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51.
Calculation of pKas in RNA: on the structural origins and functional roles of protonated nucleotides
pK(a) calculations based on the Poisson-Boltzmann equation have been widely used to study proteins and, more recently, DNA. However, much less attention has been paid to the calculation of pK(a) shifts in RNA. There is accumulating evidence that protonated nucleotides can stabilize RNA structure and participate in enzyme catalysis within ribozymes. Here, we calculate the pK(a) shifts of nucleotides in RNA structures using numerical solutions to the Poisson-Boltzmann equation. We find that significant shifts are predicted for several nucleotides in two catalytic RNAs, the hairpin ribozyme and the hepatitis delta virus ribozyme, and that the shifts are likely to be related to their functions. We explore how different structural environments shift the pK(a)s of nucleotides from their solution values. RNA structures appear to use two basic strategies to shift pK(a)s: (a) the formation of compact structural motifs with structurally-conserved, electrostatic interactions; and (b) the arrangement of the phosphodiester backbone to focus negative electrostatic potential in specific regions. 相似文献
52.
Gender differences in biomechanical properties of intramural coronary resistance arteries of rats, an in vitro microarteriographic study 总被引:1,自引:0,他引:1
Matrai M Mericli M Nadasy GL Szekeres M Varbiro S Banhidy F Acs N Monos E Szekacs B 《Journal of biomechanics》2007,40(5):1024-1030
The prevalence of ischemic heart disease is lower in premenopausal females than in males of corresponding age. This should be related to gender differences in coronary functions. We tested whether biomechanical differences exist between intramural coronary resistance arteries of male and female rats. Intramural branches of the left anterior descending coronary artery (uniformly approximately 200microm in diameter) were isolated, cannulated and studied by microarteriography. Intraluminal pressure was increased from 2 to 90mmHg in steps and steady-state diameters were measured. Measurements were repeated in the presence of vasoconstrictor U46619 (10(-6)M) and the endothelial coronary vasodilator bradykinin (BK) (10(-6)M). Finally, passive diameters were recorded in calcium-free saline. A similar inner radius and a higher wall thickness (41.5+/-2.9microm vs. 31.4+/-2.7microm at 50mmHg in the passive condition, p<0.05) resulted in lower tangential wall stresses in male rats (18.9+/-1.9kPa vs. 24.9+/-2.5kPa at 50mmHg, p<0.05). Isobaric elastic modulus of vessels from male animals was significantly smaller at higher pressures. Vasoconstrictor response was significantly stronger in male than in female animals. Endothelial relaxations induced by BK were not different. This is the first demonstration that biomechanical characteristics of intramural coronary resistance arteries of a mammalian species are different in the male and female sexes. Higher wall thickness and higher vascular contractility in males are associated with similar endothelial function and larger high-pressure elasticity compared to females. These gender differences in biomechanics of coronary resistance arteries of rats may contribute to our better understanding the characteristic physiological and pathological differences in humans. 相似文献
53.
54.
pKa predictions for proteins,RNAs, and DNAs with the Gaussian dielectric function using DelPhi pKa 下载免费PDF全文
We developed a Poisson‐Boltzmann based approach to calculate the values of protein ionizable residues (Glu, Asp, His, Lys and Arg), nucleotides of RNA and single stranded DNA. Two novel features were utilized: the dielectric properties of the macromolecules and water phase were modeled via the smooth Gaussian‐based dielectric function in DelPhi and the corresponding electrostatic energies were calculated without defining the molecular surface. We tested the algorithm by calculating values for more than 300 residues from 32 proteins from the PPD dataset and achieved an overall RMSD of 0.77. Particularly, the RMSD of 0.55 was achieved for surface residues, while the RMSD of 1.1 for buried residues. The approach was also found capable of capturing the large shifts of various single point mutations in staphylococcal nuclease (SNase) from ‐cooperative dataset, resulting in an overall RMSD of 1.6 for this set of pKa's. Investigations showed that predictions for most of buried mutant residues of SNase could be improved by using higher dielectric constant values. Furthermore, an option to generate different hydrogen positions also improves predictions for buried carboxyl residues. Finally, the calculations on two RNAs demonstrated the capability of this approach for other types of biomolecules. Proteins 2015; 83:2186–2197. © 2015 Wiley Periodicals, Inc. 相似文献
55.
Jean-Marie Burel Sébastien Besson Colin Blackburn Mark Carroll Richard K. Ferguson Helen Flynn Kenneth Gillen Roger Leigh Simon Li Dominik Lindner Melissa Linkert William J. Moore Balaji Ramalingam Emil Rozbicki Aleksandra Tarkowska Petr Walczysko Chris Allan Josh Moore Jason R. Swedlow 《Mammalian genome》2015,26(9-10):441-447
56.
Yumi Ueki Michael A Hadders Melanie B Weisser Isha Nasa Paula SoteloParrilla Lauren E Cressey Tanmay Gupta Emil P T Hertz Thomas Kruse Guillermo Montoya A Arockia Jeyaprakash Arminja Kettenbach Susanne M A Lens Jakob Nilsson 《EMBO reports》2021,22(7)
The shugoshin proteins are universal protectors of centromeric cohesin during mitosis and meiosis. The binding of human hSgo1 to the PP2A‐B56 phosphatase through a coiled‐coil (CC) region mediates cohesion protection during mitosis. Here we undertook a structure function analysis of the PP2A‐B56‐hSgo1 complex, revealing unanticipated aspects of complex formation and function. We establish that a highly conserved pocket on the B56 regulatory subunit is required for hSgo1 binding and cohesion protection during mitosis in human somatic cells. Consistent with this, we show that hSgo1 blocks the binding of PP2A‐B56 substrates containing a canonical B56 binding motif. We find that PP2A‐B56 bound to hSgo1 dephosphorylates Cdk1 sites on hSgo1 itself to modulate cohesin interactions. Collectively our work provides important insight into cohesion protection during mitosis. 相似文献
57.
Geu-Flores F Møldrup ME Böttcher C Olsen CE Scheel D Halkier BA 《The Plant cell》2011,23(6):2456-2469
The defense-related plant metabolites known as glucosinolates play important roles in agriculture, ecology, and human health. Despite an advanced biochemical understanding of the glucosinolate pathway, the source of the reduced sulfur atom in the core glucosinolate structure remains unknown. Recent evidence has pointed toward GSH, which would require further involvement of a GSH conjugate processing enzyme. In this article, we show that an Arabidopsis thaliana mutant impaired in the production of the γ-glutamyl peptidases GGP1 and GGP3 has altered glucosinolate levels and accumulates up to 10 related GSH conjugates. We also show that the double mutant is impaired in the production of camalexin and accumulates high amounts of the camalexin intermediate GS-IAN upon induction. In addition, we demonstrate that the cellular and subcellular localization of GGP1 and GGP3 matches that of known glucosinolate and camalexin enzymes. Finally, we show that the purified recombinant GGPs can metabolize at least nine of the 10 glucosinolate-related GSH conjugates as well as GS-IAN. Our results demonstrate that GSH is the sulfur donor in the biosynthesis of glucosinolates and establish an in vivo function for the only known cytosolic plant γ-glutamyl peptidases, namely, the processing of GSH conjugates in the glucosinolate and camalexin pathways. 相似文献
58.
Emil Tkadlec Lenka Lisická-Lachnitová Jan Losík Marta Heroldová 《Population Ecology》2011,53(3):495-500
Most modern population dynamics analyses of time series use simple population indices for ecological inference. These indices,
collected for many years for various agricultural pests or game animals, are generally believed not to distort systematically
feedback estimates because the assumption of linearity to population size roughly holds. To assess the relative importance
of this assumption, we examined the effect of nonlinearity in a burrow index for voles on feedback estimates obtained through
autoregressive modeling. We show that the issue of linearity is of less importance to ecological inference because the feedback
estimates are routinely obtained on a logarithmic scale. Transforming data to logs has a strong linearization effect, removing
most of the nonlinearity observed on the original scale. We conclude that the statistical tools for ecological inference,
such as autoregressive log-linear models, are sufficiently robust to the systematic error imposed by index nonlinearity and
that indices are valuable sources of ecological information even in situations when the assumed linear functional forms to
population size were not exactly validated. We suggest that for time series modelers, the issue of a large sampling variation
in small “noisy” populations is by far a more burning one than the systematic error due to index nonlinearity. 相似文献
59.
Alessandra Villa Valeria Lovato Emil Bujak Sarah Wulhfard Nadine Pasche Dario Neri 《MABS-AUSTIN》2011,3(3):264-272
Human monoclonal antibodies (mAbs) can routinely be isolated from phage display libraries against virtually any protein available in sufficient purity and quantity, but library design can influence epitope coverage on the target antigen. Here we describe the construction of a novel synthetic human antibody phage display library that incorporates hydrophilic or charged residues at position 52 of the CDR2 loop of the variable heavy chain domain, instead of the serine residue found in the corresponding germline gene. The novel library was used to isolate human mAbs to various antigens, including the alternatively-spliced EDA domain of fibronectin, a marker of tumor angiogenesis. In particular, the mAb 2H7 was proven to bind to a novel epitope on EDA, which does not overlap with the one recognized by the clinical-stage F8 antibody. F8 and 2H7 were used for the construction of chelating recombinant antibodies (CRAbs), whose tumor-targeting properties were assessed in vivo in biodistribution studies in mice bearing F9 teratocarcinoma, revealing a preferential accumulation at the tumor site.Key words: human antibody library, phage display, oncofetal fibronectin, vascular tumor targeting, scFv antibody fragments, chelating recombinant antibody (CRAb) 相似文献
60.