全文获取类型
收费全文 | 7199篇 |
免费 | 536篇 |
国内免费 | 1篇 |
出版年
2023年 | 44篇 |
2022年 | 106篇 |
2021年 | 234篇 |
2020年 | 148篇 |
2019年 | 179篇 |
2018年 | 236篇 |
2017年 | 200篇 |
2016年 | 314篇 |
2015年 | 395篇 |
2014年 | 478篇 |
2013年 | 494篇 |
2012年 | 539篇 |
2011年 | 518篇 |
2010年 | 305篇 |
2009年 | 280篇 |
2008年 | 383篇 |
2007年 | 329篇 |
2006年 | 289篇 |
2005年 | 254篇 |
2004年 | 227篇 |
2003年 | 204篇 |
2002年 | 187篇 |
2001年 | 139篇 |
2000年 | 106篇 |
1999年 | 104篇 |
1998年 | 54篇 |
1997年 | 45篇 |
1996年 | 46篇 |
1995年 | 36篇 |
1994年 | 40篇 |
1993年 | 31篇 |
1992年 | 59篇 |
1991年 | 64篇 |
1990年 | 51篇 |
1989年 | 44篇 |
1988年 | 39篇 |
1987年 | 42篇 |
1986年 | 57篇 |
1985年 | 37篇 |
1984年 | 37篇 |
1983年 | 30篇 |
1982年 | 27篇 |
1981年 | 25篇 |
1980年 | 21篇 |
1979年 | 20篇 |
1978年 | 29篇 |
1977年 | 28篇 |
1976年 | 18篇 |
1975年 | 32篇 |
1974年 | 21篇 |
排序方式: 共有7736条查询结果,搜索用时 593 毫秒
971.
Raices M Verdun RE Compton SA Haggblom CI Griffith JD Dillin A Karlseder J 《Cell》2008,132(5):745-757
Single-strand extensions of the G strand of telomeres are known to be critical for chromosome-end protection and length regulation. Here, we report that in C. elegans, chromosome termini possess 3' G-strand overhangs as well as 5' C-strand overhangs. C tails are as abundant as G tails and are generated by a well-regulated process. These two classes of overhangs are bound by two single-stranded DNA binding proteins, CeOB1 and CeOB2, which exhibit specificity for G-rich or C-rich telomeric DNA. Strains of worms deleted for CeOB1 have elongated telomeres as well as extended G tails, whereas CeOB2 deficiency leads to telomere-length heterogeneity. Both CeOB1 and CeOB2 contain OB (oligo-saccharide/oligo-nucleotide binding) folds, which exhibit structural similarity to the second and first OB folds of the mammalian telomere binding protein hPOT1, respectively. Our results suggest that C. elegans telomere homeostasis relies on a novel mechanism that involves 5' and 3' single-stranded termini. 相似文献
972.
Costa NJ Bombardieri CR Kuribayashi JS de Camargo MM Andrade LH Kagohara E Espósito BP 《化学与生物多样性》2008,5(10):2156-2159
It is shown that metal complexes of the biodegradable ligand ethylenediaminedisuccinic acid (edds) present antimicrobial activity towards fungi and bacteria. [Cd(edds)], in particular, is more toxic than free Cd2+ to Aspergillus niger, behaving as a 'Trojan Horse' in the facilitated delivery of the toxic metal into the fungus. 相似文献
973.
Is the failing heart out of fuel or a worn engine running rich? A study of mitochondria in old spontaneously hypertensive rats 总被引:1,自引:0,他引:1
Jüllig M Hickey AJ Chai CC Skea GL Middleditch MJ Costa S Choong SY Philips AR Cooper GJ 《Proteomics》2008,8(12):2556-2572
Hypertension now affects about 600 million people worldwide and is a leading cause of death in the Western world. The spontaneously hypertensive rat (SHR), provides a useful model to investigate hypertensive heart failure (HF). The SHR model replicates the clinical progression of hypertension in humans, wherein early development of hypertension is followed by a long stable period of compensated cardiac hypertrophy that slowly progresses to HF. Although the hypertensive failing heart generally shows increased substrate preference towards glucose and impaired mitochondrial function, the cause-and-effect relationship between these characteristics is incompletely understood. To explore these pathogenic processes, we compared cardiac mitochondrial proteomes of 20-month-old SHR and Wistar-Kyoto controls by iTRAQ-labelling combined with multidimensional LC/MS/MS. Of 137 high-scoring proteins identified, 79 differed between groups. Changes were apparent in several metabolic pathways, chaperone and antioxidant systems, and multiple subunits of the oxidative phosphorylation complexes were increased (complexes I, III and IV) or decreased (complexes II and V) in SHR heart mitochondria. Respiration assays on skinned fibres and isolated mitochondria showed markedly lower respiratory capacity on succinate. Enzyme activity assays often also showed mismatches between increased protein expression and activities suggesting elevated protein expression may be compensatory in the face of pathological stress. 相似文献
974.
Cuervo P Cupolillo E Britto C González LJ E Silva-Filho FC Lopes LC Domont GB De Jesus JB 《Journal of Proteomics》2008,71(1):109-122
A comparative analysis of proteomic maps of long-term grown and fresh clinical Trichomonas vaginalis isolates exhibiting low and high virulence phenotypes, respectively, was performed using two-dimensional gel electrophoresis and mass spectrometry. Of 29 protein spots differentially expressed between the isolates, 19 were over-expressed in the isolate exhibiting high virulence phenotype: proteins associated with cytoskeletal dynamics, such as coronin and several isoforms of actin, as well as proteins involved in signal transduction, protein turnover, proteolysis, and energetic and polyamine metabolisms were identified. Some malate dehydrogenase, fructose-1,6-bisphosphate aldolase and ornithine cyclodeamidase isoforms were exclusively expressed by the highly virulent isolate. During interaction assays with VEC, parasites exhibiting high virulence phenotype rapidly adhered and switched to amoeboid forms. In contrast, low adhesion and no morphological transformation were observed in parasites displaying low virulence phenotype. Our findings demonstrate that expression of specific proteins by high and low virulence parasites could be associated with the ability of each isolate to undergo morphological transformation and interact with host cells. Such data represent an important step towards understanding of the complex interaction network of proteins that participate in the mechanism of pathogenesis of this protozoan. 相似文献
975.
Matilde Marchi Angela D'Antoni Ivan Formentini Riccardo Parra Riccardo Brambilla Gian Michele Ratto Mario Costa 《PloS one》2008,3(12)
The Extracellular Regulated Kinase 1 and 2 transduce a variety of extracellular stimuli regulating processes as diverse as proliferation, differentiation and synaptic plasticity. Once activated in the cytoplasm, ERK1 and ERK2 translocate into the nucleus and interact with nuclear substrates to induce specific programs of gene expression. ERK1/2 share 85% of aminoacid identity and all known functional domains and thence they have been considered functionally equivalent until recent studies found that the ablation of either ERK1 or ERK2 causes dramatically different phenotypes. To search a molecular justification of this dichotomy we investigated whether the different functions of ERK1 and 2 might depend on the properties of their cytoplasmic-nuclear trafficking. Since in the nucleus ERK1/2 is predominantly inactivated, the maintenance of a constant level of nuclear activity requires continuous shuttling of activated protein from the cytoplasm. For this reason, different nuclear-cytoplasmic trafficking of ERK1 and 2 would cause a differential signalling capability. We have characterised the trafficking of fluorescently tagged ERK1 and ERK2 by means of time-lapse imaging in living cells. Surprisingly, we found that ERK1 shuttles between the nucleus and cytoplasm at a much slower rate than ERK2. This difference is caused by a domain of ERK1 located at its N-terminus since the progressive deletion of these residues converted the shuttling features of ERK1 into those of ERK2. Conversely, the fusion of this ERK1 sequence at the N-terminus of ERK2 slowed down its shuttling to a similar value found for ERK1. Finally, computational, biochemical and cellular studies indicated that the reduced nuclear shuttling of ERK1 causes a strong reduction of its nuclear phosphorylation compared to ERK2, leading to a reduced capability of ERK1 to carry proliferative signals to the nucleus. This mechanism significantly contributes to the differential ability of ERK1 and 2 to generate an overall signalling output. 相似文献
976.
Blanco YC Farias AS Goelnitz U Lopes SC Arrais-Silva WW Carvalho BO Amino R Wunderlich G Santos LM Giorgio S Costa FT 《PloS one》2008,3(9):e3126
Background
Cerebral malaria (CM) is a syndrome characterized by neurological signs, seizures and coma. Despite the fact that CM presents similarities with cerebral stroke, few studies have focused on new supportive therapies for the disease. Hyperbaric oxygen (HBO) therapy has been successfully used in patients with numerous brain disorders such as stroke, migraine and atherosclerosis.Methodology/Principal Findings
C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were exposed to daily doses of HBO (100% O2, 3.0 ATA, 1–2 h per day) in conditions well-tolerated by humans and animals, before or after parasite establishment. Cumulative survival analyses demonstrated that HBO therapy protected 50% of PbA-infected mice and delayed CM-specific neurological signs when administrated after patent parasitemia. Pressurized oxygen therapy reduced peripheral parasitemia, expression of TNF-α, IFN-γ and IL-10 mRNA levels and percentage of γδ and αβ CD4+ and CD8+ T lymphocytes sequestered in mice brains, thus resulting in a reduction of blood-brain barrier (BBB) dysfunction and hypothermia.Conclusions/Significance
The data presented here is the first indication that HBO treatment could be used as supportive therapy, perhaps in association with neuroprotective drugs, to prevent CM clinical outcomes, including death. 相似文献977.
978.
Guizzetti M Moore NH Giordano G Costa LG 《The Journal of biological chemistry》2008,283(46):31884-31897
Astrocytes have been shown to release factors that have promoting or inhibiting effects on neuronal development. However, mechanisms controlling the release of such factors from astrocytes are not well established. Astrocytes express muscarinic receptors whose activation stimulates a robust intracellular signaling, although the role of these receptors in glial cells is not well understood. Acetylcholine and acetylcholine receptors are present in the brain before synaptogenesis occurs and are believed to be involved in neuronal maturation. The present study was undertaken to investigate whether stimulation of muscarinic receptors in astrocytes would modulate neurite outgrowth in hippocampal neurons. Rat hippocampal neurons, co-cultured with rat cortical astrocytes previously exposed to the cholinergic agonist carbachol, displayed longer neurites. The effect of carbachol in astrocytes was due to the activation of M3 muscarinic receptors. Exposure of astrocytes to carbachol increased the expression of the extracellular matrix proteins fibronectin and laminin-1 in these cells. This effect was mediated in part by an increase in laminin-1 and fibronectin mRNA levels and in part by the up-regulation of the production and release of plasminogen activator inhibitor-1, an inhibitor of the proteolytic degradation of the extracellular matrix. The inhibition of fibronectin activity strongly reduced the effect of carbachol on the elongation of all the neurites, whereas inhibition of laminin-1 activity reduced the elongation of minor neurites only. Plasminogen activator inhibitor-1 also induced neurite elongation through a direct effect on neurons. Taken together, these results demonstrate that cholinergic muscarinic stimulation of astrocytes induces the release of permissive factors that accelerate neuronal development. 相似文献
979.
Lynn PA Chen BN Zagorodnyuk VP Costa M Brookes SJ 《American journal of physiology. Gastrointestinal and liver physiology》2008,295(4):G862-G871
The effects of trinitrobenzene sulfonic acid (TNBS)-induced inflammation on specialized, low-threshold, slowly adapting rectal mechanoreceptors were investigated in the guinea pig. Under isoflurane anesthesia, 300 microl saline or TNBS (15 mg/ml) in 30% ethanol was instilled 7 cm from the anal sphincter. Six or 30 days later, single unit extracellular recordings were made from rectal nerve trunks in flat-sheet in vitro preparations attached to a mechanical tissue stretcher. TNBS treatment caused macroscopic ulceration of the rectal mucosa at 6 days, which fully resolved by 30 days. Muscle contractility was unaffected by TNBS treatment. At 6 days posttreatment, responses of low-threshold rectal mechanoreceptors to circumferential stretch were increased, and the proportion of afferents responding with von Frey hair thresholds 相似文献
980.