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61.
Advances in sequencing technology have led to a sharp decrease in the cost of ''data generation''. But is this sufficient to ensure cost-effective and efficient ''knowledge generation''? 相似文献
62.
Majumdar S Burgman M Haselton N Grinnell S Ocampo J Pasternak AR Pasternak GW 《Bioorganic & medicinal chemistry letters》2011,21(13):4001-4004
Tritiated opioid radioligands have proven valuable in exploring opioid binding sites. However, tritium has many limitations. Its low specific activity and limited counting efficiency makes it difficult to examine low abundant, high affinity sites and its disposal is problematic due to the need to use organic scintillants and its relatively long half-life. To overcome these issues, we have synthesized both unlabeled and carrier-free radioiodinated iodobenzoyl derivatives of 6β-naltrexamine (125I-BNtxA, 18), 6β-naloxamine (125I-BNalA, 19) and 6β-oxymorphamine (125I-BOxyA, 20) with specific activities of 2100 Ci/mmol. To optimize the utility of the radioligand, we designed a synthesis in which the radiolabel is incorporated in the last synthetic step, which required the selective iodination of the benzoyl moiety without incorporation into the phenolic A ring. Competition studies demonstrated high affinity of the unlabelled compounds for opioid receptors in transfected cell lines, as did the direct binding of the 125I-ligands to the opioid receptors. The radioligand displayed very high sensitivity, enabling a marked reduction in tissue, as well as excellent signal/noise characteristics. These new 125I-radioligands should prove valuable in future studies of opioid binding sites. 相似文献
63.
Jensen TB Henriksen JR Rasmussen BE Rasmussen LM Andresen TL Wengel J Pasternak A 《Bioorganic & medicinal chemistry》2011,19(16):4739-4745
Thrombin binding aptamer is a DNA 15-mer which forms a G-quadruplex structure and possess promising anticoagulant properties due to specific interactions with thrombin. Herein we present the influence of a single 2'-C-piperazino-UNA residue and UNA residues incorporated in several positions on thermodynamics, kinetics and biological properties of the aptamer. 2'-C-Piperazino-UNA is characterized by more efficient stabilization of quadruplex structure in comparison to regular UNA and increases thermodynamic stability of TBA by 0.28-0.44 kcal/mol in a position depending manner with retained quadruplex topology and molecularity. The presence of UNA-U in positions U3, U7, and U12 results in the highest stabilization of G-quadruplex structure (ΔΔG(37)(°)=-1.03kcal/mol). On the contrary, the largest destabilization mounting to 1.79 kcal/mol was observed when UNA residues were placed in positions U7, G8, and U9. Kinetic studies indicate no strict correlation between thermodynamic stability of modified variants and their binding affinity to thrombin. Most of the studied variants bind thrombin, albeit with decreased affinity in reference to unmodified TBA. Thrombin time assay studies indicate three variants as being as potent as TBA in fibrin clotting inhibition. 相似文献
64.
Zaritsky A Ben-Dov E Borovsky D Boussiba S Einav M Gindin G Horowitz AR Kolot M Melnikov O Mendel Z Yagil E 《Bioengineered bugs》2010,1(5):341-344
Various subspecies (ssp.) of Bacillus thuringiensis (Bt) are considered the best agents known so far to control insects, being highly specific and safe, easily mass produced and with long shelf life.1 The para-crystalline body that is produced during sporulation in the exosporium includes polypeptides named δ-endotoxins, each killing a specific set of insects. The different entomopathogenic toxins of various Bt ssp. can be manipulated genetically in an educated way to construct more efficient transgenic bacteria or plants that express combinations of toxin genes to control pests.2 Joint research projects in our respective laboratories during the last decade demonstrate what can be done by implementing certain ideas using molecular biology with Bt ssp. israelensis (Bti) as a model system. Here, we describe our progress achieved with Gram-negative bacterial species, including cyanobacteria, and some preliminary experiments to form transgenic plants, mainly to control mosquitoes (Diptera), but also a particular Lepidopteran and Coleopteran pest species. In addition, a system is described by which environment-damaging genes can be removed from the recombinants thus alleviating procedures for obtaining permits to release them in nature. 相似文献
65.
Background
Activity-induced structural remodeling of dendritic spines and glial cells was recently proposed as an important factor in neuroplasticity and suggested to accompany the induction of long-term potentiation (LTP). Although T1 and diffusion MRI have been used to study structural changes resulting from long-term training, the cellular basis of the findings obtained and their relationship to neuroplasticity are poorly understood.Methodology/Principal Finding
Here we used diffusion tensor imaging (DTI) to examine the microstructural manifestations of neuroplasticity in rats that performed a spatial navigation task. We found that DTI can be used to define the selective localization of neuroplasticity induced by different tasks and that this process is age-dependent in cingulate cortex and corpus callosum and age-independent in the dentate gyrus.Conclusion/Significance
We relate the observed DTI changes to the structural plasticity that occurs in astrocytes and discuss the potential of MRI for probing structural neuroplasticity and hence indirectly localizing LTP. 相似文献66.
67.
Pasternak A Goble SD Vicario PP Di Salvo J Ayala JM Struthers M DeMartino JA Mills SG Yang L 《Bioorganic & medicinal chemistry letters》2008,18(3):994-998
This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the I(Kr) channel; poor selectivity against I(Kr) had been a liability of earlier analogs in this series. 相似文献
68.
Pasternak A Goble SD Doss GA Tsou NN Butora G Vicario PP Ayala JM Struthers M Demartino JA Mills SG Yang L 《Bioorganic & medicinal chemistry letters》2008,18(4):1374-1377
In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold. 相似文献
69.
Panov AV Fesenko SV Aleksakhin RM Pasternak AD Prudnikov PV 《Radiatsionnaia biologiia, radioecologiia / Rossi?skaia akademiia nauk》2007,47(2):224-230
The effectiveness of countermeasures on private farms in rural settlements of the Russian Federation affected by the Chernobyl accident for the period of 1986-2005 was assessed. The averted collective doses to the residents of these settlements and the contribution of restrictive and agricultural countermeasures to dose reduction in the rural population have been estimated. 相似文献
70.
The evolution of bacterial pathogens from nonpathogenic ancestors is marked principally by the acquisition of virulence gene clusters on plasmids and pathogenicity islands via horizontal gene transfer. The flip side of this evolutionary force is the equally important adaptation of the newly minted pathogen to its new host niche. Pathoadaptive mutations take the form of modification of gene expression such that the pathogen is better fit to survive within the new niche. This mini-review describes the concept of pathoadaptation by loss of gene function. In this process, genes that are no longer compatible with the novel lifestyle of the pathogen are selectively inactivated either by point mutation, insertion, or deletion. These genes are called 'antivirulence genes'. Selective pressure sometimes leads to the deletion of large regions of the genome that contain antivirulence genes generating 'black holes' in the pathogen genome. Inactivation of antivirulence genes leads to a pathogen that is highly adapted to its host niche. Identification of antivirulence genes for a particular pathogen can lead to a better understanding of how it became a pathogen and the types of genetic traits that need to be silenced in order for the pathogen to colonize its new host niche successfully. 相似文献