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771.
The ensemble folding of two 21-residue alpha-helical peptides has been studied using all-atom simulations under several variants of the AMBER potential in explicit solvent using a global distributed computing network. Our extensive sampling, orders of magnitude greater than the experimental folding time, results in complete convergence to ensemble equilibrium. This allows for a quantitative assessment of these potentials, including a new variant of the AMBER-99 force field, denoted AMBER-99 phi, which shows improved agreement with experimental kinetic and thermodynamic measurements. From bulk analysis of the simulated AMBER-99 phi equilibrium, we find that the folding landscape is pseudo-two-state, with complexity arising from the broad, shallow character of the "native" and "unfolded" regions of the phase space. Each of these macrostates allows for configurational diffusion among a diverse ensemble of conformational microstates with greatly varying helical content and molecular size. Indeed, the observed structural dynamics are better represented as a conformational diffusion than as a simple exponential process, and equilibrium transition rates spanning several orders of magnitude are reported. After multiple nucleation steps, on average, helix formation proceeds via a kinetic "alignment" phase in which two or more short, low-entropy helical segments form a more ideal, single-helix structure. 相似文献
772.
Integrins bind to their ligand in the extracellular matrix (ECM), such as fibronectin (FN), through a specific interaction between the amino acid motifs in the ligand, and binding sites in the extracellular domains of the integrin molecule generated jointly by its alpha and beta subunits. It has been proposed that membrane cholesterol and glycosphingolipids (GSLs) can regulate integrin-ECM interactions and it has been demonstrated that increased membrane cholesterol leads to increased cell adhesion to FN. Here, we have shown that a specific glycosphingolipid GM3 binds directly to alpha5beta1 integrin and an increase in membrane cholesterol results in the redistribution of GM3-associated alpha5beta1 integrin molecules specifically on the surface that is in contact with the substratum. Our results suggest that GM3-associated alpha5beta1 integrins bind less avidly to FN than GM3-free integrins and that cholesterol and GM3 play an interdependent role in the distribution of alpha5beta1integrin molecules in the membrane and regulation of cell adhesion. 相似文献
773.
Bryan Glenn J. McLean Karen Pande Barnaly Purvis Andy Hackett Christine A. Bradshaw John E. Waugh Robbie 《Molecular breeding : new strategies in plant improvement》2004,14(2):105-116
Potato Cyst Nematodes (PCN) currently represent a serious threat to potato cultivation. However, many sources of resistance are known amongst primitive and wild relatives of cultivated potato, Solanum tuberosum ssp. tuberosum. Currently, in the UK, the major threat is due to Globodera pallida, resistance to which has not yet been effectively deployed in potato cultivars. We have performed linkage and QTL analysis of a tetraploid potato population segregating for the H3 source of resistance to G. pallida that was introgressed into cultivated potato from the primitive species, Solanum tuberosum ssp. andigena. This source is highly effective against the most common UK pathotype of G. pallida (Pa2/3) and its deployment in breeding material is a major goal. We adopted an approach involving bulked segregant analysis (BSA) as well as genome wide linkage analysis using AFLP and SSR markers. BSA provided a concentration of markers linked in coupling to a QTL on linkage group IV, and improved the accuracy of the QTL localisation. By performing an analysis on residual scores after removal of the effects due to the major QTL, we detected a second QTL on linkage group XI. 相似文献
774.
We have used distributed computing techniques and a supercluster of thousands of computer processors to study folding of the C-terminal beta-hairpin from protein G in atomistic detail using the GB/SA implicit solvent model at 300 K. We have simulated a total of nearly 38 micros of folding time and obtained eight complete and independent folding trajectories. Starting from an extended state, we observe relaxation to an unfolded state characterized by non-specific, temporary hydrogen bonding. This is followed by the appearance of interactions between hydrophobic residues that stabilize a bent intermediate. Final formation of the complete hydrophobic core occurs cooperatively at the same time that the final hydrogen bonding pattern appears. The folded hairpin structures we observe all contain a closely packed hydrophobic core and proper beta-sheet backbone dihedral angles, but they differ in backbone hydrogen bonding pattern. We show that this is consistent with the existing experimental data on the hairpin alone in solution. Our analysis also reveals short-lived semi-helical intermediates which define a thermodynamic trap. Our results are consistent with a three-state mechanism with a single rate-limiting step in which a varying final hydrogen bond pattern is apparent, and semi-helical off-pathway intermediates may appear early in the folding process. We include details of the ensemble dynamics methodology and a discussion of our achievements using this new computational device for studying dynamics at the atomic level. 相似文献
775.
We have studied the mitotic reassembly of the nuclear envelope, using antibodies to nuclear marker proteins and NPA58 in F-111 rat fibroblast cells. In earlier studies we have proposed that NPA58, a 58 kDa rat nuclear protein, is involved in nuclear protein import. In this report, NPA58 is shown to be localized on the cytoplasmic face of the envelope in interphase cells, in close association with nuclear pores. In mitotic cells NPA58 is dispersed in the cytoplasm till anaphase. The targeting of NPA58 to the reforming nuclear envelope in early telophase coincides with the recruitment of a well-characterized class of nuclear pore proteins recognized by the antibody mAb 414, and occurs prior to the incorporation of lamin B1 into the envelope. Significant protein import activity is detectable only after localization of NPA58 in the newly-formed envelope. The early targeting of NPA58 is consistent with its proposed role in nuclear transport. 相似文献
776.
Bhunia S Bharambe MS Singh R Premendran J Pande S 《Indian journal of experimental biology》2000,38(3):237-241
To study the effects of microinjections of 5 hydroxytryptamine and adrenaline in central grey on pain responsiveness during acute food deprivation, experiments were conducted in nine male rats. Microinjections of 5 HT (10 micrograms/microliter) and adrenaline (10 micrograms/microliter) were given in central grey before and at the end of 6, 12, 18 and 24 hr food deprivation and the effects on pain threshold, cardiorespiratory parameters and body temperature were noted. Observations showed that 5 HT increased the pain threshold (antinociception) significantly (P < 0.05) with no change in cardiorespiratory response and body temperature, adrenaline did not alter pain threshold with no change in cardiorespiratory response and body temperature. The observations suggest the possible existence of two types of monoaminergic receptors or pathways in the central grey. 相似文献
777.
Markov state models (MSMs) have proven to be useful tools in simulating large and slowly-relaxing biological systems like proteins. MSMs model proteins through dynamics on a discrete-state energy landscape, allowing molecules to effectively sample large regions of phase space. In this work, we use aspects of MSMs to ask: is protein folding mechanistically robust? We first provide a definition of mechanism in the context of Markovian models, and we later use perturbation theory and the concept of parametric sloppiness to show that parts of the MSM eigenspectrum are resistant to perturbation. We introduce a new, to our knowledge, Bayesian metric by which eigenspectrum robustness can be evaluated, and we discuss the implications of mechanistic robustness and possible new applications of MSMs to understanding biophysical phenomena. 相似文献
778.
Paslay LC Abel BA Brown TD Koul V Choudhary V McCormick CL Morgan SE 《Biomacromolecules》2012,13(8):2472-2482
Antimicrobial peptides (AMPs) show great potential as alternative therapeutic agents to conventional antibiotics as they can selectively bind and eliminate pathogenic bacteria without harming eukaryotic cells. It is of interest to develop synthetic macromolecules that mimic AMPs behavior, but that can be produced more economically at commercial scale. Herein, we describe the use of aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization to prepare primary and tertiary amine-containing polymers with precise molecular weight control and narrow molecular weight distributions. Specifically, N-(3-aminopropyl)methacrylamide (APMA) was statistically copolymerized with N-[3-(dimethylamino)propyl]methacrylamide (DMAPMA) or N-[3-(diethylamino)propyl]methacrylamide (DEAPMA) to afford a range of (co)polymer compositions. Analysis of antimicrobial activity against E. coli (Gram-negative) and B. subtilis (Gram-positive) as a function of buffer type, salt concentration, pH, and time indicated that polymers containing large fractions of primary amine were most effective against both strains of bacteria. Under physiological pH and salt conditions, the polymer with the highest primary amine content caused complete inhibition of bacterial growth at low concentrations, while negligible hemolysis was observed over the full range of concentrations tested, indicating exceptional selectivity. The cytotoxicity of select polymers was evaluated against MCF-7 cells. 相似文献
779.
ABSTRACT: BACKGROUND: The Non-Structural (NS1) protein of Influenza A viruses is an extensively studied multifunctional protein which is commonly considered as key viral component to fight against host immune responses. Even though there has been a lot of studies on the involvement of NS1 protein in host immune responses there are still ambiguities regarding its role in apoptosis in infected cells. Interactions of NS1 protein with host factors, role of NS1 protein in regulating cellular responses and apoptosis are quiet complicated and further studies are still needed to understand it completely. RESULTS: NS1 genes of influenza A/Chicken/India/WBNIV2664/2008 (H5N1) and A/Aquatic bird/India/NIV-17095/2007(H11N1) were cloned and expressed in Human embryonic kidney (293T) cells. Microarray based approach to study the host cellular responses to NS1 protein of the two influenza A viruses of different pathogenicity showed significant differences in the host gene expression profile. NS1 protein of H5N1 resulted in suppression of IFN-beta mediated innate immune responses in 293T cells, leading to down-regulation of the components of JAK-STAT pathway like STAT1 which further suppressed the expression of pro-inflammatory cytokines like CXCL10 and CCL5. The degree of suppression of host immune genes was found considerable with NS1 protein of H11N1 but was not as prominent as with H5N1-NS1. TUNEL assay analyses were found to be positive in both the NS1 transfected cells indicating both H5N1 as well as H11N1 NS1 proteins were able to induce apoptosis in transfected cells. CONCLUSIONS: We propose that NS1 protein of both H5N1 and H11N1 subtypes of influenza viruses are capable of influencing host immune responses and possess necessary functionality to support apoptosis in host cells. H11N1, a low pathogenic virus without any proven evidence to infect mammals, contains a highly potential NS1 gene which might contribute to greater virus virulence in different gene combinations. 相似文献
780.