全文获取类型
收费全文 | 2350篇 |
免费 | 158篇 |
国内免费 | 4篇 |
专业分类
2512篇 |
出版年
2023年 | 19篇 |
2022年 | 36篇 |
2021年 | 54篇 |
2020年 | 40篇 |
2019年 | 35篇 |
2018年 | 57篇 |
2017年 | 69篇 |
2016年 | 96篇 |
2015年 | 134篇 |
2014年 | 166篇 |
2013年 | 152篇 |
2012年 | 186篇 |
2011年 | 186篇 |
2010年 | 129篇 |
2009年 | 91篇 |
2008年 | 135篇 |
2007年 | 116篇 |
2006年 | 128篇 |
2005年 | 122篇 |
2004年 | 113篇 |
2003年 | 96篇 |
2002年 | 69篇 |
2001年 | 21篇 |
2000年 | 16篇 |
1999年 | 26篇 |
1998年 | 23篇 |
1997年 | 16篇 |
1996年 | 13篇 |
1995年 | 13篇 |
1994年 | 17篇 |
1993年 | 3篇 |
1992年 | 17篇 |
1991年 | 9篇 |
1990年 | 7篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 11篇 |
1986年 | 5篇 |
1985年 | 5篇 |
1984年 | 3篇 |
1983年 | 6篇 |
1982年 | 9篇 |
1981年 | 6篇 |
1980年 | 4篇 |
1979年 | 6篇 |
1978年 | 11篇 |
1977年 | 4篇 |
1976年 | 4篇 |
1975年 | 4篇 |
1974年 | 7篇 |
排序方式: 共有2512条查询结果,搜索用时 0 毫秒
991.
Tomás M Lázaro-Diéguez F Durán JM Marín P Renau-Piqueras J Egea G 《Journal of neurochemistry》2003,87(1):220-229
Ethanol induces severe alterations in membrane trafficking in hepatocytes and astrocytes, the molecular basis of which is unclear. One of the main candidates is the cytoskeleton and the molecular components that regulate its organization and dynamics. Here, we examine the effect of chronic exposure to ethanol on the organization and dynamics of actin and microtubule cytoskeletons and glucose uptake in rat astrocytes. Ethanol-treated cells cultured in either the presence or absence of fetal calf serum showed a significant increase in 2-deoxyglucose uptake. Ethanol also caused alterations in actin organization, consisting of the dissolution of stress fibres and the appearance of circular filaments beneath the plasma membrane. When lysophosphatidic acid (LPA), which is a normal constituent of serum and a potent intercellular lipid mediator with growth factor and actin rearrangement activities, was added to ethanol-treated astrocytes cultured without fetal calf serum, it induced the re-appearance of actin stress fibres and the normalization of 2-deoxyglucose uptake. Furthermore, ethanol also perturbed the microtubule dynamics, which delayed the recovery of the normal microtubule organization following removal of the microtubule-disrupting agent nocodazole. Again, pre-treatment with LPA prevented this alteration. Ethanol-treated rodent fibroblast NIH3T3 cells that constitutively express an activated Rho mutant protein (GTP-bound form) were insensitive to ethanol, as they showed no alteration either in actin stress-fibre organization or in 2-deoxyglucose uptake. We discuss the putative signalling targets by which ethanol could alter the cytoskeleton and hexose uptake and the cytoprotective effect of LPA against ethanol-induced damages. The latter opens the possibility that LPA or a similar non-hydrolysable lipid derivative could be used as a cytoprotective agent against the noxious effects of ethanol. 相似文献
992.
Carole D. Mitnick Molly F. Franke Michael L. Rich Felix A. Alcantara Viru Sasha C. Appleton Sidney S. Atwood Jaime N. Bayona Cesar A. Bonilla Katiuska Chalco Hamish S. F. Fraser Jennifer J. Furin Dalia Guerra Rocio M. Hurtado Keith Joseph Karim Llaro Lorena Mestanza Joia S. Mukherjee Maribel Mu?oz Eda Palacios Epifanio Sanchez Kwonjune J. Seung Sonya S. Shin Alexander Sloutsky Arielle W. Tolman Mercedes C. Becerra 《PloS one》2013,8(3)
Rationale
A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen.Objectives
This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort.Methods
This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death.Measurements and Main Results
In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93).Conclusions
The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB. 相似文献993.
Jaime Guillén 《生物化学与生物物理学报:生物膜》2010,1798(3):327-337
We have identified a membrane-active region in the HCV NS4B protein by studying membrane rupture induced by a NS4B-derived peptide library on model membranes. This segment corresponds to one of two previously predicted amphipathic helix and define it as a new membrane association domain. We report the binding and interaction with model membranes of a peptide patterned after this segment, peptide NS4BH2, and show that NS4BH2 strongly partitions into phospholipid membranes, interacts with them, and is located in a shallow position in the membrane. Furthermore, changes in the primary sequence cause the disruption of the hydrophobicity along the structure and prevent the resulting peptide from interacting with the membrane. Our results suggest that the region where the NS4BH2 is located might have an essential role in the membrane replication and/or assembly of the viral particle through the modulation of the replication complex. Our findings therefore identify an important region in the HCV NS4B protein which might be implicated in the HCV life cycle and possibly in the formation of the membranous web. 相似文献
994.
995.
Previous studies using mitochondrial markers and microsatellites revealed a new highly differentiated Atlantic lineage of brown trout in the Iberian Peninsula mainly confined to the Upper Duero Basin. Data suggest that Duero lineage (DU) hybridizes with previously described Atlantic (AT) lineages in that basin. However, nuclear and cytogenetic data suggest another hybrid zone between divergent lineages might be present in the Miño Basin, another Atlantic drainage located to the north. Here, we extend those studies by analyzing the mitochondrial haplotype variability of brown trout populations from northwestern Spain, a poorly studied area, to obtain an accurate picture of the distribution of DU. Results show that the DU haplotype is fixed in several isolated populations from the upper course of the Miño River and its main tributary the Sil River. DU haplotype co-occurs with two related AT haplotypes in the Miño Basin revealing a new secondary contact zone. The identification of both longtime stable populations of DU and several other populations showing introgression with widespread AT lineages will be useful for the management and conservation of such an endemic lineage. 相似文献
996.
Pilar Regueiro Jaime Monreal Ricardo S. Díaz Felipe Sierra 《Journal of neurochemistry》1996,67(5):2146-2154
Abstract: Myelin vesicles, reconstituted liposomes with proteolipid protein (PLP), the main protein component of myelin, and electrophysiological patch-clamp are potentially powerful tools to study the role of myelin in functional ionic channels. However, technical difficulties in the vesiculation of myelin and the small size of the vesicles obtained do not permit the application of micropipettes for current recordings. From a suspension of purified myelin we have prepared oligolamellar vesicles (mean diameter of 144 nm) using the so-called French pressure system. From this preparation we obtained giant myelin vesicles ∼10 µm in mean diameter, using a dehydration-rehydration procedure. Qualitative analysis of proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed no significant loss of any component in these vesicles due to pressure, in comparison with non-vesiculated myelin. A way of preparing giant liposomes of ∼80–100 µm and proteoliposomes of ∼30 µm in mean diameter, using the same dehydration-rehydration procedure, is also reported. Reconstitution of purified PLP in giant liposomes was confirmed by fluorescent labeling of PLP and by fluorescence microscopy. The current recordings from these vesicles prove the validity of these methods and provide significant evidence of the existence of ionic channels in myelin membranes and the possibility that PLP functions as a channel. The physiological significance and characterization of these channels remain yet unresolved. These results have a special significance for elucidating the molecular role of myelin in the regulation of neural activity and in the brain ion microenvironment. 相似文献
997.
Summary Specific proteolytic activities are known to be induced in Escherichia coli following irradiation. Consequently it seemed of interest to investigate whether variations in proteinase activities occur in yeast.Among the five most well known proteinases of Saccharomyces cerevisiae, we have found that proteinase B activity increases up to three times in wild-type RAD
+
yeast cells after a dose of 50 Jm-2 of 254 nm ultraviolet light (40% survival). Carboxypeptidase Y and aminopeptidase I (leucin aminopeptidase) activities were only moderately increased. Proteinase A activity was only slightly enhanced, while aminopeptidase II (lysin aminopeptidase) was unaffected in both RAD
+
strains studied.The observed post UV-increase in proteinase B activity was inhibited by cycloheximide and was dose dependent. Increases in proteinase B levels were independent of the activation method used to destroy the proteinase B-inhibitor complex present in the crude yeast extracts.A standard method for comparison of the postirradiation levels among different proteinases, strains and methods of activation is presented.Abbreviations UV
Ultraviolet
- BRIJ-35
Polyoxyethylene-23-lauryl ether
- EDTA
Ethylene diamine tetraacetic acid
- EGTA
Ethylene glycol bis (-aminoethyl ether) tetraacetic acid
- MOPS
3-[N-morpholine]propansulfonic acid
- HEPES
N-2-Hydroxyethylpiperazine-N-2-ethansulfonic acid
- Tris
Tris(hydroxy methyl)amino methane
- BTPNA
N-benzoyl-L-tyrosine-p-nitroanilide
- CP.Y
Carboxypeptidase Y
- Leu.AP
Leucin amino peptidase
- Lys.AP
Lysin amino peptidase
- DMFA
Dimethyl formamide
- CHX
Cycloheximide
- PMSF
Phenylmethyl sulfonyl fluoride
- TCA
Trichloroacetic acid
Code Number of Enzymes EC. 3.4.23.8
Proteinase A
- EC. 3.4.22.9
Proteinase B
- EC. 3.4.12.8
Carboxypeptidase Y
- EC. 3.4.24.4
Thermolysin
- EC. 3.4.23.1
Pepsin A 相似文献
998.
The preference in the choice of hibernacula of the convergent lady beetle,Hippodamia convergens Guérin-Meneville, was investigated with regard to morphological aspects of 2 introduced range grasses,Panicum coloratum (L.), andEragrostis curvula (Schrad.) Beetles strongly preferred tussocks with a ratio in the range of 1.0–3.0 stems per cm2 for lovegrass. Preference for klein grass tussocks ranging from 110–130 stems/clump was found. No preference was shown for a particular tussock circumference. It was demonstrated that tussocks could successfully be designated as suitable for beetle aggregation. 相似文献
999.
The detection of spatial variation in macroinvertebrate drift depends on the spatial scale of investigation in streams of the La Selva Biological Station, Costa Rica. Drift samples were taken in a spatially nested design, with two streams, two reaches per stream, two riffles per reach, and four replicate samples per riffle. Drift showed little variation among streams, but varied significantly at the scales of reach and riffle, with variation among samples also high. In addition, sampling took place at two temporal scales: diel and at two different periods that differed in rainfall conditions. Drift diel periodicity was a clear pattern, while only density of individuals varied among sampling periods. This is the first study of macroinvertebrate drift at multiple spatial scales, despite the recognition that multi‐scale studies are essential for a more complete understanding of community patterns and processes. 相似文献
1000.
Norma de Magalhães Erismann Ana M. Fernandez Jaime Baeza Juanita Freer Hector Mansilla Nelson Duran 《Biotechnology letters》1990,12(4):305-308
Summary We report the delignification ofPinus
radiata D Don,Eucalyptus
globulus andEucalyptus
grandis woods (formic acid treated and untreated) by 2 h treatment with a hemin/hydrogen peroxide system. The untreated chips and sawdust ofE.
globulus were 30% and 50% delignified respectively. No significant effects were found forP.
radiata sawdust;P.
radiata treated chips (organosolv pulp) did not show any further delignification upon hemin/peroxide action, 25% delignification was achieved in untreated chips. In the case ofE.
grandis untreated wood the delignification was better in sawdust than in chips, but in smaller percentage than in the otherEucalyptus species. This relation is maintained in substrates, treated with formic acid or untreated. The delignification of chips in both species ofEucalyptus was improved when they were pre-treated with formic acid. The loss of lignin in theE.
grandis andE.
globulus sawdust (pre-treated with formic acid) was 79% and 75% respectively. 相似文献