全文获取类型
收费全文 | 23402篇 |
免费 | 2180篇 |
国内免费 | 2292篇 |
出版年
2024年 | 44篇 |
2023年 | 316篇 |
2022年 | 385篇 |
2021年 | 647篇 |
2020年 | 638篇 |
2019年 | 774篇 |
2018年 | 719篇 |
2017年 | 723篇 |
2016年 | 714篇 |
2015年 | 822篇 |
2014年 | 916篇 |
2013年 | 1342篇 |
2012年 | 834篇 |
2011年 | 1119篇 |
2010年 | 995篇 |
2009年 | 1440篇 |
2008年 | 1362篇 |
2007年 | 1430篇 |
2006年 | 1381篇 |
2005年 | 1384篇 |
2004年 | 1250篇 |
2003年 | 1052篇 |
2002年 | 946篇 |
2001年 | 595篇 |
2000年 | 555篇 |
1999年 | 591篇 |
1998年 | 560篇 |
1997年 | 466篇 |
1996年 | 391篇 |
1995年 | 430篇 |
1994年 | 360篇 |
1993年 | 306篇 |
1992年 | 264篇 |
1991年 | 215篇 |
1990年 | 214篇 |
1989年 | 196篇 |
1988年 | 159篇 |
1987年 | 150篇 |
1986年 | 107篇 |
1985年 | 159篇 |
1984年 | 166篇 |
1983年 | 115篇 |
1982年 | 134篇 |
1981年 | 76篇 |
1980年 | 95篇 |
1979年 | 59篇 |
1978年 | 47篇 |
1977年 | 36篇 |
1976年 | 37篇 |
1973年 | 41篇 |
排序方式: 共有10000条查询结果,搜索用时 187 毫秒
991.
Hongyan Zheng Alina Beliavsky Anatoli Tchigvintsev Joseph S. Brunzelle Greg Brown Robert Flick Elena Evdokimova Zdzislaw Wawrzak Radhakrishnan Mahadevan Wayne F. Anderson Alexei Savchenko Alexander F. Yakunin 《Proteins》2013,81(6):1031-1041
Aldehyde dehydrogenases are found in all organisms and play an important role in the metabolic conversion and detoxification of endogenous and exogenous aldehydes. Genomes of many organisms including Escherichia coli and Salmonella typhimurium encode two succinate semialdehyde dehydrogenases with low sequence similarity and different cofactor preference (YneI and GabD). Here, we present the crystal structure and biochemical characterization of the NAD(P)+‐dependent succinate semialdehyde dehydrogenase YneI from S. typhimurium. This enzyme shows high activity and affinity toward succinate semialdehyde and exhibits substrate inhibition at concentrations of SSA higher than 0.1 mM. YneI can use both NAD+ and NADP+ as cofactors, although affinity to NAD+ is 10 times higher. High resolution crystal structures of YneI were solved in a free state (1.85 Å) and in complex with NAD+ (1.90 Å) revealing a two domain protein with the active site located in the interdomain interface. The NAD+ molecule is bound in the long channel with its nicotinamide ring positioned close to the side chain of the catalytic Cys268. Site‐directed mutagenesis demonstrated that this residue, as well as the conserved Trp136, Glu365, and Asp426 are important for activity of YneI, and that the conserved Lys160 contributes to the enzyme preference to NAD+. Our work has provided further insight into the molecular mechanisms of substrate selectivity and activity of succinate semialdehyde dehydrogenases. © 2012 Wiley Periodicals, Inc. 相似文献
992.
Here, we report the NMR solution structures of Mycobacterium tuberculosis (M. tuberculosis) thioredoxin C in both oxidized and reduced states, with discussion of structural changes that occur in going between redox states. The NMR solution structure of the oxidized TrxC corresponds closely to that of the crystal structure, except in the C‐terminal region. It appears that crystal packing effects have caused an artifactual shift in the α4 helix in the previously reported crystal structure, compared with the solution structure. On the basis of these TrxC structures, chemical shift mapping, a previously reported crystal structure of the M. tuberculosis thioredoxin reductase (not bound to a Trx) and structures for intermediates in the E. coli thioredoxin catalytic cycle, we have modeled the complete M. tuberculosis thioredoxin system for the various steps in the catalytic cycle. These structures and models reveal pockets at the TrxR/TrxC interface in various steps in the catalytic cycle, which can be targeted in the design of uncompetitive inhibitors as potential anti‐mycobacterial agents, or as chemical genetic probes of function. © Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
993.
With the rise of antibody based therapeutics as successful medicines, there is an emerging need to understand the fundamental antibody conformational dynamics and its implications towards stability of these medicines. Both deglycosylation and thermal stress have been shown to cause conformational destabilization and aggregation in monoclonal antibodies. Here, we study instabilities caused by deglycosylation and by elevated temperature (400 K) by performing molecular dynamic simulations on a full length murine IgG2a mAb whose crystal structure is available in the Protein Data bank. Cα‐atom root mean square deviation and backbone root mean square fluctuation calculations show that deglycosylation perturbs quaternary and tertiary structures in the CH2 domains. In contrast, thermal stress pervades throughout the antibody structure and both Fabs and Fc regions are destabilized. The thermal stress applied in this study was not sufficient to cause large scale unfolding within the simulation time and most amino acid residues showed similar average solvent accessible surface area and secondary structural conformations in all trajectories. CH3 domains were the most successful at resisting the conformational destabilization. The simulations helped identify aggregation prone regions, which may initiate cross‐β motif formation upon deglycosylation and upon applying thermal stress. Deglycosylation leads to increased backbone fluctuations and solvent exposure of a highly conserved APR located in the edge β‐strand A of the CH2 domains. Aggregation upon thermal stress is most likely initiated by two APRs that overlap with the complementarity determining regions. This study has important implications for rational design of antibody based therapeutics that are resistant towards aggregation. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
994.
Michael I. Sadowski 《Proteins》2013,81(2):253-260
It has been known even since relatively few structures had been solved that longer protein chains often contain multiple domains, which may fold separately and play the role of reusable functional modules found in many contexts. In many structural biology tasks, in particular structure prediction, it is of great use to be able to identify domains within the structure and analyze these regions separately. However, when using sequence data alone this task has proven exceptionally difficult, with relatively little improvement over the naive method of choosing boundaries based on size distributions of observed domains. The recent significant improvement in contact prediction provides a new source of information for domain prediction. We test several methods for using this information including a kernel smoothing‐based approach and methods based on building alpha‐carbon models and compare performance with a length‐based predictor, a homology search method and four published sequence‐based predictors: DOMCUT, DomPRO, DLP‐SVM, and SCOOBY‐DOmain. We show that the kernel‐smoothing method is significantly better than the other ab initio predictors when both single‐domain and multidomain targets are considered and is not significantly different to the homology‐based method. Considering only multidomain targets the kernel‐smoothing method outperforms all of the published methods except DLP‐SVM. The kernel smoothing method therefore represents a potentially useful improvement to ab initio domain prediction. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
995.
Protein chemical shifts encode detailed structural information that is difficult and computationally costly to describe at a fundamental level. Statistical and machine learning approaches have been used to infer correlations between chemical shifts and secondary structure from experimental chemical shifts. These methods range from simple statistics such as the chemical shift index to complex methods using neural networks. Notwithstanding their higher accuracy, more complex approaches tend to obscure the relationship between secondary structure and chemical shift and often involve many parameters that need to be trained. We present hidden Markov models (HMMs) with Gaussian emission probabilities to model the dependence between protein chemical shifts and secondary structure. The continuous emission probabilities are modeled as conditional probabilities for a given amino acid and secondary structure type. Using these distributions as outputs of first‐ and second‐order HMMs, we achieve a prediction accuracy of 82.3%, which is competitive with existing methods for predicting secondary structure from protein chemical shifts. Incorporation of sequence‐based secondary structure prediction into our HMM improves the prediction accuracy to 84.0%. Our findings suggest that an HMM with correlated Gaussian distributions conditioned on the secondary structure provides an adequate generative model of chemical shifts. Proteins 2013; © 2012 Wiley Periodicals, Inc. 相似文献
996.
Gerald Grellet-Tinner Stephen Wroe Michael B. Thompson Qiang Ji 《Historical Biology》2013,25(4):273-277
Based on examination of eggshell structure and predicted vapor conductances in eggshells in recently described material from Argentina and China we conclude that pterosaurs buried their eggs. Egg-burying imposes theoretical restrictions on the distribution of pterosaurs, both geographically and spatially, raises the possibility of thermal sex determination and supports previous suggestions that they exhibited nesting fidelity. Some features associated with egg-burying, such as weight savings, are likely to have been fortuitous pre-adaptations for these flying reptiles, but others may have disadvantaged them relative to avian competitors or increased their vulnerability to extinction in a cooling climate. 相似文献
997.
Twenty novel simple alkyl isocyanides derived from citronellol were synthesized and evaluated for their antifouling activity and toxicity against cypris larvae of the barnacle, Balanus amphitrite. The anti-barnacle activity of the synthesized isocyanides was in the EC50 range of 0.08–1.49 μg ml?1. Simple isocyanides containing a benzoate and chloro group showed the most potent anti-barnacle activity. In addition, none of the synthesized compounds showed significant toxicity and LC50 values were <10 μg ml?1. The LC50/EC50 ratios of almost all of the synthesized compounds were >102. The results indicate that these simple isocyanides are promising low-toxicity antifouling agents. 相似文献
998.
Settlement and metamorphosis of pediveliger larvae of Mytilus coruscus in response to natural biofilms was investigated in the laboratory. Pediveliger larvae settled and metamorphosed in response to biofilms and post-larval settlement and metamorphosis increased with biofilm age. The activity of the biofilm was positively correlated with biofilm age, dry weight, bacterial density and diatom density, but had no apparent relationship with chlorophyll a concentration. The change in bacterial community composition corresponding to biofilm age may explain differences in the age-dependent inducing activities of biofilms, which in turn may play an important role in larval settlement in this species. 相似文献
999.
Surfaces of buildings at the archaeological site of Palenque, Mexico, are colonized by cyanobacteria that form biofilms, which in turn cause aesthetic and structural damage. The structural characterization and species composition of biofilms from the walls of one of these buildings, El Palacio, are reported. The distribution of photosynthetic microorganisms in the biofilms, their relationship with the colonized substratum, and the three-dimensional structure of the biofilms were studied by image analysis. The differences between local seasonal microenvironments at the Palenque site, the bioreceptivity of stone and the relationship between biofilms and their substrata are described. The implications for the development and permanence of species capable of withstanding temporal heterogeneity in and on El Palacio, mainly due to alternating wet and dry seasons, are discussed. Knowledge on how different biofilms contribute to biodegradation or bioprotection of the substratum can be used to develop maintenance and conservation protocols for cultural heritage. 相似文献
1000.
Abstract We have performed NPT molecular dynamics simulations (Langevin Piston Method) on two types of solvated proteins-‘denaturation-unfavorable’ protein (insulin) and ‘denaturation-favorable protein’ (ribonuclease A) at high pressure (from 1 bar up to 20 kbar). The method is based on the extended system formalism introduced by Andersen, where the deterministic equations of motion for the piston degree of freedom are replaced by Langevin equation. We report the structural changes of proteins (ribonuclease A and insulin) and water molecules through radius of gyration, solvent accessible surface area, hydrogen bond pattern, and the topology of water clusters connected by the hydrogen bonded circular network. The solvent accessibility of ribonuclease A is mainly decreased by hydrophilic residues rather than hydrophobic residues under high pressure. From the results of hydrogen bond analysis, we have found that α-helix is more stable than β-sheet under high pressure. In addition, from the analysis of the water cluster, we have observed that for ribonuclease A, 5-membered ring structure is more favorable than 6-membered ring at higher pressure. However, for insulin, the ratio of 5 to 6-ring is constant over the pressure ranges for which we have performed MD simulation. This indicates that the water structure around insulin does not change under high pressure. 相似文献