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An increase in the life expectancy during the last decades in most world countries has resulted in the growing number of people suffering from neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, fron-totemporal dementia, and others. Familial forms of neurodegenerative diseases account for 5–10% of all cases and are caused by mutations in specific genes often resulting in pathological protein deposition. The risk factors for neurodegeneration include trauma, lifestyle, and allelic variants of disease-associated genes with incomplete penetrance. Many of these gene variants are located in immunity-related loci, particularly in the human leukocyte antigen locus (HLA class II) coding for proteins of the major histocompatibility complex class II (MHCII). HLA class II plays a key role in the antigen presentation and is expressed in microglial cells. Microglia is a component of innate immunity. On the one hand, microglial cells phagocytize pathological protein deposits; on the other hand, they produce proinflammatory factors accelerating neuronal death. The involvement of adaptive immunity mechanisms (antigen presentation, T cell response, antibody production) in the development of neurodegenerative diseases remains unclear and requires further research, including more detailed studies of the role of identified HLA class II genetic variants. 相似文献
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Utkin YN Weise C Kasheverov IE Andreeva TV Kryukova EV Zhmak MN Starkov VG Hoang NA Bertrand D Ramerstorfer J Sieghart W Thompson AJ Lummis SC Tsetlin VI 《The Journal of biological chemistry》2012,287(32):27079-27086
Azemiopsin, a novel polypeptide, was isolated from the Azemiops feae viper venom by combination of gel filtration and reverse-phase HPLC. Its amino acid sequence (DNWWPKPPHQGPRPPRPRPKP) was determined by means of Edman degradation and mass spectrometry. It consists of 21 residues and, unlike similar venom isolates, does not contain cysteine residues. According to circular dichroism measurements, this peptide adopts a β-structure. Peptide synthesis was used to verify the determined sequence and to prepare peptide in sufficient amounts to study its biological activity. Azemiopsin efficiently competed with α-bungarotoxin for binding to Torpedo nicotinic acetylcholine receptor (nAChR) (IC(50) 0.18 ± 0.03 μm) and with lower efficiency to human α7 nAChR (IC(50) 22 ± 2 μm). It dose-dependently blocked acetylcholine-induced currents in Xenopus oocytes heterologously expressing human muscle-type nAChR and was more potent against the adult form (α1β1εδ) than the fetal form (α1β1γδ), EC(50) being 0.44 ± 0.1 μm and 1.56 ± 0.37 μm, respectively. The peptide had no effect on GABA(A) (α1β3γ2 or α2β3γ2) receptors at a concentration up to 100 μm or on 5-HT(3) receptors at a concentration up to 10 μm. Ala scanning showed that amino acid residues at positions 3-6, 8-11, and 13-14 are essential for binding to Torpedo nAChR. In biological activity azemiopsin resembles waglerin, a disulfide-containing peptide from the Tropidechis wagleri venom, shares with it a homologous C-terminal hexapeptide, but is the first natural toxin that blocks nAChRs and does not possess disulfide bridges. 相似文献
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Mutations in lipase H (LIPH) and lysophosphatidic acid receptor 6 (LPAR6), which are essential for the lysophosphatidic acid (LPA) signalling pathway, are associated with hypotrichosis and wooly hair in humans. Mutations in LPAR6 and keratin 71 (KRT71), result in unusual fur growth and hair structure in several cat breeds (Cornish Rex, Devon Rex and Selkirk Rex). Here, we performed target sequencing of the LIPH, LPAR6 and KRT71 genes in six cat breeds with specific hair-growth phenotypes. A LIPH genetic variant (LIPH:c.478_483del; LIPH:p.Ser160_Gly161del) was found in Ural Rex cats with curly coats from Russia, but was absent in all other cat breeds tested. In silico three-dimensional analysis of the LIPH mutant protein revealed a contraction of the α3-helix structure in the enzyme phospholipid binding site that may affect its activity. 相似文献
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A great variety of cellular functions are regulated by protein serine/threonine phosphatases (PP). This review summarises the current knowledge of the structural features, patterns of expression and involvement in signal transduction pathways of protein serine/threonine phosphatases related to PP5 and RdgC. Designated now as PP5/RdgC subfamily by P. T. W. Cohen in her 1997 study published in Trends in Biochemical Sciences, (Vol. 22, pp. 245-251), this heterogeneous group comprises phosphatases PP5/PPT, containing regulatory domains with tetratricopeptide repeats, RdgC/PPEF, which possess Ca2+-binding EF hand-type sites, and, recently discovered in plants, PP7. PP5 is ubiquitously expressed and appears to be a multifunctional phosphatase involved in a number of different signalling pathways. In contrast, expression of RdgC/PPEF phosphatases and PP7 is confined primarily to specialised sensory cells in animals and plants, respectively, which may be indicative of their more specialised roles in sensory signal transduction. 相似文献
127.
On recent evidence, the efficiency of catalysis and the specificity of aspartic proteases depend considerably on the dynamic properties of particular molecular regions and their correlations. Analysis of the three-dimensional structures of these enzymes showed the presence of a continuous chain of hydrogen-bonded groups, which connects regions with highly correlated dynamic parameters and provides for a “cross-hand” interaction between domains. This chain includes the inner oxygens of the active carboxyls and the conserved internal water molecules. The so-called “fireman grip” interdomain hydrogen bonding is part of this chain. Such networks are abortive in retroviral proteases. The role of these interactions in the functions of aspartic proteases is discussed. 相似文献
128.
T. V. Danilova M. Yu. Kuklev G. N. Andreeva V. S. Shevelukha G. I. Karlov 《Russian Journal of Genetics》2007,43(4):381-386
Using a combination of degenerate primers designed from the NBS domains of the resistance genes, amplification and subsequent cloning of the resistance gene fragments from sunflower (Helianthus agrophyllus) was conducted. Sequences of cloned PCR products differed from one another and displayed homology to NBS domain fragments of the already known plant resistance genes, as well as to the analogous genes from different classes. The highest homology was shown to the NBS domain regions of cultivated sunflower and the other members of the family Compositae. Two cloned fragments had open reading frames, while the other sequences carried stop codons and seemed to belong to pseudogenes. Amino acid sequences of Helianthus agrophyllus analyzed contained conservative regions typical of NBS domains of the resistance gene products. 相似文献
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