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831.
832.
Ricky C. K. Cheng Denis B. Tikhonov Boris S. Zhorov 《The Journal of biological chemistry》2009,284(41):28332-28342
Phenylalkylamines (PAAs), a major class of L-type calcium channel (LTCC) blockers, have two aromatic rings connected by a flexible chain with a nitrile substituent. Structural aspects of ligand-channel interactions remain unclear. We have built a KvAP-based model of LTCC and used Monte Carlo energy minimizations to dock devapamil, verapamil, gallopamil, and other PAAs. The PAA-LTCC models have the following common features: (i) the meta-methoxy group in ring A, which is proximal to the nitrile group, accepts an H-bond from a PAA-sensing Tyr_IIIS6; (ii) the meta-methoxy group in ring B accepts an H-bond from a PAA-sensing Tyr_IVS6; (iii) the ammonium group is stabilized at the focus of P-helices; and (iv) the nitrile group binds to a Ca2+ ion coordinated by the selectivity filter glutamates in repeats III and IV. The latter feature can explain Ca2+ potentiation of PAA action and the presence of an electronegative atom at a similar position of potent PAA analogs. Tyr substitution of a Thr in IIIS5 is known to enhance action of devapamil and verapamil. Our models predict that the para-methoxy group in ring A of devapamil and verapamil accepts an H-bond from this engineered Tyr. The model explains structure-activity relationships of PAAs, effects of LTCC mutations on PAA potency, data on PAA access to LTCC, and Ca2+ potentiation of PAA action. Common and class-specific aspects of action of PAAs, dihydropyridines, and benzothiazepines are discussed in view of the repeat interface concept.L-type calcium channels (LTCCs)2 are targets for different drugs. Benzo(thi)azepines (BTZs), dihydropyridines (DHPs), and phenylalkylamines (PAAs) constitute the three major classes of the LTCC ligands (for reviews, see Refs. 1 and 2). All of these ligands bind to overlapping binding sites in the pore-forming domain of the α1 subunit, but each class demonstrates unique characteristics of action. Depending on their chemical structure, DHPs act as agonists or antagonists (3). All known PAAs and BTZs are antagonists, but they have different access pathways to their binding sites: external for BTZs (4, 5) and predominantly internal for PAAs (6). Clinical use of verapamil in treatments of hypertension and arrhythmias (7) had stimulated intensive electrophysiological, mutational, and pharmacological studies involving PAAs.The pore-forming domain of LTCC includes the pore-lining inner helices S6, the outer helices S5, and the P-loops from all four repeats of the α1 subunit. According to mutational analyses, the PAA-binding site is located in the interface between repeats III and IV. In particular, residues in transmembrane helices IIIS5, IIIS6, and IVS6 and P-loops of repeats III and IV contribute to binding of PAAs (8–14).Structure-activity relationships of PAAs were intensively studied (15–17). A common feature of potent PAAs is the presence of two methoxylated aromatic rings (named A and B). The rings are connected by a flexible alkylamine chain with a nitrile and an isopropyl group at the chiral tetrasubstituted carbon atom, which is proximal to ring A. Ring B is proximal to the amino group (see Fig. 1).Open in a separate windowFIGURE 1.Structural formulae of PAAs.Despite the fact that some specific contacts between functional groups of PAAs and PAA-sensing residues (residues that, when mutated, affect action of PAAs) have been proposed (10, 14), the flexibility of the ligands did not allow the characterization of the binding mode and the general pattern of ligand-channel interactions. In the absence of such knowledge, it is hardly possible to provide a molecular basis for structure-activity relationships. The problem is further complicated by the dependence of PAA action on the functional state of the channel, the ionic environment, the transmembrane voltage, and other factors. For example, it is generally believed that PAAs bind to the open/inactivated channels with higher affinities than to the closed state (for review, see Ref 1). However, the molecular basis for this state dependence is unclear.Lipkind and Fozzard (18) docked devapamil in a KcsA-based homology model of the L-type Ca2+ channel. They suggested an angular conformation of the drug, with ring B extended into the III/IV repeat interface and ring A in the central cavity. They also suggested that the protonated amino group of devapamil interacts directly with the selectivity filter glutamates. This model explains the effect of some mutations, particularly those in the P-loops and IVS6. However, other important aspects of PAA action such as the role of the nitrile group, the Ca2+ potentiation effect, and the effects of mutations in IIIS6 and IIIS5 remain unexplained.The gap between the amount of experimental data on PAA action and the level of understanding of the atomic level mechanisms necessitates further studies. In the absence of x-ray structures of Ca2+ channels, molecular modeling is the only available approach to address the structural aspects of PAA-LTCC interactions. Recently, we proposed molecular models for the action of other classes of L-type channel ligands. In the BTZ-LTCC models (19), the main body of the ligands binds in the repeat interface, whereas the amino group protrudes into the inner pore, where it is stabilized by nucleophilic C-terminal ends of the pore helices. In the DHP-LTCC models (20), the ligands also bind in the interface between repeats III and IV, whereas the moieties that differ between agonist and antagonists extend to the pore. Both models suggest direct interactions between the ligands and a Ca2+ ion bound to the selectivity filter glutamates in repeats III and IV.In this work, we elaborate molecular models for PAA·LTCC complexes that agree with a large body of experimental data. We further discuss common and different aspects of action of different ligands on LTCC and propose that certain aspects of the ligand action may be relevant to other P-loop channels. 相似文献
833.
Annette C. Hurst Philip A. Gottlieb Boris Martinac 《European biophysics journal : EBJ》2009,38(4):415-425
The spider peptide GsMTx4, at saturating concentration of 5 μM, is an effective and specific inhibitor for stretch-activated
mechanosensitive (MS) channels found in a variety of eukaryotic cells. Although the structure of the peptide has been solved,
the mode of action remains to be determined. Because of its amphipathic structure, the peptide is proposed to interact with
lipids at the boundaries of the MS channel proteins. In addition, GsMTx4 has antimicrobial effects, inhibiting growth of several
species of bacteria in the range of 5–64 μM. Previous studies on prokaryotic MS channels, which serve as model systems to
explore the principle of MS channel gating, have shown that various amphipathic compounds acting at the protein–lipid interface
affect MS channel gating. We have therefore analyzed the effect of different concentrations of extracellular GsMTx4 on MS
channels of small conductance, MscS and MscK, in the cytoplasmic membrane of wild-type E. coli spheroplasts using the patch-clamp technique. Our study shows that the peptide GsMTx4 exhibits a biphasic response in which
peptide concentration determines inhibition or potentiation of activity in prokaryotic MS channels. At low peptide concentrations
of 2 and 4 μM the gating of the prokaryotic MS channels was hampered, manifested by a decrease in pressure sensitivity. In
contrast, application of peptide at concentrations of 12 and 20 μM facilitated prokaryotic MS channel opening by increasing
the pressure sensitivity. 相似文献
834.
The response of an oscillator to perturbations is described by its phase-response curve (PRC), which is related to the type
of bifurcation leading from rest to tonic spiking. In a recent experimental study, we have shown that the type of PRC in cortical
pyramidal neurons can be switched by cholinergic neuromodulation from type II (biphasic) to type I (monophasic). We explored
how intrinsic mechanisms affected by acetylcholine influence the PRC using three different types of neuronal models: a theta
neuron, single-compartment neurons and a multi-compartment neuron. In all of these models a decrease in the amount of a spike-frequency
adaptation current was a necessary and sufficient condition for the shape of the PRC to change from biphasic (type II) to
purely positive (type I). 相似文献
835.
Chemoenzymatic synthesis of multivalent neoglycoconjugates carrying the helminth glycan antigen LDNF
Boris Tefsen Caroline M.W. van Stijn Marloes van den Broek Hakan Kalay Jaco C. Knol Connie R. Jimenez Irma van Die 《Carbohydrate research》2009,344(12):1-4307
Several parasitic helminthes, such as the human parasite Schistosoma mansoni, express glycoconjugates that contain terminal GalNAcβ1-4(Fucα1-3)GlcNAcβ-R (LDNF) moieties. These LDNF glycans are dominant antigens of the parasite and are recognized by human dendritic cells via the C-type lectin DC-SIGN. To study the functional role of the LDNF antigen in interaction with the immune system, we have developed an easy chemoenzymatic method to synthesize multivalent neoglycoconjugates carrying defined amounts of LDNF antigens. An acceptor substrate providing a terminal N-acetylglucosamine was prepared by coupling a fluorescent hydrophobic aglycon, 2,6-diaminopyridine (DAP), to N,N′-diacetylchitobiose. By the subsequent action of recombinant Caenorhabditis elegans β1,4-N-acetylgalactosaminyltransferase and human α1,3-fucosyltransferase VI (FucT-VI), this substrate was converted to the LDNF antigen. We showed that human FucT-VI has a relatively high affinity for the unusual substrate GalNAcβ1-4GlcNAc (LDN), and this enzyme was used to produce micromolar amounts of LDNF–DAP. The synthesized LDNF–DAP was coupled to carrier protein via activation of the DAP moiety by diethyl squarate. By varying the molar glycan:protein ratio, neoglycoconjugates were constructed with defined amounts of LDNF, as was determined by MALDI-TOF analysis and ELISA using an anti-LDNF antibody. 相似文献
836.
The lamellipod, the locomotory region of migratory cells, is shaped by the balance of protrusion and contraction. The latter is the result of myosin-generated centripetal flow of the viscoelastic actin network. Recently, quantitative flow data was obtained, yet there is no detailed theory explaining the flow in a realistic geometry. We introduce models of viscoelastic actin mechanics and myosin transport and solve the model equations numerically for the flat, fan-shaped lamellipodial domain of keratocytes. The solutions demonstrate that in the rapidly crawling cell, myosin concentrates at the rear boundary and pulls the actin network inward, so the centripetal actin flow is very slow at the front, and faster at the rear and at the sides. The computed flow and respective traction forces compare well with the experimental data. We also calculate the graded protrusion at the cell boundary necessary to maintain the cell shape and make a number of other testable predictions. We discuss model implications for the cell shape, speed, and bi-stability. 相似文献
837.
Voltage gated proton channels and NADPH oxidase function cooperatively in phagocytes during the respiratory burst, when reactive oxygen species are produced to kill microbial invaders. Although these molecules are distinct entities, with no proven physical interaction, their presence and activity in many cells appears to be coordinated. We describe these interactions and discuss several types of mechanisms that might explain them. 相似文献
838.
839.
840.
Sergey A. Shiryaev Albert G. Remacle Alexei Y. Savinov Andrei V. Chernov Piotr Cieplak Ilian A. Radichev Roy Williams Tatiana N. Shiryaeva Katarzyna Gawlik Tatiana I. Postnova Boris I. Ratnikov Alexei M. Eroshkin Khatereh Motamedchaboki Jeffrey W. Smith Alex Y. Strongin 《The Journal of biological chemistry》2009,284(44):30615-30626