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1.
A human recombinant haemoglobin designed for use as a blood substitute. 总被引:19,自引:0,他引:19
D Looker D Abbott-Brown P Cozart S Durfee S Hoffman A J Mathews J Miller-Roehrich S Shoemaker S Trimble G Fermi 《Nature》1992,356(6366):258-260
The need to develop a blood substitute is now urgent because of the increasing concern over blood-transmitted viral and bacterial pathogens. Cell-free haemoglobin solutions and human haemoglobin synthesized in Escherichia coli and Saccharomyces cerevisiae have been investigated as potential oxygen-carrying substitutes for red blood cells. But these haemoglobins cannot be used as a blood substitute because (1) the oxygen affinity in the absence of 2,3-bisphosphoglycerate is too high to allow unloading of enough oxygen in the tissues, and (2) they dissociate into alpha beta dimers that are cleared rapidly by renal filtration, which can result in long-term kidney damage. We have produced a human haemoglobin using an expression vector containing one gene encoding a mutant beta-globin with decreased oxygen affinity and one duplicated, tandemly fused alpha-globin gene. Fusion of the two alpha-globin subunits increases the half-life of this haemoglobin molecule in vivo by preventing its dissociation into alpha beta dimers and therefore also eliminates renal toxicity. 相似文献
2.
Charged groups play a critical role in the stability of the helix formed by the isolated C-peptide (residues 1-13 of ribonuclease A) in aqueous solution. One charged-group effect may arise from interactions between charged residues at either end of the helix and the helix dipole. We report here that studies of C-peptide analogues support the helix dipole model, and provide further evidence for the importance of electrostatic interactions not included in the Zimm-Bragg model for alpha-helix formation. 相似文献
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Published fish blood parameters are limited to commercially cultured species (e.g. rainbow trout [ Oncorhynchus mykiss ] and channel catfish [ Ictalurus punctatus ]). However, as walleye ( Stizostedion vitreum ) and other fish increase in value to the angler, hatchery and fish managers will require data on these species. Blood sera were collected from live walleye in the field, creatinine values were determined colorimetrically, and health range values were established from these data. Creatinine levels of walleye serum (0.06-0.72 mg/dl) were higher in three species but lower than recognized in a recent catfish study. Creatinine levels may be important in predicting diseases in which the kidney is adversely affected. 相似文献
5.
Phosphorylation fails to activate chloride channels from cystic fibrosis airway cells 总被引:3,自引:0,他引:3
R A Schoumacher R L Shoemaker D R Halm E A Tallant R W Wallace R A Frizzell 《Nature》1987,330(6150):752-754
Chloride impermeability of epithelial cells can account for many of the experimental and clinical manifestations of cystic fibrosis (CF). Activation of apical-membrane Cl- channels by cyclic AMP-mediated stimuli is defective in CF airway epithelial cells, despite normal agonist-induced increases in cellular cAMP levels. This defect in Cl- channel regulation has been localized to the apical membrane by exposing the cytoplasmic surface of excised membrane patches to the catalytic subunit (C subunit) of cAMP-dependent protein kinase and ATP. In membranes from normal cells, C-subunit activated Cl- channels with properties identical to those stimulated by cAMP-dependent agonists during cell-attached recording. Activation by the C subunit was not observed in CF membranes, but the presence of Cl- channels was verified by voltage-induced activation. The failure of the C subunit to activate the Cl- channels of CF membranes indicates that the block in their cAMP-mediated activation lies distal to induction of cAMP-dependent protein kinase activity and focuses our attention on the Cl- channel and its membrane-associated regulatory proteins as the probable site of the CF defect. 相似文献
6.
Genomic profiling of drug sensitivities via induced haploinsufficiency 总被引:20,自引:0,他引:20
Giaever G Shoemaker DD Jones TW Liang H Winzeler EA Astromoff A Davis RW 《Nature genetics》1999,21(3):278-283
Lowering the dosage of a single gene from two copies to one copy in diploid yeast results in a heterozygote that is sensitized to any drug that acts on the product of this gene. This haploinsufficient phenotype thereby identifies the gene product of the heterozygous locus as the likely drug target. We exploited this finding in a genomic approach to drug-target identification. Genome sequence information was used to generate molecularly tagged heterozygous yeast strains that were pooled, grown competitively in drug and analysed for drug sensitivity using high-density oligonucleotide arrays. Individual heterozygous strain analysis verified six known drug targets. Parallel analysis identified the known target and two hypersensitive loci in a mixed culture of 233 strains in the presence of the drug tunicamycin. Our discovery that both drug target and hypersensitive loci exhibit drug-induced haploinsufficiency may have important consequences in pharmacogenomics and variable drug toxicity observed in human populations. 相似文献
7.
Oltersdorf T Elmore SW Shoemaker AR Armstrong RC Augeri DJ Belli BA Bruncko M Deckwerth TL Dinges J Hajduk PJ Joseph MK Kitada S Korsmeyer SJ Kunzer AR Letai A Li C Mitten MJ Nettesheim DG Ng S Nimmer PM O'Connor JM Oleksijew A Petros AM Reed JC Shen W Tahir SK Thompson CB Tomaselli KJ Wang B Wendt MD Zhang H Fesik SW Rosenberg SH 《Nature》2005,435(7042):677-681
Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice. 相似文献
8.
K Jacobs C Shoemaker R Rudersdorf S D Neill R J Kaufman A Mufson J Seehra S S Jones R Hewick E F Fritsch 《Nature》1985,313(6005):806-810
The glycoprotein hormone erythropoietin regulates the level of oxygen in the blood by modulating the number of circulating erythrocytes, and is produced in the kidney or liver of adult and the liver of fetal or neonatal mammals. Neither the precise cell types that produce erythropoietin nor the mechanisms by which the same or different cells measure the circulating oxygen concentration and consequently regulate erythropoietin production are known. Cells responsive to erythropoietin have been identified in the adult bone marrow, fetal liver or adult spleen. In cultures of erythropoietic progenitors, erythropoietin stimulates proliferation and differentiation to more mature red blood cells. Detailed molecular studies have been hampered, however, by the impurity and heterogeneity of target cell populations and the difficulty of obtaining significant quantities of the purified hormone. Highly purified erythropoietin may be useful in the treatment of various forms of anaemia, particularly in chronic renal failure. Here we describe the cloning of the human erythropoietin gene and the expression of an erythropoietin cDNA clone in a transient mammalian expression system to yield a secreted product with biological activity. 相似文献
9.
The effect of myofibrogranuloma (skeletal muscle degeneration) on serum calcium levels in spawning walleye ( Stizostedion vitreum ) was examined. Mean serum calcium levels for healthy male walleye (11.7 ± 1.5 mg/10 ml serum) was significantly lower ( P P < 0.1) in serum calcium were seen between healthy male and myofibrogranuloma-diseased male walleye (13.6 ± 2.1 mg/100 ml serum) and between healthy and myofibrogranuloma-diseased female walleye (20.2 ± 3.7 mg/100 ml serum). Elevations seen in mean serum calcium levels suggest the muscle degeneration and subsequent granuloma formation in later stages of myofibrogranuloma have a significant effect on serum calcium. 相似文献
10.
Experimental annotation of the human genome using microarray technology 总被引:59,自引:0,他引:59
Shoemaker DD Schadt EE Armour CD He YD Garrett-Engele P McDonagh PD Loerch PM Leonardson A Lum PY Cavet G Wu LF Altschuler SJ Edwards S King J Tsang JS Schimmack G Schelter JM Koch J Ziman M Marton MJ Li B Cundiff P Ward T Castle J Krolewski M Meyer MR Mao M Burchard J Kidd MJ Dai H Phillips JW Linsley PS Stoughton R Scherer S Boguski MS 《Nature》2001,409(6822):922-927