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21.
《Journal of molecular biology》2019,431(24):4817-4833
Factor XI (FXI), the zymogen of activated FXI (FXIa), is an attractive target for novel anticoagulants because FXI inhibition offers the potential to reduce thrombosis risk while minimizing the risk of bleeding. BAY 1213790, a novel anti-FXIa antibody, was generated using phage display technology. Crystal structure analysis of the FXIa–BAY 1213790 complex demonstrated that the tyrosine-rich complementarity-determining region 3 loop of the heavy chain of BAY 1213790 penetrated deepest into the FXIa binding epitope, forming a network of favorable interactions including a direct hydrogen bond from Tyr102 to the Gln451 sidechain (2.9 Å). The newly discovered binding epitope caused a structural rearrangement of the FXIa active site, revealing a novel allosteric mechanism of FXIa inhibition by BAY 1213790. BAY 1213790 specifically inhibited FXIa with a binding affinity of 2.4 nM, and in human plasma, prolonged activated partial thromboplastin time and inhibited thrombin generation in a concentration-dependent manner. 相似文献
22.
Protoporphyrin IX and its derivatives are used as photosensitizers in the photodynamic therapy of cancer. Protoporphyrin IX
penetrates into human red blood cells and releases oxygen from them. This leads to a change in the morphology of the cells.
Spectrophotometric studies reveal that protoporphyrin IX interacts with haemoglobin and myoglobin forming ground state complexes.
For both proteins, the binding affinity constant decreases, while the possible number of binding sites increases, as the aggregation
state of the porphyrin is increased. The interactions lead to conformational changes of both haemoglobin and myoglobin as
observed in circular dichroism studies. Upon binding with the proteins, protoporphyrin IX releases the heme-bound oxygen from
the oxyproteins, which is dependent on the stoichiometric ratios of the porphyrin: protein. The peroxidase activities of haemoglobin
and myoglobin are potentiated by the protein-porphyrin complexation. Possible mechanisms underlying the relation between the
porphyrin-induced structural modifications of the heme proteins and alterations in their functional properties have been discussed.
The findings may have a role in establishing efficacy of therapeutic uses of porphyrins as well as in elucidating their mechanisms
of action as therapeutic agents. 相似文献
23.
In this study, we used a random approach to determine which amino acid pairs in human coagulation factor IX precursor are more sensitive to its 99 variants. The results show that the randomly unpredictable amino acid pairs are more sensitive to variants. 相似文献
24.
A mutant human factor IX with arginine at 338 residual changed to alanine (hFIXR338A) by site-directed mutagenesis was introduced into AAV vectors, and a recombinant adeno-associ-ated viral vector containing hFIXR338A, prepared by rHSV/AAV hybrid helper virus system, was directly introduced to the hind leg muscle of factor IX knock out mice. The expression and the biological activity of human factor IX mutant, hFIXR338A, and the immune response against it in the treated mice were assayed and detected. The results showed that (i) the high-level expression of human factor IX mutant protein, hFIXR338A, has been detected in rAAV-hFIXR338A treated hemophilia B mice and lasted more than 15 weeks; (ii) the clotting activity of hFIXR338A in plasma is 34.2%± 5.23%, which is remarkably higher than that of (14.27%±3.4%) of wild type hFIX treated mice in the activated partial thromboplastin assay; (iii) immune response against factor IX R338A was absent, with no factor IX mutant protein (hFIXR338A) inhibitors deve 相似文献
25.
ZHANG KezhongJIANG PeihongLU DaruHUANG WeidaCHEN LiXUE Jerry L. HsuehQIU Xinfang 《中国科学:生命科学英文版》1998,41(4):406-412
Mammary gland specific expression vectors for human clotting factor IX (hFIX) and LacZ reporter gene driven by bovine β-casein
gene were constructed. Vectors were packaged by stearylamine (SA) liposome and were transferred to lactating mice via tail
vein. Both hFIX and Lac2 gene could be expressed in the mammary gland of the treated mice. The highest production of hFIX
protein was 80.28 ng per mL milk, and more than 85% of hFIX protein appeared to be γ-carboxylation and biologically active.
The results suggested that the 2.0 kb sequence of β-casein gene including promoter, exon 1 was effective to drive hFIX gene
expression in mammary gland and intron 1 of β-casein gene had an effect on the tissue specific expression. The expression
level in mouse milk injected with hFIX minigene vector containing hFIX endogenous intron 1 was increased by above 3 times
of that injected with hFIX cDNA vector.
Project supported by the State High Technology Development Program and Shanghai Science and Technology Commission. 相似文献
26.
Oxygenation measurement by multi‐wavelength oxygen‐dependent phosphorescence and delayed fluorescence: catchment depth and application in intact heart 下载免费PDF全文
Gianmarco M. Balestra Maurice C.G. Aalders Patricia A.C. Specht Can Ince Egbert G. Mik 《Journal of biophotonics》2015,8(8):615-628
Oxygen delivery and metabolism represent key factors for organ function in health and disease. We describe the optical key characteristics of a technique to comprehensively measure oxygen tension (PO2) in myocardium, using oxygen‐dependent quenching of phosphorescence and delayed fluorescence of porphyrins, by means of Monte Carlo simulations and ex vivo experiments. Oxyphor G2 (microvascular PO2) was excited at 442 nm and 632 nm and protoporphyrin IX (mitochondrial PO2) at 510 nm. This resulted in catchment depths of 161 (86) µm, 350 (307) µm and 262 (255) µm respectively, as estimated by Monte Carlo simulations and ex vivo experiments (brackets). The feasibility to detect changes in oxygenation within separate anatomical compartments is demonstrated in rat heart in vivo.
27.
Carbonic anhydrase IX: Biochemical and crystallographic characterization of a novel antitumor target
Giuseppina De Simone Claudiu T. Supuran 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(2):404-409
Isoform IX of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), CA IX, is a transmembrane protein involved in solid tumor acidification through the HIF-1α activation cascade. CA IX has a very high catalytic activity for the hydration of carbon dioxide to bicarbonate and protons, even at acidic pH values (of around 6.5), typical of solid, hypoxic tumors, which are largely unresponsive to classical chemo- and radiotherapy. Thus, CA IX is used as a marker of tumor hypoxia and as a prognostic factor for many human cancers. CA IX is involved in tumorigenesis through many pathways, such as pH regulation and cell adhesion control. The X-ray structure of the catalytic domain of CA IX has been recently reported, being shown that CA IX has a typical α-CA fold. However, the CA IX structure differs significantly from the other CA isozymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX associate to form a dimer, which is stabilized by the formation of an intermolecular disulfide bond. The active site clefts and the proteoglycan (PG) domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. As all mammalian CAs, CA IX is inhibited by several main classes of inhibitors, such as the inorganic anions, the sulfonamides and their bioisosteres (sulfamates, sulfamides, etc.), the phenols, and the coumarins. The mechanism of inhibition with all these classes of compounds is understood at the molecular level, but the sulfonamides and their congeners have important applications. It has been recently shown that both in vitro, in cell cultures, as well as in animals with transplanted tumors, CA IX inhibition with sulfonamides lead to a return of the extracellular pH to more normal values, which leads to a delay in tumor growth. As a consequence, CA IX represents a promising antitumor target for the development of anticancer agents with an alternative mechanism of action. 相似文献
28.
Franck E. Dayan Pankaj R. Daga Stephen O. Duke Ryan M. Lee Patrick J. Tranel Robert J. Doerksen 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(7):1548-1556
A rare Gly210 deletion in protoporphyrinogen oxidase (PPO) was recently discovered in herbicide-resistant Amaranthus tuberculatus. According to the published X-ray structure of Nicotiana tabacum PPO, Gly210 is adjacent to, not in, the PPO active site, so it is a matter of interest to determine why its deletion imparts resistance to herbicides. In our kinetic experiments, this deletion did not affect the affinity of protoporphyrinogen IX nor the FAD content, but decreased the catalytic efficiency of the enzyme. The suboptimal Kcat was compensated by a significant increase in the Kis for inhibitors and a switch in their interactions from competitive to mixed-type inhibition. In our protein modeling studies on herbicide-susceptible PPO and resistant PPO, we show that Gly210 plays a key role in the αL helix-capping motif at the C-terminus of the α-8 helix which helps to stabilize the helix. In molecular dynamics simulations, the deletion had significant architecture consequences, destabilizing the α-8 helix-capping region and unraveling the last turn of the helix, leading to enlargement of the active site cavity by ∼ 50%. This seemingly innocuous deletion of Gly210 of the mitochondrial PPO imparts herbicide resistance to this dual-targeted protein without severely affecting its normal physiological function, which may explain why this unusual mutation was the favored evolutionary path for achieving resistance to PPO inhibitors. 相似文献
29.
A secretory form of human α3-fucosyltransferase IX (sFUT9) was overexpressed in Spodoptera frugiperda (Sf9) insect cells using the stable expression vector pIB/V5-His-TOPO and the signal sequence of human interleukin 2 for
efficient secretion. sFUT9 was active and its three potential N-glycosylation sites were occupied. sFUT9 efficiently fucosylated the type II acceptors Galbeta4GlcNAC-R and Fucalpha2Galbeta4GlcNAc-R
(R = (CH2)3NHCO(CH2)5–NH-biotin) but not the corresponding sialylated acceptor, and only very poorly the type I (Galbeta3GlcNAc-R)
related acceptors. sFUT9 showed a clear preference for glycoproteins containing type II acceptors, with values of 121, 113
and 110 microU/million cell for asialofetuin, erythropoietin and asialoerythropoietin, respectively, values approximately
11-fold higher than those obtained for the small acceptors. 相似文献
30.
Castelfranco PA 《Photosynthesis research》2007,91(1):25-36
Our research on chlorophyll biosynthesis, over a period of approximately twenty years, has been described, emphasizing those
areas in which our laboratory made significant and timely contributions. References to some of our most important articles
are included. Portions of the chlorophyll biosynthetic pathway, in which our own laboratory was not involved, for example,
the reduction of protochlorophyllide to chlorophyllide and the phytylation of the latter to yield chlorophyll a, have not been covered in this article. Those events which preceded my involvement with chlorophyll biosynthesis, but which
contributed to the formation of my own scientific personality, are mentioned briefly in the Introduction. My non-scientific
avocations have been included at the request of the reviewers and Govindjee. 相似文献