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871.
Flynn JM Choi SW Day NU Gerencser AA Hubbard A Melov S 《Free radical biology & medicine》2011,50(7):866-873
Presynaptic nerve terminals require high levels of ATP for the maintenance of synaptic function. Failure of synaptic mitochondria to generate adequate ATP has been implicated as a causative event preceding the loss of synaptic networks in neurodegenerative disease. Endogenous oxidative stress has often been postulated as an etiological basis for this pathology, but has been difficult to test in vivo. Inactivation of the superoxide dismutase gene (Sod2) encoding the chief defense enzyme against mitochondrial superoxide radicals results in neonatal lethality. However, intervention with an SOD mimetic extends the life span of this model and uncovers a neurodegenerative phenotype providing a unique model for the examination of in vivo oxidative stress. We present here studies on synaptic termini isolated from the frontal cortex of Sod2 null mice demonstrating impaired bioenergetic function as a result of mitochondrial oxidative stress. Cortical synaptosomes from Sod2 null mice demonstrate a severe decline in mitochondrial spare respiratory capacity in response to physiological demand induced by mitochondrial respiratory chain uncoupling with FCCP or by plasma membrane depolarization induced by 4-aminopyridine treatment. However, Sod2 null animals compensate for impaired oxidative metabolism in part by the Pasteur effect allowing for normal neurotransmitter release at the synapse, setting up a potentially detrimental energetic paradigm. The results of this study demonstrate that high-throughput respirometry is a facile method for analyzing specific regions of the brain in transgenic models and can uncover bioenergetic deficits in subcellular regions due to endogenous oxidative stress. 相似文献
872.
Lim KS Kang DW Kim YS Kim MS Park SG Choi S Pearce LV Blumberg PM Lee J 《Bioorganic & medicinal chemistry letters》2011,21(1):299-302
A series of 5′-halogenated resiniferatoxin analogs have been investigated in order to examine the effect of halogenation in the A-region on their binding and the functional pattern of agonism/antagonism for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Halogenation at the 5-position in the A-region of RTX and of 4-amino RTX shifted the agonism of parent compounds toward antagonism. The extent of antagonism was greater as the size of the halogen increased (I > Br > Cl > F) while the binding affinities were similar, as previously observed for our potent agonists. In this series, 5-bromo-4-amino RTX (39) showed very potent antagonism with Ki (ant) = 2.81 nM, which was thus 4.5-fold more potent than 5′-iodo RTX, previously reported as a potent TRPV1 antagonist. Molecular modeling analyses with selected agonists and the corresponding halogenated antagonists revealed a striking conformational difference. The 3-methoxy of the A-region in the agonists remained free to interact with the receptor whereas in the case of the antagonists, the compounds assumed a bent conformation, permitting the 3-methoxy to instead form an internal hydrogen bond with the C4-hydroxyl of the diterpene. 相似文献
873.
Klöck C Jin X Choi K Khosla C Madrid PB Spencer A Raimundo BC Boardman P Lanza G Griffin JH 《Bioorganic & medicinal chemistry letters》2011,21(9):2692-2696
Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had Ki values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals. 相似文献
874.
875.
We are witnessing the growing menace of both increasing cases of drug-sensitive and drug-resistant Mycobacterium tuberculosis strains and the challenge to produce the first new tuberculosis (TB) drug in well over 40 years. The TB community, having invested in extensive high-throughput screening efforts, is faced with the question of how to optimally leverage these data to move from a hit to a lead to a clinical candidate and potentially, a new drug. Complementing this approach, yet conducted on a much smaller scale, cheminformatic techniques have been leveraged and are examined in this review. We suggest that these computational approaches should be optimally integrated within a workflow with experimental approaches to accelerate TB drug discovery. 相似文献
876.
877.
The FDA-approved drug suberoylanilide hydroxamic acid (SAHA, Vorinostat) was modified to improve its selectivity for a single histone deaetylase (HDAC) isoform. We show that attaching an ethyl group at the C3 position transforms SAHA from nonselective to an HDAC6-selective inhibitor. Theses results indicate that small structural changes in SAHA can significantly influence selectivity, which will lead future anti-cancer design efforts targeting HDAC proteins. 相似文献
878.
879.
While natural antimicrobial peptides are potential therapeutic agents, their physicochemical properties and bioactivity generally
need to be enhanced for clinical and commercial development. We have previously developed a cationic, amphipathic α-helical,
11-residue peptide (named herein GA-W2: FLGWLFKWASK-NH2) with potent antimicrobial and hemolytic activity, which was derived from a 24-residue, natural antimicrobial peptide isolated
from frog skin. Here, we attempted to optimize peptide bioactivity by a rational approach to sequence modification. Seven
analogues were generated from GA-W2, and their activities were compared with that of a 12-residue peptide, omiganan, which
is being developed for clinical and commercial applications. Most of the modifications reported here improved antimicrobial
activity. Among them, the GA-K4AL (FAKWAFKWLKK-NH2) peptide displayed the most potent antimicrobial activity with negligible hemolytic activity, superior to that of omiganan.
The therapeutic index of GA-K4AL was improved more than 53- and more than 31-fold against Gram-negative and Gram-positive
bacteria, respectively, compared to that of the starting peptide, GA-W2. Given its relatively shorter length and simpler amino
acid composition, our sequence-optimized GA-K4AL peptide may thus be a potentially useful antimicrobial peptide agent. 相似文献
880.
Choi JM Chu SJ Ahn KH Kim SK Ji JE Won JH Kim HC Back MJ Kim DK 《Molecules and cells》2011,32(4):325-331
Ceramide has been suggested to be not only a tumorsuppressive lipid but also a regulator of phagocytosis. We examined whether
exogenous cell-permeable C6-ceramide enhances the phagocytic activity of Kupffer cells (KCs) and affects the level of cellular ceramides. Rat KCs were
isolated by collagenase digestion and differential centrifugation, using Percoll system. Phagocytic activity was measured
by FACS analysis after incubating KCs with fluorescence-conjugated latex beads, and the level of cellular ceramide was analyzed
by liquid chromatography tandem-mass spectrometry (LC-MS/MS). In this study we found that permeable C6-ceramide increases the cellular levels of endogenous ceramides via a sphingosine-recycling pathway leading to enhanced phagocytosis
by KCs. 相似文献