全文获取类型
收费全文 | 1619篇 |
免费 | 100篇 |
国内免费 | 2篇 |
出版年
2023年 | 5篇 |
2022年 | 3篇 |
2021年 | 21篇 |
2020年 | 17篇 |
2019年 | 28篇 |
2018年 | 36篇 |
2017年 | 38篇 |
2016年 | 49篇 |
2015年 | 61篇 |
2014年 | 77篇 |
2013年 | 118篇 |
2012年 | 129篇 |
2011年 | 114篇 |
2010年 | 90篇 |
2009年 | 62篇 |
2008年 | 85篇 |
2007年 | 79篇 |
2006年 | 85篇 |
2005年 | 77篇 |
2004年 | 78篇 |
2003年 | 60篇 |
2002年 | 67篇 |
2001年 | 22篇 |
2000年 | 24篇 |
1999年 | 10篇 |
1998年 | 23篇 |
1997年 | 8篇 |
1996年 | 11篇 |
1995年 | 15篇 |
1994年 | 9篇 |
1993年 | 8篇 |
1992年 | 22篇 |
1991年 | 22篇 |
1990年 | 12篇 |
1989年 | 14篇 |
1988年 | 14篇 |
1987年 | 13篇 |
1986年 | 8篇 |
1985年 | 13篇 |
1984年 | 9篇 |
1983年 | 7篇 |
1982年 | 16篇 |
1981年 | 7篇 |
1980年 | 10篇 |
1979年 | 6篇 |
1978年 | 5篇 |
1977年 | 6篇 |
1976年 | 5篇 |
1973年 | 3篇 |
1968年 | 2篇 |
排序方式: 共有1721条查询结果,搜索用时 20 毫秒
61.
Paula Clemente Susana Peralta Alberto Cruz-Bermudez Lucía Echevarría Flavia Fontanesi Antoni Barrientos Miguel A. Fernandez-Moreno Rafael Garesse 《The Journal of biological chemistry》2013,288(12):8321-8331
Cytochrome c oxidase (COX) or complex IV of the mitochondrial respiratory chain plays a fundamental role in energy production of aerobic cells. In humans, COX deficiency is the most frequent cause of mitochondrial encephalomyopathies. Human COX is composed of 13 subunits of dual genetic origin, whose assembly requires an increasing number of nuclear-encoded accessory proteins known as assembly factors. Here, we have identified and characterized human CCDC56, an 11.7-kDa mitochondrial transmembrane protein, as a new factor essential for COX biogenesis. CCDC56 shares sequence similarity with the yeast COX assembly factor Coa3 and was termed hCOA3. hCOA3-silenced cells display a severe COX functional alteration owing to a decreased stability of newly synthesized COX1 and an impairment in the holoenzyme assembly process. We show that hCOA3 physically interacts with both the mitochondrial translation machinery and COX structural subunits. We conclude that hCOA3 stabilizes COX1 co-translationally and promotes its assembly with COX partner subunits. Finally, our results identify hCOA3 as a new candidate when screening for genes responsible for mitochondrial diseases associated with COX deficiency. 相似文献
62.
José M. Pastor Vicente Bernal Manuel Salvador Montserrat Argando?a Carmen Vargas Laszlo Csonka ángel Sevilla José L. Iborra Joaquín J. Nieto Manuel Cánovas 《The Journal of biological chemistry》2013,288(24):17769-17781
Bacterial osmoadaptation involves the cytoplasmic accumulation of compatible solutes to counteract extracellular osmolarity. The halophilic and highly halotolerant bacterium Chromohalobacter salexigens is able to grow up to 3 m NaCl in a minimal medium due to the de novo synthesis of ectoines. This is an osmoregulated pathway that burdens central metabolic routes by quantitatively drawing off TCA cycle intermediaries. Consequently, metabolism in C. salexigens has adapted to support this biosynthetic route. Metabolism of C. salexigens is more efficient at high salinity than at low salinity, as reflected by lower glucose consumption, lower metabolite overflow, and higher biomass yield. At low salinity, by-products (mainly gluconate, pyruvate, and acetate) accumulate extracellularly. Using [1-13C]-, [2-13C]-, [6-13C]-, and [U-13C6]glucose as carbon sources, we were able to determine the main central metabolic pathways involved in ectoines biosynthesis from glucose. C. salexigens uses the Entner-Doudoroff pathway rather than the standard glycolytic pathway for glucose catabolism, and anaplerotic activity is high to replenish the TCA cycle with the intermediaries withdrawn for ectoines biosynthesis. Metabolic flux ratios at low and high salinity were similar, revealing a certain metabolic rigidity, probably due to its specialization to support high biosynthetic fluxes and partially explaining why metabolic yields are so highly affected by salinity. This work represents an important contribution to the elucidation of specific metabolic adaptations in compatible solute-accumulating halophilic bacteria. 相似文献
63.
64.
Christof Nolte Tim Jinks Xinghao Wang María Teresa Martinez Pastor Robb Krumlauf 《Developmental biology》2013
The products of Hox genes function in assigning positional identity along the anterior–posterior body axis during animal development. In mouse embryos, Hox genes located at the 3′ end of HoxA and HoxB complexes are expressed in nested patterns in the progenitors of the secondary heart field during early cardiogenesis and the combined activities of both of these clusters are required for proper looping of the heart. Using Hox bacterial artificial chromosomes (BACs), transposon reporters, and transgenic analyses in mice, we present the identification of several novel enhancers flanking the HoxB complex which can work over a long range to mediate dynamic reporter expression in the endoderm and embryonic heart during development. These enhancers respond to exogenously added retinoic acid and we have identified two retinoic acid response elements (RAREs) within these control modules that play a role in potentiating their regulatory activity. Deletion analysis in HoxB BAC reporters reveals that these control modules, spread throughout the flanking intergenic region, have regulatory activities that overlap with other local enhancers. This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development. Regulatory analysis of the HoxA complex reveals that it also has enhancers in the 3′ flanking region which contain RAREs and have the potential to modulate expression in endoderm and heart tissues. Together, the similarities in their location, enhancer output, and dependence on retinoid signaling suggest that a conserved cis-regulatory cassette located in the 3′ proximal regions adjacent to the HoxA and HoxB complexes evolved to modulate Hox gene expression during mammalian cardiac and endoderm development. This suggests a common regulatory mechanism, whereby the conserved control modules act over a long range on multiple Hox genes to generate nested patterns of HoxA and HoxB expression during cardiogenesis. 相似文献
65.
Julio C. López-Doval Antoni Ginebreda Thierry Caquet Clifford N. Dahm Mira Petrovic Damià Barceló Isabel Muñoz 《Hydrobiologia》2013,719(1):427-450
This review examines information generated over the past decade on the pollution of rivers in regions with a mediterranean-type climate (med-climate). Pollution has clearly increased in the last 100 years and is correlated with the development of industry, agriculture and human population. Important efforts have been made in some med-climate countries in order to characterise the chemical status of rivers. In addition, the number of chemical substances detectable in mediterranean-climate rivers (med-rivers), as well as the limits of detection, have improved from the development of better analytical methods. New substances detected in rivers are gaining attention. We discuss available knowledge regarding real and potential effects of pollutants on the biota and ecosystems in med-rivers, taking into account natural environmental characteristics of these rivers. The extreme seasonal conditions in med-rivers add to the potential risk because these characteristics can enhance pollutant effects. Efforts and policies to prevent or reduce pollution effects on med-rivers are linked to the knowledge about pollution pressures associated with the degree of economic development. Aquatic communities in med-rivers are more sensitive to pollutants because they are exposed to strong natural and human stressors. 相似文献
66.
Anthropogenic global climate change is expected to cause severe range contractions among alpine plants. Alpine areas in the Mediterranean region are of special concern because of the high abundance of endemic species with narrow ranges. This study combined species distribution models, population structure analyses and Bayesian skyline plots to trace the past and future distribution and diversity of Linaria glacialis, an endangered narrow endemic species that inhabits summits of Sierra Nevada (Spain). The results showed that: (i) the habitat of this alpine‐Mediterranean species in Sierra Nevada suffered little changes during glacial and interglacial stages of late Quaternary; (ii) climatic oscillations in the last millennium (Medieval Warm Period and Little Ice Age) moderately affected the demographic trends of L. glacialis; (iii) future warming conditions will cause severe range contractions; and (iv) genetic diversity will not diminish at the same pace as the distribution range. As a consequence of the low population structure of this species, genetic impoverishment in the alpine zones of Sierra Nevada should be limited during range contraction. We conclude that maintenance of large effective population sizes via high mutation rates and high levels of gene flow may promote the resilience of alpine plant species when confronted with global warming. 相似文献
67.
Aleksandra Zambrowicz Monika Timmer Antoni Polanowski Gert Lubec Tadeusz Trziszka 《Amino acids》2013,44(2):315-320
Numerous studies have shown that food proteins may be a source of bioactive peptides. Those peptides are encrypted in the protein sequence. They stay inactive within the parental protein until release by proteolytic enzymes (Mine and Kovacs-Nolan in Worlds Poult Sci J 62(1):87–95, 2006; Hartman and Miesel in Curr Opin Biotechnol 18:163–169, 2007). Once released the bioactive peptides exhibit several biofunctionalities and may serve therapeutic roles in body systems. Opioid peptides, peptides lowering high blood pressure, inhibiting platelet aggregation as well as being carriers of metal ions and peptides with immunostimulatory, antimicrobial and antioxidant activities have been described (Hartman and Miesel in Curr Opin Biotechnol 18:163–169, 2007). The biofunctional abilities of the peptides have therefore aroused a lot of scientific, technological and consumer interest with respect to the role of dietary proteins in controlling and influencing health (Möller et al. in Eur J Nutr 47(4):171–182, 2008). Biopeptides may find wide application in food production, the cosmetics industry as well as in the prevention and treatment of various medical conditions. They are manufactured by chemical and biotechnological methods (Marx in Chem Eng News 83(11):17–24. 2005; Hancock and Sahl in Nat Biotechnol 24(12):1551–1557, 2006). Depending on specific needs (food or pharmaceutical industry) different degrees of peptide purifications are required. This paper discusses the practicability of manufacturing bioactive peptides, especially from food proteins. 相似文献
68.
J Jaramillo-Merchán J Jones J L Ivorra D Pastor M C Viso-León J A Armengól M D Moltó E Geijo-Barrientos S Martínez 《Cell death & disease》2013,4(8):e779
Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain''s white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrow-derived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft. 相似文献
69.
Gemma Navarro Estefania Moreno Jordi Bonaventura Marc Brugarolas Daniel Farré David Aguinaga Josefa Mallol Antoni Cortés Vicent Casadó Carmen Lluís Sergi Ferre Rafael Franco Enric Canela Peter J. McCormick 《PloS one》2013,8(4)
Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D1-like family of dopamine receptors and inputs of aversion coming from neurons containing the D2-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D1 reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D2 receptors function, we present evidence of σ1 receptor molecular and functional interaction with dopamine D2 receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D2 receptors (the long isoform of the D2 receptor) can complex with σ1 receptors, a result that is specific to D2 receptors, as D3 and D4 receptors did not form heteromers. We demonstrate that the σ1-D2 receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to σ1 -D2 receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from σ1 knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D2 receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D1 and D2 receptor containing neurons in the brain. 相似文献
70.