallographic solutions reveals a high proportion of correctly predicted side chains. The loops were not correctly predicted because imprinted distortions of the backbone increased the energy of the near-native conformation and thus made the solution unrecognizable. Interestingly, the energy terms were found to be reliable and the sampling of conformational space sufficient. The implications of this finding for the strategies of future comparative modeling are discussed. © 1995 Wiley-Liss, Inc. 相似文献
159.
Kenneth J. Snibson David Woodcock Jacqueline M. Orian Malcolm R. Brandon Timothy E. Adams 《Transgenic research》1995,4(2):114-122
We have examined transgene methylation in the DNA from the livers of a pedigree of mice carrying three copies of an integrated MToGH1 transgene. Utilizing the methylation-sensitive isoschizomersMsp I andHpa II, Southern blot analysis revealed that all second generation animals derived from a transgenic female had hypermethylated DNA, whereas first generation animals sired by a transgenic male displayed a range of methylation phenotypes ranging from no methylation to hypermethylation of the transgene sequences. Of the mice that exhibited hypermethylation of the transgene in CpG dinucleotides (CmCGG), a minority of these animals also exhibited apparent CpC methylation (i.e. inhibition ofMsp I cutting, presumably blocked by methylation of the outer C of CCGG). Methylation was also examined in the inner C of CC(A/T)GG sequences in the MToGH1 transgene using the isoschizomer pairBstN I andEcoR II. A minority of MToGH1 animals in the F1 generation showed clear evidence of methylation in these sites as well as in the inner and outer Cs of CCGG sites. An examination of MToGH1 expression in terms of oGH levels in serum revealed that there was a high degree of variation in the levels of circulating oGH between animals of this pedigree. There was a weak inverse relationship between the serum level of oGH and the extent of methylation of the transgene. In particular, mice exhibiting CpC together with CpG methylation were found to have very low levels of circulating oGH. Our results highlight the nature and complexity of epigenetic factors associated with transgene sequences which may ultimately influence expression of introduced genes in the mammalian genome. 相似文献
160.
A discrete, environmentally coupled, size-specific model of microbial population dynamics in continuous culture is presented. It is mathematically simpler than other models based on similar assumptions and lends itself to numerical and analytic solutions. It displays several phenomena which have been reported in the experimental literature but which are not well understood; specifically, a loose relationship between biomass and numbers (i.e., a time lag between mass growth and cell division) and a critical damping of biomass while numbers continue to oscillate. In addition, the model provides several new predictions: The stable biomass distribution is independent of the environmental factors considered in the model and uniformly distributes the biomass among the size classes. The rate of approach to stability and the frequency of waves through the size distributions are a function of the flow rate and the variance in rate of growth and size at division. The model should provide a useful basis for studying the effects of size specificity on the dynamics of microbial populations cultured in chemostats. 相似文献