全文获取类型
收费全文 | 943篇 |
免费 | 50篇 |
专业分类
993篇 |
出版年
2022年 | 9篇 |
2021年 | 15篇 |
2020年 | 6篇 |
2019年 | 14篇 |
2018年 | 17篇 |
2017年 | 13篇 |
2016年 | 17篇 |
2015年 | 31篇 |
2014年 | 39篇 |
2013年 | 43篇 |
2012年 | 94篇 |
2011年 | 128篇 |
2010年 | 90篇 |
2009年 | 59篇 |
2008年 | 65篇 |
2007年 | 54篇 |
2006年 | 55篇 |
2005年 | 34篇 |
2004年 | 27篇 |
2003年 | 29篇 |
2002年 | 25篇 |
2001年 | 6篇 |
2000年 | 5篇 |
1999年 | 2篇 |
1998年 | 3篇 |
1997年 | 4篇 |
1996年 | 2篇 |
1995年 | 5篇 |
1993年 | 4篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 5篇 |
1989年 | 7篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 2篇 |
1985年 | 11篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1980年 | 5篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1976年 | 4篇 |
1962年 | 2篇 |
1947年 | 2篇 |
1946年 | 2篇 |
1943年 | 2篇 |
1941年 | 3篇 |
排序方式: 共有993条查询结果,搜索用时 15 毫秒
101.
Baugh L Le Trong I Cerutti DS Mehta N Gülich S Stayton PS Stenkamp RE Lybrand TP 《Biochemistry》2012,51(2):597-607
We report a point mutation in the second contact shell of the high-affinity streptavidin-biotin complex that appears to reduce binding affinity through transmitted effects on equilibrium dynamics. The Y54F streptavidin mutation causes a 75-fold loss of binding affinity with 73-fold faster dissociation, a large loss of binding enthalpy (ΔΔH = 3.4 kcal/mol at 37 °C), and a small gain in binding entropy (TΔΔS = 0.7 kcal/mol). The removed Y54 hydroxyl is replaced by a water molecule in the bound structure, but there are no observable changes in structure in the first contact shell and no additional changes surrounding the mutation. Molecular dynamics simulations reveal a large increase in the atomic fluctuation amplitudes for W79, a key biotin contact residue, compared to the fluctuation amplitudes in the wild-type. The increased W79 atomic fluctuation amplitudes are caused by loss of water-mediated hydrogen bonds between the Y54 hydroxyl group and peptide backbone atoms in and near W79. We propose that the increased atomic fluctuation amplitudes diminish the integrity of the W79-biotin interaction and represents a loosening of the "tryptophan collar" that is critical to the slow dissociation and high affinity of streptavidin-biotin binding. These results illustrate how changes in protein dynamics distal to the ligand binding pocket can have a profound impact on ligand binding, even when equilibrium structure is unperturbed. 相似文献
102.
Reconciling extremely strong barriers with high levels of gene exchange in annual sunflowers 总被引:1,自引:0,他引:1
Sambatti JB Strasburg JL Ortiz-Barrientos D Baack EJ Rieseberg LH 《Evolution; international journal of organic evolution》2012,66(5):1459-1473
In several cases, estimates of gene flow between species appear to be higher than we might predict given the strength of interspecific barriers separating these species pairs. However, as far as we are aware, detailed measurements of reproductive isolation have not previously been compared with a coalescent-based assessment of gene flow. Here, we contrast these two measures in two species of sunflower, Helianthus annuus and H. petiolaris. We quantified the total reproductive barrier strength between these species by compounding the contributions of the following prezygotic and postzygotic barriers: ecogeographic isolation, reproductive asynchrony, niche differentiation, pollen competition, hybrid seed formation, hybrid seed germination, hybrid fertility, and extrinsic postzygotic isolation. From this estimate, we calculated the probability that a reproductively successful hybrid is produced: estimates of P(hyb) range from 10(-4) to 10(-6) depending on the direction of the cross and the degree of independence among reproductive barriers. We then compared this probability with population genetic estimates of the per generation migration rate (m). We showed that the relatively high levels of gene flow estimated between these sunflower species (N(e) m= 0.34-0.76) are mainly due to their large effective population sizes (N(e) > 10(6)). The interspecific migration rate (m) is very small (<10(-7)) and an order of magnitude lower than that expected based on our reproductive barrier strength estimates. Thus, even high levels of reproductive isolation (>0.999) may produce genomic mosaics. 相似文献
103.
Yang SH Chang SY Tu Y Lawson GW Bergo MO Fong LG Young SG 《Journal of lipid research》2012,53(1):77-86
Protein farnesyltransferase (FTase) and protein geranylgeranyltransferase-I (GGTase-I) add 15- or 20-carbon lipids, respectively, to proteins that terminate with a CaaX motif. These posttranslational modifications of proteins with lipids promote protein interactions with membrane surfaces in cells, but the in vivo importance of the CaaX prenyltransferases and the protein lipidation reactions they catalyze remain incompletely defined. One study concluded that a deficiency of FTase was inconsequential in adult mice and led to little or no tissue pathology. To assess the physiologic importance of the CaaX prenyltransferases, we used conditional knockout alleles and an albumin-Cre transgene to produce mice lacking FTase, GGTase-I, or both enzymes in hepatocytes. The hepatocyte-specific FTase knockout mice survived but exhibited hepatocellular disease and elevated transaminases. Mice lacking GGTase-I not only had elevated transaminases but also had dilated bile cannaliculi, hyperbilirubinemia, hepatosplenomegaly, and reduced survival. Of note, GGTase-I-deficient hepatocytes had a rounded shape and markedly reduced numbers of actin stress fibers. Hepatocyte-specific FTase/GGTase-I double-knockout mice closely resembled mice lacking GGTase-I alone, but the disease was slightly more severe. Our studies refute the notion that FTase is dispensable and demonstrate that GGTase-I is crucial for the vitality of hepatocytes. 相似文献
104.
Borowsky AD Bandhuvula P Kumar A Yoshinaga Y Nefedov M Fong LG Zhang M Baridon B Dillard L de Jong P Young SG West DB Saba JD 《Journal of lipid research》2012,53(9):1920-1931
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in immunity, inflammation, angiogenesis, and cancer. S1P lyase (SPL) is the essential enzyme responsible for S1P degradation. SPL augments apoptosis and is down-regulated in cancer. SPL generates a S1P chemical gradient that promotes lymphocyte trafficking and as such is being targeted to treat autoimmune diseases. Despite growing interest in SPL as a disease marker, antioncogene, and pharmacological target, no comprehensive characterization of SPL expression in mammalian tissues has been reported. We investigated SPL expression in developing and adult mouse tissues by generating and characterizing a β-galactosidase-SPL reporter mouse combined with immunohistochemistry, immunoblotting, and enzyme assays. SPL was expressed in thymic and splenic stromal cells, splenocytes, Peyer's Patches, colonic lymphoid aggregates, circulating T and B lymphocytes, granulocytes, and monocytes, with lowest expression in thymocytes. SPL was highly expressed within the CNS, including arachnoid lining cells, spinal cord, choroid plexus, trigeminal nerve ganglion, and specific neurons of the olfactory bulb, cerebral cortex, midbrain, hindbrain, and cerebellum. Expression was detected in brown adipose tissue, female gonads, adrenal cortex, bladder epithelium, Harderian and preputial glands, and hair follicles. This unique expression pattern suggests SPL has many undiscovered physiological functions apart from its role in immunity. 相似文献
105.
Staton SE Bakken BH Blackman BK Chapman MA Kane NC Tang S Ungerer MC Knapp SJ Rieseberg LH Burke JM 《The Plant journal : for cell and molecular biology》2012,72(1):142-153
Aside from polyploidy, transposable elements are the major drivers of genome size increases in plants. Thus, understanding the diversity and evolutionary dynamics of transposable elements in sunflower (Helianthus annuus L.), especially given its large genome size (~3.5 Gb) and the well‐documented cases of amplification of certain transposons within the genus, is of considerable importance for understanding the evolutionary history of this emerging model species. By analyzing approximately 25% of the sunflower genome from random sequence reads and assembled bacterial artificial chromosome (BAC) clones, we show that it is composed of over 81% transposable elements, 77% of which are long terminal repeat (LTR) retrotransposons. Moreover, the LTR retrotransposon fraction in BAC clones harboring genes is disproportionately composed of chromodomain‐containing Gypsy LTR retrotransposons (‘chromoviruses’), and the majority of the intact chromoviruses contain tandem chromodomain duplications. We show that there is a bias in the efficacy of homologous recombination in removing LTR retrotransposon DNA, thereby providing insight into the mechanisms associated with transposable element (TE) composition in the sunflower genome. We also show that the vast majority of observed LTR retrotransposon insertions have likely occurred since the origin of this species, providing further evidence that biased LTR retrotransposon activity has played a major role in shaping the chromatin and DNA landscape of the sunflower genome. Although our findings on LTR retrotransposon age and structure could be influenced by the selection of the BAC clones analyzed, a global analysis of random sequence reads indicates that the evolutionary patterns described herein apply to the sunflower genome as a whole. 相似文献
106.
Bode CM Boezio AA Albrecht BK Bellon SF Berry L Broome MA Choquette D Dussault I Lewis RT Lin MH Rex K Whittington DA Yang Y Harmange JC 《Bioorganic & medicinal chemistry letters》2012,22(12):4089-4093
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model. 相似文献
107.
Laura A. McAllister Justin I. Montgomery Joseph A. Abramite Usa Reilly Matthew F. Brown Jinshan M. Chen Rose A. Barham Ye Che Seung Won Chung Carol A. Menard Mark Mitton-Fry Lisa M. Mullins Mark C. Noe John P. O’Donnell Robert M. Oliver Joseph B. Penzien Mark Plummer Loren M. Price Veerabahu Shanmugasundaram Andrew P. Tomaras Daniel P. Uccello 《Bioorganic & medicinal chemistry letters》2012,22(22):6832-6838
The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae. 相似文献
108.
Environmental DNA 总被引:4,自引:0,他引:4
109.
110.
I Anderson E Saunders A Lapidus M Nolan S Lucas H Tice TG Del Rio JF Cheng C Han R Tapia LA Goodwin S Pitluck K Liolios K Mavromatis I Pagani N Ivanova N Mikhailova A Pati A Chen K Palaniappan M Land L Hauser CD Jeffries YJ Chang EM Brambilla M Rohde S Spring M Göker JC Detter T Woyke J Bristow JA Eisen V Markowitz P Hugenholtz NC Kyrpides HP Klenk 《Standards in genomic sciences》2012,6(2):155-164
Thermodesulfatator indicus Moussard et al. 2004 is a member of the Thermodesulfobacteriaceae, a family in the phylum Thermodesulfobacteria that is currently poorly characterized at the genome level. Members of this phylum are of interest because they represent a distinct, deep-branching, Gram-negative lineage. T. indicus is an anaerobic, thermophilic, chemolithoautotrophic sulfate reducer isolated from a deep-sea hydrothermal vent. Here we describe the features of this organism, together with the complete genome sequence, and annotation. The 2,322,224 bp long chromosome with its 2,233 protein-coding and 58 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. 相似文献