全文获取类型
收费全文 | 4758篇 |
免费 | 447篇 |
国内免费 | 2篇 |
专业分类
5207篇 |
出版年
2023年 | 17篇 |
2022年 | 53篇 |
2021年 | 119篇 |
2020年 | 72篇 |
2019年 | 86篇 |
2018年 | 80篇 |
2017年 | 77篇 |
2016年 | 153篇 |
2015年 | 239篇 |
2014年 | 253篇 |
2013年 | 285篇 |
2012年 | 417篇 |
2011年 | 422篇 |
2010年 | 257篇 |
2009年 | 194篇 |
2008年 | 326篇 |
2007年 | 348篇 |
2006年 | 268篇 |
2005年 | 300篇 |
2004年 | 267篇 |
2003年 | 229篇 |
2002年 | 235篇 |
2001年 | 34篇 |
2000年 | 48篇 |
1999年 | 53篇 |
1998年 | 59篇 |
1997年 | 34篇 |
1996年 | 31篇 |
1995年 | 29篇 |
1994年 | 16篇 |
1993年 | 12篇 |
1992年 | 13篇 |
1991年 | 13篇 |
1990年 | 11篇 |
1989年 | 11篇 |
1987年 | 7篇 |
1986年 | 9篇 |
1985年 | 5篇 |
1984年 | 9篇 |
1983年 | 12篇 |
1982年 | 8篇 |
1981年 | 8篇 |
1980年 | 8篇 |
1979年 | 6篇 |
1978年 | 8篇 |
1977年 | 8篇 |
1976年 | 4篇 |
1974年 | 9篇 |
1973年 | 4篇 |
1965年 | 4篇 |
排序方式: 共有5207条查询结果,搜索用时 47 毫秒
131.
Ferguson HA Marietta PM Van Den Berg CL 《The Journal of biological chemistry》2003,278(46):45793-45800
The importance of the mitochondria in UV-induced apoptosis has become increasingly apparent. Following DNA damage cytochrome c and other pro-apoptotic factors are released from the mitochondria, allowing for formation of the apoptosome and subsequent cleavage and activation of caspase-9. Active caspase-9 then activates downstream caspases-3 and/or -7, which in turn cleave poly(ADP)-ribose polymerase (PARP) and other down-stream targets, resulting in apoptosis. In an effort to understand the mechanisms of Akt-mediated cell survival in breast cancer, we studied the effects of insulin-like growth factor (IGF)-I treatment on UV-treated MCF-7 human breast cancer cells. Apoptosis was induced in MCF-7 cells after UV treatment, as measured by caspase-7 and PARP cleavage, and IGF-I co-treatment protected against this response. Surprisingly caspase-9 cleavage was unchanged with UV and/or IGF-I treatment. Using MCF-7 cells overexpressing caspase-3 we have shown that resistance of caspase-9 to cleavage was not altered by the expression of caspase-3. Furthermore, overexpression of caspase-9 did not enhance PARP or caspase-7 cleavage after UV treatment. Because caspase-8 was activated with UV treatment alone, we believe that UV-induced apoptosis in MCF-7 cells occurs independently of cytochrome c and caspase-9, supporting the existence of a cytoplasmic inhibitor of cytochrome c in MCF-7 cells. We anticipate that such inhibitors may be overexpressed in cancer cells, allowing for treatment resistance. 相似文献
132.
Myostatin-deficient mice lose more skeletal muscle mass than wild-type controls during hindlimb suspension 总被引:1,自引:0,他引:1
McMahon CD Popovic L Oldham JM Jeanplong F Smith HK Kambadur R Sharma M Maxwell L Bass JJ 《American journal of physiology. Endocrinology and metabolism》2003,285(1):E82-E87
Myostatin inhibits myogenesis. Therefore, we sought to determine if mice lacking the myostatin gene [Mstn(-/-)] would lose less muscle mass than wild-type mice during 7 days of hindlimb suspension (HS). Male Mstn(-/-) and wild-type (C57) mice were subjected to HS or served as ground-based controls (n = 6/group). Wild-type mice lost 8% of body mass and approximately 13% of wet mass from biceps femoris, quadriceps femoris, and soleus, whereas the mass of extensor digitorum longus (EDL) was unchanged after HS. Unexpectedly, Mstn(-/-) mice lost more body (13%, P < 0.05) and quadriceps femoris (17%, P < 0.05) mass than wild-type mice and lost 33% of EDL mass (P < 0.01) after HS. Protein expression of myostatin in biceps femoris and quadriceps femoris was not altered, whereas expression of MyoD, Myf-5, and myogenin increased in wild-type mice and tended to decrease in muscles of Mstn(-/-) mice. These data suggest that HS induced myogenesis in wild-type mice to counter atrophy, whereas myogenesis was not induced in Mstn(-/-) mice, thereby resulting in a greater loss of muscle mass. 相似文献
133.
To determine the importance of fibroblast growth factor receptors (fgfrs) 1 and 2 in the metanephric mesenchyme, we generated conditional knockout mice (fgfr(Mes-/-)). Fgfr1(Mes-/-) and fgfr2(Mes-/-) mice develop normal-appearing kidneys. Deletion of both receptors (fgfr1/2(Mes-/-)) results in renal aplasia. Fgfr1/2(Mes-/-) mice develop a ureteric bud (and occasionally an ectopic bud) that does not elongate or branch, and the mice do not develop an obvious metanephric mesenchyme. By in situ hybridization, regions of mutant mesenchyme near the ureteric bud(s) express Eya1 and Six1, but not Six2, Sall1, or Pax2, while the ureteric bud expresses Ret and Pax2 normally. Abnormally high rates of apoptosis and relatively low rates of proliferation are present in mutant mesenchyme dorsal to the mutant ureteric bud at embryonic day (E) 10.5, while mutant ureteric bud tissues undergo high rates of apoptosis by E11.5. Thus, fgfr1 and fgfr2 together are critical for normal formation of metanephric mesenchyme. While the ureteric bud(s) initiates, it does not elongate or branch infgfr1/2(Mes-/-) mice. In metanephric mesenchymal rudiments, fgfr1 and fgfr2 appear to function downstream of Eya1 and Six1, but upstream of Six2, Sall1, and Pax2. Finally, this is the first example of renal aplasia in a conditional knockout model. 相似文献
134.
Raitsimring AM Astashkin AV Feng C Wilson HL Rajagopalan KV Enemark JH 《Inorganica chimica acta》2008,361(4):941-946
The Mo(V) forms of the Tyr343Phe (Y343F) mutant of human sulfite oxidase (SO) have been investigated by continuous wave (CW) and variable frequency pulsed EPR spectroscopies as a function of pH. The CW EPR spectrum recorded at low-pH (∼6.9) has g-values similar to those known for the low-pH form of the native vertebrate SO (original lpH form); however, unlike the spectrum of original lpH SO, it does not show any hyperfine splittings from a nearby exchangeable proton. The detailed electron spin echo (ESE) envelope modulation (ESEEM) and pulsed electron-nuclear double resonance (ENDOR) experiments also did not reveal any nearby protons that could belong to an exchangeable ligand at the molybdenum center. These results suggest that under low-pH conditions the active site of Y343F SO is in the “blocked” form, with the Mo(V) center coordinated by sulfate. With increasing pH the EPR signal from the “blocked” form decreases, while a signal similar to that of the original lpH form appears and becomes the dominant signal at pH >9. In addition, both the CW EPR and ESE-detected field-sweep spectra reveal a considerable contribution from a signal similar to that usually detected for the high-pH form of native vertebrate SO (original hpH form). The nearby exchangeable protons in both of the component forms observed at high-pH were studied by the ESEEM spectroscopy. These results indicate that the Y343F mutation increases the apparent pKa of the transition from the lpH to hpH forms by ∼2 pH units. 相似文献
135.
We present full-genome genotype imputations for 100 classical laboratory mouse strains, using a novel method. Using genotypes at 549,683 SNP loci obtained with the Mouse Diversity Array, we partitioned the genome of 100 mouse strains into 40,647 intervals that exhibit no evidence of historical recombination. For each of these intervals we inferred a local phylogenetic tree. We combined these data with 12 million loci with sequence variations recently discovered by whole-genome sequencing in a common subset of 12 classical laboratory strains. For each phylogenetic tree we identified strains sharing a leaf node with one or more of the sequenced strains. We then imputed high- and medium-confidence genotypes for each of 88 nonsequenced genomes. Among inbred strains, we imputed 92% of SNPs genome-wide, with 71% in high-confidence regions. Our method produced 977 million new genotypes with an estimated per-SNP error rate of 0.083% in high-confidence regions and 0.37% genome-wide. Our analysis identified which of the 88 nonsequenced strains would be the most informative for improving full-genome imputation, as well as which additional strain sequences will reveal more new genetic variants. Imputed sequences and quality scores can be downloaded and visualized online. 相似文献
136.
Brandes N Reichmann D Tienson H Leichert LI Jakob U 《The Journal of biological chemistry》2011,286(48):41893-41903
To understand and eventually predict the effects of changing redox conditions and oxidant levels on the physiology of an organism, it is essential to gain knowledge about its redoxome: the proteins whose activities are controlled by the oxidation status of their cysteine thiols. Here, we applied the quantitative redox proteomic method OxICAT to Saccharomyces cerevisiae and determined the in vivo thiol oxidation status of almost 300 different yeast proteins distributed among various cellular compartments. We found that a substantial number of cytosolic and mitochondrial proteins are partially oxidized during exponential growth. Our results suggest that prevailing redox conditions constantly control central cellular pathways by fine-tuning oxidation status and hence activity of these proteins. Treatment with sublethal H(2)O(2) concentrations caused a subset of 41 proteins to undergo substantial thiol modifications, thereby affecting a variety of different cellular pathways, many of which are directly or indirectly involved in increasing oxidative stress resistance. Classification of the identified protein thiols according to their steady-state oxidation levels and sensitivity to peroxide treatment revealed that redox sensitivity of protein thiols does not predict peroxide sensitivity. Our studies provide experimental evidence that the ability of protein thiols to react to changing peroxide levels is likely governed by both thermodynamic and kinetic parameters, making predicting thiol modifications challenging and de novo identification of peroxide sensitive protein thiols indispensable. 相似文献
137.
Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4)). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information. 相似文献
138.
Staining patterns suggest that in the adeno-associated satellite virion there exist quasi single-stranded regions which are renatured after extraction to exhibit double strandedness. 相似文献
139.
Pierrel F Hernandez HL Johnson MK Fontecave M Atta M 《The Journal of biological chemistry》2003,278(32):29515-29524
In Escherichia coli, the MiaB protein catalyzes the methylthiolation of N-6-isopentenyl adenosine in tRNAs, the last reaction step during biosynthesis of 2-methylthio-N-6-isopentenyl adenosine (ms2i6A-37). For the first time the thermophilic bacterium Thermotoga maritima is shown here to contain such a MiaB tRNA-modifying enzyme, named MiaBTm, and to synthesize ms2i6A-37 as demonstrated by an analysis of modified nucleosides from tRNA hydrolysates. The corresponding gene (TM0653) was identified by sequence similarity to the miaB gene cloned and expressed in E. coli. MiaBTm was purified to homogeneity and thoroughly characterized by biochemical and spectroscopic methods. It is a monomer of 443 residues with a molecular mass of 50,710 kilodaltons. Its amino acid sequence shares the CysXXX-CysXXCys sequence with MiaB from E. coli as well as with biotin synthase and lipoate synthase. This sequence was shown to be essential for chelation of an iron-sulfur center and for activity in these enzymes. As isolated, MiaBTm contains both iron and sulfide and an apoprotein form can coordinate up to 4 iron and 4 sulfur atoms per polypeptide chain. UV-visible absorption, resonance Raman, variable temperature magnetic circular dichroism, and EPR spectroscopy of MiaBTm indicate the presence of a [4Fe-4S]+2/+1 cluster under reducing and anaerobic conditions, whereas [3Fe-4S]+1 and [2Fe-2S]+2 forms are generated under aerobic conditions. The redox potential of the [4Fe-4S]+2/+1 transition is -495 +/- 10 mV (versus the normal hydrogen electrode). Finally, the expression of MiaBTm from T. maritima in an E. coli mutant strain lacking functional miaB gene allowed production of ms2i6A-37. These results provide further information on the enzymes involved in methylthiolation of tRNAs. 相似文献
140.
Marlene M. Hao Joel C. Bornstein Pieter Vanden Berghe Alan E. Lomax Heather M. Young Jaime P.P. Foong 《Developmental biology》2013
The enteric nervous system (ENS) is a vital part of the autonomic nervous system that regulates many gastrointestinal functions, including motility and secretion. All neurons and glia of the ENS arise from neural crest-derived cells that migrate into the gastrointestinal tract during embryonic development. It has been known for many years that a subpopulation of the enteric neural crest-derived cells expresses pan-neuronal markers at early stages of ENS development. Recent studies have demonstrated that some enteric neurons exhibit electrical activity from as early as E11.5 in the mouse, with further maturation of activity during embryonic and postnatal development. This article discusses the maturation of electrophysiological and morphological properties of enteric neurons, the formation of synapses and synaptic activity, and the influence of neural activity on ENS development. 相似文献