全文获取类型
收费全文 | 561篇 |
免费 | 74篇 |
专业分类
635篇 |
出版年
2016年 | 10篇 |
2015年 | 12篇 |
2014年 | 10篇 |
2013年 | 18篇 |
2012年 | 18篇 |
2011年 | 23篇 |
2010年 | 7篇 |
2009年 | 10篇 |
2008年 | 18篇 |
2007年 | 17篇 |
2006年 | 19篇 |
2005年 | 23篇 |
2004年 | 25篇 |
2003年 | 20篇 |
2002年 | 18篇 |
2001年 | 19篇 |
2000年 | 22篇 |
1999年 | 14篇 |
1998年 | 5篇 |
1997年 | 8篇 |
1996年 | 6篇 |
1995年 | 9篇 |
1994年 | 6篇 |
1993年 | 7篇 |
1992年 | 16篇 |
1991年 | 16篇 |
1990年 | 10篇 |
1989年 | 14篇 |
1988年 | 12篇 |
1987年 | 18篇 |
1986年 | 9篇 |
1985年 | 12篇 |
1984年 | 11篇 |
1983年 | 13篇 |
1982年 | 10篇 |
1981年 | 9篇 |
1980年 | 10篇 |
1979年 | 7篇 |
1978年 | 20篇 |
1976年 | 6篇 |
1975年 | 8篇 |
1974年 | 11篇 |
1973年 | 14篇 |
1972年 | 5篇 |
1971年 | 9篇 |
1970年 | 4篇 |
1969年 | 5篇 |
1968年 | 6篇 |
1967年 | 6篇 |
1966年 | 6篇 |
排序方式: 共有635条查询结果,搜索用时 15 毫秒
51.
Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms 总被引:7,自引:0,他引:7
Sandberg M Hassett C Adman ET Meijer J Omiecinski CJ 《The Journal of biological chemistry》2000,275(37):28873-28881
Human soluble epoxide hydrolase (sEH), an enzyme directing the functional disposition of a variety of endogenous and xenobiotic-derived chemical epoxides, was characterized at the genomic level for interindividual variation capable of impacting function. RNA was isolated from 25 human liver samples and used to generate full-length copies of soluble epoxide hydrolase cDNA. The resulting cDNAs were polymerase chain reaction amplified, sequenced, and eight variant loci were identified. The coding region contained five silent single nucleotide polymorphisms (SNPs) and two variant loci resulting in altered protein sequence. An amino acid substitution was identified at residue 287 in exon 8, where the more common arginine was replaced by glutamine. A second variant locus was identified in exon 13 where an arginine residue was inserted following serine 402 resulting in the sequence, arginine 403-404, instead of the more common, arginine 403. This amino acid insertion was confirmed by analyzing genomic DNA from individuals harboring the polymorphic allele. Slot blot hybridization analyses of the liver samples indicated that sEH mRNA steady-state expression varied approximately 10-fold. Transient transfection experiments with CHO and COS-7 cells were used to demonstrate that the two new alleles possess catalytic activity using trans-stilbene oxide as a model substrate. Although the activity of the glutamine 287 variant was similar to the sEH wild type allele, proteins containing the arginine insertion exhibited strikingly lower activity. Allelic forms of human sEH, with markedly different enzymatic profiles, may have important physiological implications with respect to the disposition of epoxides formed from the oxidation of fatty acids, such as arachidonic acid-derived intermediates, as well in the regulation of toxicity due to xenobiotic epoxide exposures. 相似文献
52.
Sandberg JA Sproul CD Blanchard KS Bellon L Sweedler D Powell JA Caputo FA Kornbrust DJ Parker VP Parry TJ Blatt LM 《Antisense & nucleic acid drug development》2000,10(3):153-162
The potential acute toxicity of a ribozyme (ANGIOZYME) targeting the flt-1 vascular endothelial growth factor (VEGF) receptor mRNA was evaluated in cynomolgus monkeys following i.v. infusion or s.c. injection. ANGIOZYME was administered as a 4-hour i.v. infusion at doses of 10, 30, or 100 mg/kg or a s.c. bolus at 100 mg/kg. End points included blood pressure, electrocardiogram (ECG), clinical chemistry, hematology, complement factors, coagulation parameters, and ribozyme plasma concentrations. ANGIOZYME was well tolerated, with no drug-associated morbidity or mortality. There was no clear evidence of ANGIOZYME-related adverse effects in this study. Slight increases in spleen weight and lymphoid hyperplasia were observed in several animals. However, these changes were not dose dependent. Steady-state concentrations of ANGIOZYME were achieved during the 4-hour infusion of 10, 30, or 100 mg/kg. Dose-dependent elimination of ANGIOZYME was observed, with faster clearance at the two highest doses. ANGIOZYME was slowly absorbed after s.c. administration, resulting in steady-state concentrations for the 9-hour sampling period. Monkeys in this toxicology study received significant plasma ANGIOZYME exposure by both the s.c. and i.v. routes. 相似文献
53.
Anders ?stin Mariusz Kowalyczk Rishikesh P. Bhalerao G?ran Sandberg 《Plant physiology》1998,118(1):285-296
The metabolism of indole-3-acetic
acid (IAA) was investigated in 14-d-old Arabidopsis plants grown in
liquid culture. After ruling out metabolites formed as an effect of
nonsterile conditions, high-level feeding, and spontaneous
interconversions, a simple metabolic pattern emerged. Oxindole-3-acetic
acid (OxIAA), OxIAA conjugated to a hexose moiety via the carboxyl
group, and the conjugates indole-3-acetyl aspartic acid (IAAsp) and
indole-3-acetyl glutamate (IAGlu) were identified by mass spectrometry
as primary products of IAA fed to the plants. Refeeding experiments
demonstrated that none of these conjugates could be hydrolyzed back to
IAA to any measurable extent at this developmental stage. IAAsp was
further oxidized, especially when high levels of IAA were fed into the
system, yielding OxIAAsp and OH-IAAsp. This contrasted with the
metabolic fate of IAGlu, since that conjugate was not further
metabolized. At IAA concentrations below 0.5 μm, most of
the supplied IAA was metabolized via the OxIAA pathway, whereas only a
minor portion was conjugated. However, increasing the IAA
concentrations to 5 μm drastically altered the metabolic
pattern, with marked induction of conjugation to IAAsp and IAGlu. This
investigation used concentrations for feeding experiments that were
near endogenous levels, showing that the metabolic pathways controlling
the IAA pool size in Arabidopsis are limited and, therefore, make good
targets for mutant screens provided that precautions are taken to avoid
inducing artificial metabolism.The plant hormone IAA is an important signal molecule in the
regulation of plant development. Its central role as a growth regulator
makes it necessary for the plant to have mechanisms that strictly
control its concentration. The hormone is believed to be active
primarily as the free acid, and endogenous levels are controlled in
vivo by processes such as synthesis, oxidation, and conjugation. IAA
has been shown to form conjugates with sugars, amino acids, and small
peptides. Conjugates are believed to be involved in IAA transport, in
the storage of IAA for subsequent use, in the homeostatic control of
the pool of the free hormone, and as a first step in the catabolic
pathways (Cohen and Bandurski, 1978; Nowacki and Bandurski, 1980;
Tuominen et al., 1994; Östin et al., 1995; Normanly, 1997). It is
generally accepted that in some species conjugated IAA is the major
source of free IAA during the initial stages of seed germination (Ueda
and Bandurski, 1969; Sandberg et al., 1987; Bialek and Cohen, 1989),
and there is also evidence that in some plants (but not all; see Bialek
et al., 1992), the young seedling is entirely dependent on the release
of free IAA from conjugated pools until the plant itself is capable of
de novo synthesis (Epstein et al., 1980; Sandberg et al., 1987).The function of conjugated IAA during vegetative growth is somewhat
less clear. It has been shown that conjugated IAA constitutes as much
as 90% of the total IAA in the plant during vegetative growth
(Normanly, 1997). However, the role of the IAA conjugates at this stage
of the plant''s life cycle remains unknown. Analysis of endogenous IAA
conjugates in vegetative tissues has revealed the presence of a variety
of different compounds, including indole-3-acetyl-inositol,
indole-3-acetyl-Ala, IAAsp, and IAGlu (Anderson and Sandberg, 1982;
Cohen and Baldi, 1983; Chisnell, 1984; Cohen and Ernstsen, 1991;
Östin et al., 1992). Studies of vegetative tissues have indicated
that IAAsp, one of the major conjugates in many plants, is the first
intermediate in an irreversible deactivation pathway (Tsurumi and Wada,
1986; Tuominen et al., 1994; Östin, 1995). Another mechanism that
is believed to be involved in the homeostatic control of the IAA pool
is catabolism by direct oxidation of IAA to OxIAA, which has been shown
to occur in several plant species (Reinecke and Bandurski, 1983;
Ernstsen et al., 1987).One area in the study of IAA metabolism in which our knowledge is
increasing is the analysis of the homeostatic controls of IAA levels in
plants. It has been possible, for instance, to increase the levels of
IAA in transgenic plants expressing iaaM and iaaH
genes from Agrobacterium tumefaciens. Analysis of these
transgenic plants has indicated that plants have several pathways that
can compensate for the increased production of IAA (Klee et al., 1987;
Sitbon, 1992). It is expected that future studies using now-available
genes will provide further insight into IAA metabolism. For example, a
gene in maize encoding IAA-Glc synthetase has been identified, and
several genes (including ILR1, which may be involved
in hydrolysis of the indole-3-acetyl-Leu conjugate) have been cloned
from Arabidopsis (Szerszen et al., 1994; Bartel and Fink,
1995). Furthermore, Chou et al. (1996) identified a gene that
hydrolyzes the conjugate IAAsp to free IAA in the bacterium
Enterobacter aggloremans.Because of its small genome size, rapid life cycle, and the ease of
obtaining mutants, Arabidopsis is increasingly used as a
genetic model system to investigate various aspects of plant growth and
development. IAA signal transduction is also being investigated
intensively in Arabidopsis in many laboratories (Leyser, 1997). Mutants
with altered responses to externally added auxins or IAA conjugates
have been identified in Arabidopsis. The identified mutants are either
signal transduction mutants such as axr1-4 (Lincoln et al.,
1990), or have mutations in genes involved in auxin uptake or
transport, such as aux1 and pin1 (Okada et al.,
1991; Bennett et al., 1996). A few mutants that are unable to regulate
IAA levels or are unable to hydrolyze IAA conjugates, sur1-2
and ilr1, respectively, have also been identified (Bartel
and Fink, 1995; Boerjan et al., 1995). To our knowledge, no mutant that
is auxotrophic for IAA has been identified to date, which may
reflect the redundancy in IAA biosynthetic pathways or the lethality of
such mutants.In spite of the work reported thus far, many aspects of the metabolism
of IAA in Arabidopsis require further investigation, because few
details of the processes involved in IAA regulation are known. This
lack of knowledge puts severe constraints on genetic analysis of IAA
metabolism in Arabidopsis. For example, it is essential to have prior
knowledge of IAA metabolism to devise novel and relevant screens with
which to identify mutants of IAA metabolism. We have sought to address
this issue by identifying the metabolic pathways involved in catabolism
and conjugation under conditions that minimally perturb physiological
processes. In this investigation we studied the conjugation and
catabolic pattern of IAA by supplying relatively low levels of labeled
IAA and identifying the catabolites and conjugates by MS. Different
feeding systems were tested to optimize the application of IAA and to
avoid irregularities in metabolism attributable to culturing, feeding
conditions, or microbial activity. It is well documented that IAA
metabolism is altered according to the amount of exogenous auxin
applied; therefore, we placed special emphasis on distinguishing
between catabolic routes that occur at near-physiological
concentrations and those that occur at the high auxin concentrations
commonly used in mutant screens. 相似文献
54.
Effect of Serine and Ethanolamine Administration on Phospholipid-Related Compounds and Neurotransmitter Amino Acids in the Rabbit Hippocampus 总被引:1,自引:1,他引:0
Sandra Buratta Anders Hamberger Henrik Ryberg Britta Nyström Mats Sandberg Rita Mozzi 《Journal of neurochemistry》1998,71(5):2145-2150
Abstract: The report concerns mechanisms for the increase of extracellular levels of ethanolamine and phosphoethanolamine in CNS regions, such as the hippocampus, in transient brain ischemia, hypoglycemia, seizures, etc. l -Serine (2.5–10 m M ), d -serine (10 m M ), or ethanolamine (10 m M ) was administered for 20 min via a microdialysis tubing to the hippocampus of unanesthetized rabbits. The concentrations of primary amines were determined in the dialysates. When levels were elevated 10–100 times in the extracellular fluid, l -serine caused a dose-dependent increase of the concentration of extracellular ethanolamine. Ethanolamine caused a corresponding, although somewhat smaller, increase in serine levels. Furthermore, l -serine also induced an increased concentration of phosphoethanolamine that was delayed in time relative to the peak of ethanolamine. d -Serine was as effective as l -serine in raising ethanolamine levels but had no effect on phosphoethanolamine. Ethanolamine, but not l -serine, also increased extracellular glutamate/aspartate levels in an MK-801-dependent fashion. A similar effect, but delayed in time, was observed with d -serine. These effects were inhibited by MK-801. The concentrations of other amino acids were not significantly affected. The characteristics of the effects are suggestive of base exchange reactions between serine and ethanolamine and between ethanolamine and serine glycerophospholipids, respectively, in neuronal plasma membranes. 相似文献
55.
56.
The impact of trapping on the recombination dynamics in polymer:fullerene blends is clarified using the highly ordered bulk heterojunction (BHJ) blend poly[2,5‐bis(3‐tetradecylthiophen‐2‐yl)thieno[3,2‐b]thiophene] (PBTTT) and [6,6]‐phenyl‐C61‐butyric acid methyl ester (PCBM) at different weight ratios as a model system. The recombination dynamics are determined using both transient charge extraction and steady‐state techniques. The results show that both the decay of photogenerated charge and the light ideality factor at a polymer:fullerene weight ratio of 1:4 are fully consistent with 2D Langevin recombination; in the 1:1 case the recombination is seen to be affected by electron trapping. The theory of 2D Langevin recombination is extended to the case with high trap density in agreement with the observations in the 1:1 case. The recombination capture coefficients are derived both for trap‐assisted and band‐to‐band recombination and it can be seen that anisotropic charge transport reduces the capture coefficients in both cases resulting in a reduced overall recombination. 相似文献
57.
Andrew T. Miller Carol Dahlberg Mark L. Sandberg Ben G. Wen Daniel R. Beisner John A. H. Hoerter Albert Parker Christian Schmedt Monique Stinson Jacqueline Avis Cynthia Cienfuegos Mark McPate Pamela Tranter Martin Gosling Paul J. Groot-Kormelink Janet Dawson Shifeng Pan Shin-Shay Tian H. Martin Seidel Michael P. Cooke 《PloS one》2015,10(6)
Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease. 相似文献
58.
Sei-Ichi Matsui Hiroshi Yoshida Herbert Weinfeld Avery A. Sandberg 《The Journal of cell biology》1972,54(1):120-132
Fusion of an interphase cell with a metaphase cell results in profound changes in the interphase chromatin that have been called "chromosome pulverization" or "premature chromosome condensation" In addition to the usual light microscopy, the nature of the changes has been investigated in the present study with electron microscopy and biochemical techniques Metaphase and interphase cells were mixed and fused at 37°C by means of ultraviolet-inactivated Sendai virus. After cell fusion, morphological changes in interphase nuclei occurred only in binucleate cells which contained one intact set of metaphase chromosomes Irrespective of the nuclear stage at the time of cell fusion, the morphologic changes that occurred 5–20 min later simulated very closely a sequence of events that characterizes the normal G2-prophase transition. Radioautography revealed that, late in the process, substantial amounts of RNA and probably protein were transferred from the interphase nucleus into the cytoplasm of fused cells. Thus, the findings indicate the existence in metaphase cells of factor(s) which are capable of initiating biochemical and morphological events in interphase nuclei intrinsic to the normal mitotic process. 相似文献
59.
Versatile bioanalytical assays to detect chemically stabilized hammerhead ribozyme and putative ribozyme metabolites from plasma are described. The extraction protocols presented are based on serial solid-phase extractions performed on a 96-well plate format and are compatible with either IEX-HPLC or CGE back-end analysis. A validation of both assays confirmed that both the HPLC and the CGE methods possess the required linearity, accuracy, and precision to accurately measure concentrations of hammerhead ribozyme extracted from plasma. These methods should be of general use to detect and quantitate ribozymes from other biological fluids such as serum and urine. 相似文献
60.
Germinating seed ofDalbergia dolichopetala converted both [2H5]l-tryptophan and [2H5]indole-3-ethanol to [2H5]indole-3-acetic acid (IAA). Metabolism of [2-14C]IAA resulted in the production of indole-3-acetylaspartic acid (IAAsp), as well as several unidentified components, referred to as metabolites I, II, IV and V. Re-application of [14C]IAAsp to the germinating seed led to the accumulation of the polar, water-soluble compound, metabolite V, as the major metabolite, together with a small amount of IAA. Metabolites I, II and IV were not detected, nor were these compounds associated with the metabolism of [2-14C]IAA by shoots and excised cotyledons and roots from 26-d-oldD. dolichopetala seedlings. Both shoots and cotyledons converted IAA to IAAsp and metabolite V, while IAAsp was the only metabolite detected in extracts from excised roots. The available evidence indicates that inDalbergia, and other species, IAAsp may not act as a storage product that can be hydrolysed to provide the plant with a ready supply of IAA.Abbreviations HPLC-RC
high-performance liquid chromatography-radiocounting
- IAA
indole-3-acetic acid
- IAAsp
indole-3-acetylaspartic acid
- IAlnos
2-O-indole-3-acetyl-myo-inositol
- IEt
indole-3-ethanol 相似文献