全文获取类型
收费全文 | 625篇 |
免费 | 74篇 |
专业分类
699篇 |
出版年
2024年 | 2篇 |
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 15篇 |
2020年 | 11篇 |
2019年 | 18篇 |
2018年 | 23篇 |
2017年 | 25篇 |
2016年 | 25篇 |
2015年 | 30篇 |
2014年 | 30篇 |
2013年 | 39篇 |
2012年 | 35篇 |
2011年 | 40篇 |
2010年 | 33篇 |
2009年 | 25篇 |
2008年 | 26篇 |
2007年 | 36篇 |
2006年 | 26篇 |
2005年 | 27篇 |
2004年 | 24篇 |
2003年 | 16篇 |
2002年 | 15篇 |
2001年 | 14篇 |
2000年 | 15篇 |
1999年 | 23篇 |
1998年 | 18篇 |
1997年 | 9篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 6篇 |
1993年 | 11篇 |
1992年 | 12篇 |
1991年 | 11篇 |
1990年 | 9篇 |
1989年 | 6篇 |
1988年 | 5篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1967年 | 2篇 |
1964年 | 1篇 |
排序方式: 共有699条查询结果,搜索用时 15 毫秒
91.
P. Marcos R. Coveas J.A. Narvez G. Tramu J.A. Aguirre S. Gonzlez-Barn 《Peptides》1993,14(6):1263-1269
This paper examines the distribution of fibers and cell bodies containing alpha-neo-endorphin in the cat brain stem by using an indirect immunoperoxidase technique. A high or moderate density of immunoreactive cell bodies was found in the superior central nucleus, nucleus incertus, dorsal tegmental nucleus, nucleus of the trapezoid body, and in the laminar spinal trigeminal nucleus, whereas a low density of such perikarya was observed in the inferior colliculus, nucleus praepositus hypoglossi, dorsal nucleus of the raphe, nucleus of the brachium of the inferior colliculus, and in the nucleus of the solitary tract. The highest density of immunoreactive fibers was found in the substantia nigra, dorsal motor nucleus of the vagus, nucleus coeruleus, lateral tegmental field, marginal nucleus of the brachium conjunctivum, and in the inferior and medial vestibular nuclei. These results indicate that alpha-neo-endorphin is widely distributed in the cat brain stem and suggest that the peptide could play an important role in several physiological functions, e.g., those involved in respiratory, cardiovascular, auditory, and motor mechanisms. 相似文献
92.
Background
Although more than 246 loci/genes are associated with inherited retinal diseases, the mechanistic events that link genetic mutations to photoreceptor cell death are poorly understood. miRNAs play a relevant role during retinal development and disease. Thus, as a first step in characterizing miRNA involvement during disease expression and progression, we examined miRNAs expression changes in normal retinal development and in four canine models of retinal degenerative disease.Results
The initial microarray analysis showed that 50 miRNAs were differentially expressed (DE) early (3 vs. 7 wks) in normal retina development, while only 2 were DE between 7 and 16 wks, when the dog retina is fully mature. miRNA expression profiles were similar between dogs affected with xlpra2, an early-onset retinal disease caused by a microdeletion in RPGRORF15, and normal dogs early in development (3 wks) and at the peak of photoreceptor death (7 wks), when only 2 miRNAs were DE. However, the expression varied much more markedly during the chronic cell death stage at 16 wks (118 up-/55 down-regulated miRNAs). Functional analyses indicated that these DE miRNAs are associated with an increased inflammatory response, as well as cell death/survival. qRT-PCR of selected apoptosis-related miRNAs (“apoptomirs”) confirmed the microarray results in xlpra2, and extended the analysis to the early-onset retinal diseases rcd1 (PDE6B-mutation) and erd (STK38L-mutation), as well as the slowly progressing prcd (PRCD-mutation). The results showed up-regulation of anti-apoptotic (miR-9, -19a, -20, -21, -29b, -146a, -155, -221) and down-regulation of pro-apoptotic (miR-122, -129) apoptomirs in the early-onset diseases and, with few exceptions, also in the prcd-mutants.Conclusions
Our results suggest that apoptomirs might be expressed by diseased retinas in an attempt to counteract the degenerative process. The pattern of expression in diseased retinas mirrored the morphology and cell death kinetics previously described for these diseases. This study suggests that common miRNA regulatory mechanisms may be involved in retinal degeneration processes and provides attractive opportunities for the development of novel miRNA-based therapies to delay the progression of the degenerative process.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-172) contains supplementary material, which is available to authorized users. 相似文献93.
The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307) 总被引:30,自引:0,他引:30
Aguirre V Uchida T Yenush L Davis R White MF 《The Journal of biological chemistry》2000,275(12):9047-9054
Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function. 相似文献
94.
Emma Barahona Ana Navazo Fátima Yousef‐Coronado Daniel Aguirre de Cárcer Francisco Martínez‐Granero Manuel Espinosa‐Urgel Marta Martín Rafael Rivilla 《Environmental microbiology》2010,12(12):3185-3195
Motility is a key trait for rhizosphere colonization by Pseudomonas fluorescens. Mutants with reduced motility are poor competitors, and hypermotile, more competitive phenotypic variants are selected in the rhizosphere. Flagellar motility is a feature associated to planktonic, free‐living single cells, and although it is necessary for the initial steps of biofilm formation, bacteria in biofilm lack flagella. To test the correlation between biofilm formation and rhizosphere colonization, we have used P. fluorescens F113 hypermotile derivatives and mutants affected in regulatory genes which in other bacteria modulate biofilm development, namely gacS (G), sadB (S) and wspR (W). Mutants affected in these three genes and a hypermotile variant (V35) isolated from the rhizosphere were impaired in biofilm formation on abiotic surfaces, but colonized the alfalfa root apex as efficiently as the wild‐type strain, indicating that biofilm formation on abiotic surfaces and rhizosphere colonization follow different regulatory pathways in P. fluorescens. Furthermore, a triple mutant gacSsadBwspR (GSW) and V35 were more competitive than the wild‐type strain for root‐tip colonization, suggesting that motility is more relevant in this environment than the ability to form biofilms on abiotic surfaces. Microscopy showed the same root colonization pattern for P. fluorescens F113 and all the derivatives: extensive microcolonies, apparently held to the rhizoplane by a mucigel that seems to be plant produced. Therefore, the ability to form biofilms on abiotic surfaces does not necessarily correlates with efficient rhizosphere colonization or competitive colonization. 相似文献
95.
Loss of MT1‐MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid 下载免费PDF全文
Ana Gutiérrez‐Fernández Clara Soria‐Valles Fernando G Osorio Jesús Gutiérrez‐Abril Cecilia Garabaya Alina Aguirre Antonio Fueyo María Soledad Fernández‐García Xose S Puente Carlos López‐Otín 《The EMBO journal》2015,34(14):1875-1888
MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14−/− mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure. Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16INK4a and p21CIP1/WAF1, increased activity of senescence-associated β-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations. Consistent with the role of retinoic acid signaling in nuclear lamina stabilization, treatment of Mmp14−/− mice with all-trans retinoic acid reversed the nuclear lamina alterations, partially rescued the cell senescence phenotypes, ameliorated the pathological defects in bone, skin, and heart, and extended their life span. These results demonstrate that nuclear architecture and cell senescence can be modulated by a membrane protease, in a process involving the ECM as a key regulator of nuclear stiffness under cell stress conditions. 相似文献
96.
Salvador?Peiru Andres?Aguirre Florencia?Eberhardt Mauricio?Braia Rodolfo?Cabrera Hugo?G.?MenzellaEmail author 《Biotechnology for biofuels》2015,8(1):223
Background
Biodiesels produced from transesterification of vegetable oils have a major quality problem due to the presence of precipitates, which need to be removed to avoid clogging of filters and engine failures. These precipitates have been reported to be mostly composed of steryl glucosides (SGs), but so far industrial cost-effective methods to remove these compounds are not available. Here we describe a novel method for the efficient removal of SGs from biodiesel, based on the hydrolytic activity of a thermostable β-glycosidase obtained from Thermococcus litoralis.Results
A steryl glucosidase (SGase) enzyme from T. litoralis was produced and purified from Escherichia coli cultures expressing a synthetic gene, and used to treat soybean-derived biodiesel. Several optimization steps allowed for the selection of optimal reaction conditions to finally provide a simple and efficient process for the removal of SGs from crude biodiesel. The resulting biodiesel displayed filterability properties similar to distilled biodiesel according to the total contamination (TC), the cold soak filtration test (CSFT), filter blocking tendency (FBT), and cold soak filter blocking tendency (CSFBT) tests. The process was successfully scaled up to a 20 ton reactor, confirming its adaptability to industrial settings.Conclusions
The results presented in this work provide a novel path for the removal of steryl glucosides from biodiesel using a cost-effective, environmentally friendly and scalable enzymatic process, contributing to the adoption of this renewable fuel.97.
Florencia Eberhardt Andres Aguirre Hugo G. Menzella Salvador Peiru 《Journal of industrial microbiology & biotechnology》2017,44(1):141-147
Biodiesels produced from transesterification of vegetable oils have a major problem in quality due to the presence of precipitates, which are mostly composed of steryl glucosides (SGs). We have recently described an enzymatic method for the efficient removal of SGs from biodiesel, based on the activity of a thermostable β-glycosidase from Thermococcus litoralis. In the present work, we describe the development of an Escherichia coli-based expression system and a high cell density fermentation process. Strain and process engineering include the assessment of different promoters to drive the expression of a codon-optimized gene, the co-expression of molecular chaperones and the development of a high cell density fermentation process. A 200-fold increase in the production titers was achieved, which directly impacts on the costs of the industrial process for treating biodiesel. 相似文献
98.
Goñi-Allo B Puerta E Ramos M Lasheras B Jordán J Aguirre N 《Journal of neurochemistry》2008,104(4):914-925
Preconditioning has emerged as a valid strategy against different neurotoxic insults. Although the mechanisms underlying preconditioning are not fully understood, the activation of ATP-sensitive potassium (KATP) channels has been proposed to play a pivotal role in neuronal preconditioning. In the present work we examine whether minoxidil a KATP channel activator protects against the long-term toxicity caused by the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) in rats. Our data show that intrastriatal administration of minoxidil prevents MDMA-induced long-term indole depletions in the rat striatum. This effect was not related to an effect on core temperature, as pre-treatment with minoxidil did not significantly alter MDMA-induced hyperthermia. Taking into account that minoxidil opens both sarcolemmal and mitochondrial KATP channels, we examined the role of each type of channels in the protective effects of minoxidil using specific inhibitors. The administration of HMR-1098, a blocker of the sarcolemmal KATP channels, along with minoxidil did not affect the protection afforded by the latter. On the contrary the selective mitochondrial KATP channel blocker 5-hydroxydecanoic acid completely reversed the protection afforded by minoxidil, thereby implicating the involvement of mitochondrial (but not sarcolemmal) KATP channels. Furthermore our data show the participation of Akt and extracellular signal-regulated kinases in minoxidil-afforded protection. Intrastriatal administration of wortmannin or PD98059 (inhibitors of phosphatidylinositol-3-kinase and mitogen-activated protein kinase/extracellular regulated protein kinase, respectively), along with minoxidil abolished the protective effect of minoxidil against the serotonergic toxicity caused by MDMA. These results demonstrate that minoxidil by opening mitochondrial KATP channels completely prevents MDMA toxicity and that Akt and MAP kinases are involved in minoxidil-afforded neuroprotection. 相似文献
99.
Masatomo So Yuto Kimura Keiichi Yamaguchi Toshihiko Sugiki Toshimichi Fujiwara Cesar Aguirre Kensuke Ikenaka Hideki Mochizuki Yasushi Kawata Yuji Goto 《Protein science : a publication of the Protein Society》2021,30(8):1701
Amyloid fibril formation is associated with various amyloidoses, including neurodegenerative diseases such as Alzheimer''s and Parkinson''s diseases. Amyloid fibrils form above the solubility of amyloidogenic proteins or peptides upon breaking supersaturation, followed by a nucleation and elongation mechanism, which is similar to the crystallization of solutes. Many additives, including salts, detergents, and natural compounds, promote or inhibit amyloid formation. However, the underlying mechanisms of the opposing effects are unclear. We examined the effects of two polyphenols, that is, epigallocatechin gallate (EGCG) and kaempferol‐7─O─glycoside (KG), with high and low solubilities, respectively, on the amyloid formation of α‐synuclein (αSN). EGCG and KG inhibited and promoted amyloid formation of αSN, respectively, when monitored by thioflavin T (ThT) fluorescence or transmission electron microscopy (TEM). Nuclear magnetic resonance (NMR) analysis revealed that, although interactions of αSN with soluble EGCG increased the solubility of αSN, thus inhibiting amyloid formation, interactions of αSN with insoluble KG reduced the solubility of αSN, thereby promoting amyloid formation. Our study suggests that opposing effects of polyphenols on amyloid formation of proteins and peptides can be interpreted based on the solubility of polyphenols. 相似文献
100.
Dias J Arzel J Aguirre P Corraze G Kaushik S 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2003,135(1):183-196
Two trials were undertaken with European seabass (Dicentrarchus labrax) to estimate the protein requirements for maintenance and growth as well as the effect of dietary protein level on the activity of hepatic acetyl coenzyme-A carboxylase (ACoAC). Six diets were formulated to contain graded levels of protein (from 5 to 55% crude protein (CP)) at a constant (12%) lipid level. Three other diets were also formulated to contain 35, 45 and 55% CP, but with a higher lipid level (19%). Groups of 10 individually marked fish (IBW: 100 g) and groups of 8 fish (IBW: 160 g) were used in trial I and II, respectively. Fish were fed to visual satiety and intake was recorded. At the end of both studies, whole body, liver and plasma samples were withdrawn for analyses. Growth rate was improved with increasing dietary CP level. Despite not being the object of a statistical analysis, feed efficiency tended to be enhanced at higher dietary CP level and protein efficiency ratio tended to decrease with increased protein intake. The reduction of the dietary protein/energy ratio, due to the increase of dietary lipids further improved growth and feed utilisation. Data from both experiments indicate 4.5+/-0.5 g kg(-1) d(-1) as the daily protein intake for maximum N gain and 520+/-50 mg kg(-1) d(-1) as the maintenance needs for nitrogen balance. An increase of dietary CP level, up to 25%, increased ACoAC activity. A further increase in dietary CP level (35 to 55%) did not affect liver ACoAC activity. The increase in dietary lipid level depressed significantly liver ACoAC specific activity. 相似文献