全文获取类型
收费全文 | 471篇 |
免费 | 33篇 |
出版年
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 5篇 |
2017年 | 5篇 |
2016年 | 7篇 |
2015年 | 8篇 |
2014年 | 14篇 |
2013年 | 20篇 |
2012年 | 19篇 |
2011年 | 31篇 |
2010年 | 33篇 |
2009年 | 22篇 |
2008年 | 18篇 |
2007年 | 16篇 |
2006年 | 21篇 |
2005年 | 15篇 |
2004年 | 18篇 |
2003年 | 20篇 |
2002年 | 16篇 |
2001年 | 10篇 |
2000年 | 16篇 |
1999年 | 14篇 |
1998年 | 8篇 |
1997年 | 6篇 |
1996年 | 6篇 |
1995年 | 6篇 |
1994年 | 7篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 7篇 |
1989年 | 5篇 |
1988年 | 11篇 |
1987年 | 3篇 |
1985年 | 10篇 |
1984年 | 10篇 |
1983年 | 4篇 |
1982年 | 7篇 |
1981年 | 6篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 3篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1971年 | 3篇 |
1968年 | 3篇 |
1967年 | 5篇 |
排序方式: 共有504条查询结果,搜索用时 31 毫秒
451.
452.
Schossig A Wolf NI Fischer C Fischer M Stocker G Pabinger S Dander A Steiner B Tönz O Kotzot D Haberlandt E Amberger A Burwinkel B Wimmer K Fauth C Grond-Ginsbach C Koch MJ Deichmann A von Kalle C Bartram CR Kohlschütter A Trajanoski Z Zschocke J 《American journal of human genetics》2012,90(4):701-707
Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta. The molecular basis has not yet been elucidated. Here, we report that KTS is caused by mutations in ROGDI. Using a combination of autozygosity mapping and exome sequencing, we identified a homozygous frameshift deletion, c.229_230del (p.Leu77Alafs∗64), in ROGDI in two affected individuals from a consanguineous family. Molecular studies in two additional KTS-affected individuals from two unrelated Austrian and Swiss families revealed homozygosity for nonsense mutation c.286C>T (p.Gln96∗) and compound heterozygosity for the splice-site mutations c.531+5G>C and c.532-2A>T in ROGDI, respectively. The latter mutation was also found to be heterozygous in the mother of the Swiss affected individual in whom KTS was reported for the first time in 1974. ROGDI is highly expressed throughout the brain and other organs, but its function is largely unknown. Possible interactions with DISC1, a protein involved in diverse cytoskeletal functions, have been suggested. Our finding that ROGDI mutations cause KTS indicates that the protein product of this gene plays an important role in neuronal development as well as amelogenesis. 相似文献
453.
Johnson CN Spring AM Desai S Cunningham RP Germann MW 《Journal of molecular biology》2012,416(3):425-437
DNA sequence context has long been known to modulate detection and repair of DNA damage. Recent studies using experimental and computational approaches have sought to provide a basis for this observation. We have previously shown that an α-anomeric adenosine (αA) flanked by cytosines (5'CαAC-3') resulted in a kinked DNA duplex with an enlarged minor groove. Comparison of different flanking sequences revealed that a DNA duplex containing a 5'CαAG-3' motif exhibits unique substrate properties. However, this substrate was not distinguished by unusual thermodynamic properties. To understand the structural basis of the altered recognition, we have determined the solution structure of a DNA duplex with a 5'CαAG-3' core, using an extensive set of restraints including dipolar couplings and backbone torsion angles. The NMR structure exhibits an excellent agreement with the data (total R(X) <5.3%). The αA base is intrahelical, in a reverse Watson-Crick orientation, and forms a weak base pair with a thymine of the opposite strand. In comparison to the DNA duplex with a 5'CαAC-3' core, we observe a significant reduction of the local perturbation (backbone, stacking, tilt, roll, and twist), resulting in a straighter DNA with narrower minor groove. Overall, these features result in a less perturbed DNA helix and obscure the presence of the lesion compared to the 5'CαAC-3' sequence. The improved stacking of the 5'CαAG-3' core also affects the energetics of the DNA deformation that is required to form a catalytically competent complex. These traits provide a rationale for the modulation of the recognition by endonuclease IV. 相似文献
454.
Wuchter P Boda-Heggemann J Straub BK Grund C Kuhn C Krause U Seckinger A Peitsch WK Spring H Ho AD Franke WW 《Cell and tissue research》2007,328(3):499-514
Substrate-adherent cultured cells derived from human bone marrow or umbilical cord blood (“mesenchymal stem cells”) are of
special interest for regenerative medicine. We report that such cells, which can display considerable heterogeneity with respect
to their cytoskeletal protein complement, are often interconnected by special tentacle-like cell processes contacting one
or several other cells. These processus adhaerentes, studded with many (usually small) puncta adhaerentia and varying greatly in length (up to more than 400 μm long), either contact each other in the intercellular space (“ET touches”)
or insert in a tight-fitting manner into deep plasma membrane invaginations (recessus adhaerentes), thus forming a novel kind of long (up to 50 μm) continuous cuff-like junction (manubria adhaerentia). The cell processes contain an actin microfilament core that is stabilized with ezrin, α-actinin, and myosin and accompanied
by microtubules, and their adhering junctions are characterized by a molecular complement comprising the transmembrane glycoproteins
N-cadherin and cadherin-11, in combination with the cytoplasmic plaque proteins α- and β-catenin, together with p120ctn, plakoglobin, and afadin. The processes are also highly dynamic and rapidly foreshorten as cell colonies approach a denser
state of cell packing. These structures are obviously able to establish cell-cell connections, even over long distances, and
can form deep-rooted and tight cell-cell adhesions. The possible relationship to similar cell processes in the embryonic primary
mesenchyme and their potential in cell sorting and tissue formation processes in the body are discussed.
Patrick Wuchter and Judit Boda-Heggemann contributed equally to this work.
This work was supported in part by the Joachim Siebeneicher Foundation, by the Deutsche Forschungsgemeinschaft (grant HO 914/4-1
to A.D.H.), by the Deutsche Krebshilfe (grant 10-2049-Fr 1 to W.W.F), and by a grant from the German Ministry for Research
and Technology in the special funding program “Regenerative Medicine” (“START-MSC”, grants to A.D.H. and W.W.F). 相似文献
455.
Jan Kuever Michael Visser Claudia Loeffler Matthias Boll Petra Worm Diana Z. Sousa Caroline M. Plugge Peter J. Schaap Gerard Muyzer Ines A.C. Pereira Sofiya N. Parshina Lynne A. Goodwin Nikos C. Kyrpides Janine Detter Tanja Woyke Patrick Chain Karen W. Davenport Manfred Rohde Stefan Spring Hans-Peter Klenk Alfons J.M. Stams 《Standards in genomic sciences》2014,9(3):821-839
Desulfotomaculum gibsoniae is a mesophilic member of the polyphyletic spore-forming genus Desulfotomaculum within the family Peptococcaceae. This bacterium was isolated from a freshwater ditch and is of interest because it can grow with a large variety of organic substrates, in particular several aromatic compounds, short-chain and medium-chain fatty acids, which are degraded completely to carbon dioxide coupled to the reduction of sulfate. It can grow autotrophically with H2 + CO2 and sulfate and slowly acetogenically with H2 + CO2, formate or methoxylated aromatic compounds in the absence of sulfate. It does not require any vitamins for growth. Here, we describe the features of D. gibsoniae strain GrollT together with the genome sequence and annotation. The chromosome has 4,855,529 bp organized in one circular contig and is the largest genome of all sequenced Desulfotomaculum spp. to date. A total of 4,666 candidate protein-encoding genes and 96 RNA genes were identified. Genes of the acetyl-CoA pathway, possibly involved in heterotrophic growth and in CO2 fixation during autotrophic growth, are present. The genome contains a large set of genes for the anaerobic transformation and degradation of aromatic compounds, which are lacking in the other sequenced Desulfotomaculum genomes. 相似文献
456.
Se-Lyun Yoon Yunhee Jeong Heui-Soo Kim Eun-Kyung Ahn So-Young Seol Sang-Yeop Lee Yun-Gil Roh Jeong-An Gim Spring Yewon Hwang Tae-Hong Kang Jin Woong Chung Sun-Hee Leem 《Genes & genomics.》2014,36(3):375-385
The neuronally expressed Shc adaptor homolog SCK1/SHC2 gene contains an unusually high number of minisatellites. In humans, twelve different minisatellite sequences are located in introns of SCK1/SHC2 and ten of them are highly polymorphic. Here we used primers developed for humans to screen ten intronic loci of SCK1/SHC2 in chimpanzee and gorilla, and undertook a comprehensive analysis of the genomic sequence to address the evolutionary events driving these variable repeats. All ten loci amplified in chimpanzee and gorilla contained hypervariable and low-variability minisatellites. The human polymorphic locus TR1 was monomorphic in chimpanzee and gorilla, but we detected polymorphic alleles in these apes for the human monomorphic TR7 locus. When we examined the repeat size among these hominoids, there was no consistent variation by length from humans to great apes. In spite of the inconsistent evolutionary dynamics in repeat length variation, exon 16 was highly conserved between humans and great apes. These results suggest that non-coding intronic minisatellites do not show a consistent evolutionary paradigm but evolved with different patterns among each minisatellite locus. These findings provide important insight for minisatellite conservation during hominoid evolution. 相似文献
457.
Samir K. Maji Rachel R. Ogorzalek Loo Mohammed Inayathullah Sean M. Spring Sabrina S. Vollers Margaret M. Condron Gal Bitan Joseph A. Loo David B. Teplow 《The Journal of biological chemistry》2009,284(35):23580-23591
Understanding the structural and assembly dynamics of the amyloid β-protein (Aβ) has direct relevance to the development of therapeutic agents for Alzheimer disease. To elucidate these dynamics, we combined scanning amino acid substitution with a method for quantitative determination of the Aβ oligomer frequency distribution, photo-induced cross-linking of unmodified proteins (PICUP), to perform “scanning PICUP.” Tyr, a reactive group in PICUP, was substituted at position 1, 10, 20, 30, or 40 (for Aβ40) or 42 (for Aβ42). The effects of these substitutions were probed using circular dichroism spectroscopy, thioflavin T binding, electron microscopy, PICUP, and mass spectrometry. All peptides displayed a random coil → α/β → β transition, but substitution-dependent alterations in assembly kinetics and conformer complexity were observed. Tyr1-substituted homologues of Aβ40 and Aβ42 assembled the slowest and yielded unusual patterns of oligomer bands in gel electrophoresis experiments, suggesting oligomer compaction had occurred. Consistent with this suggestion was the observation of relatively narrow [Tyr1]Aβ40 fibrils. Substitution of Aβ40 at the C terminus decreased the population conformational complexity and substantially extended the highest order of oligomers observed. This latter effect was observed in both Aβ40 and Aβ42 as the Tyr substitution position number increased. The ability of a single substitution (Tyr1) to alter Aβ assembly kinetics and the oligomer frequency distribution suggests that the N terminus is not a benign peptide segment, but rather that Aβ conformational dynamics and assembly are affected significantly by the competition between the N and C termini to form a stable complex with the central hydrophobic cluster.Alzheimer disease (AD)4 is the most common cause of late-life dementia (1) and is estimated to afflict more than 27 million people worldwide (2). An important etiologic hypothesis is that amyloid β-protein (Aβ) oligomers are the proximate neurotoxins in AD. Substantial in vivo and in vitro evidence supports this hypothesis (3–12). Neurotoxicity studies have shown that Aβ assemblies are potent neurotoxins (5, 13–20), and the toxicity of some oligomers can be greater than that of the corresponding fibrils (21). Soluble Aβ oligomers inhibit hippocampal long term potentiation (4, 5, 13, 15, 17, 18, 22) and disrupt cognitive function (23). Compounds that bind and disrupt the formation of oligomers have been shown to block the neurotoxicity of Aβ (24, 25). Importantly, recent studies in higher vertebrates (dogs) have shown that substantial reduction in amyloid deposits in the absence of decreases in oligomer concentration has little effect on recovery of neurological function (26).Recent studies of Aβ oligomers have sought to correlate oligomer size and biological activity. Oligomers in the supernatants of fibril preparations centrifuged at 100,000 × g caused sustained calcium influx in rat hippocampal neurons, leading to calpain activation and dynamin 1 degradation (27). Aβ-derived diffusible ligand-like Aβ42 oligomers induced inflammatory responses in cultured rat astrocytes (28). A 90-kDa Aβ42 oligomer (29) has been shown to activate ERK1/2 in rat hippocampal slices (30) and bind avidly to human cortical neurons (31), in both cases causing apoptotic cell death. A comparison of the time dependence of the toxic effects of the 90-kDa assembly with that of Aβ-derived diffusible ligands revealed a 5-fold difference, Aβ-derived diffusible ligands requiring more time for equivalent effects (31). A 56-kDa oligomer, “Aβ*56,” was reported to cause memory impairment in middle-aged transgenic mice expressing human amyloid precursor protein (32). A nonamer also had adverse effects. Impaired long term potentiation in rat brain slices has been attributed to Aβ trimers identified in media from cultured cells expressing human amyloid precursor protein (33). Dimers and trimers from this medium also have been found to cause progressive loss of synapses in organotypic rat hippocampal slices (10). In mice deficient in neprilysin, an enzyme that has been shown to degrade Aβ in vivo (34), impairment in neuronal plasticity and cognitive function correlated with significant increases in Aβ dimer levels and synapse-associated Aβ oligomers (35).The potent pathologic effects of Aβ oligomers provide a compelling reason for elucidating the mechanism(s) of their formation. This has been a difficult task because of the metastability and polydispersity of Aβ assemblies (36). To obviate these problems, we introduced the use of the method of photo-induced cross-linking of unmodified proteins (PICUP) to rapidly (<1 s) and covalently stabilize oligomer mixtures (for reviews see Refs. 37, 38). Oligomers thus stabilized no longer exist in equilibrium with monomers or each other, allowing determination of oligomer frequency distributions by simple techniques such as SDS-PAGE (37). Recently, to obtain population-average information on contributions to fibril formation of amino acid residues at specific sites in Aβ, we employed a scanning intrinsic fluorescence approach (39). Tyr was used because it is a relatively small fluorophore, exists natively in Aβ, and possesses the side chain most reactive in the PICUP chemistry (40). Using this approach, we found that the central hydrophobic cluster region (Leu17–Ala21) was particularly important in controlling fibril formation of Aβ40, whereas the C terminus was the predominant structural element controlling Aβ42 assembly (39). Here we present results of studies in which key strategic features of the two methods have been combined to enable execution of “scanning PICUP” and the consequent revelation of site-specific effects on Aβ oligomerization. 相似文献
458.
459.
Grassi P Urías Reyes TS Sosa S Tubaro A Hofer O Zitterl-Eglseer K 《Zeitschrift für Naturforschung. C, Journal of biosciences》2006,61(3-4):165-170
Separation and isolation of the two main compounds suaveolol and methyl suaveolate from leaves of chichinguaste (Hyptis suaveolens Poit., Lamiaceae) could be achieved by means of repeated column chromatography and repeated preparative thin layer chromatography. Their chemical structures were approved by MS, 1H NMR, 13C NMR and 2D-NMR experiments. The anti-inflammatory activity of the two compounds was tested for the first time as inhibition of croton oil-induced dermatitis of the mouse ear. Suaveolol and methyl suaveolate showed nearly the same dose-dependent topical anti-inflammatory activity, only two to three times lower than that of the reference drug indomethacin. The anti-inflammatory properties of these compounds could contribute to the antiphlogistic activity of extracts of Hyptis species and confirm the rational use of Hyptis suaveolens extracts in dermatological diseases. 相似文献
460.
Stephan Jung Claudia Fladerer Frank Braendle Johannes Madlung Otmar Spring Alfred Nordheim 《Proteome science》2010,8(1):24