ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2335270

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

Each year National Institutes of Health (NIH) grant recipients must submit a noncompeting continuation application before receiving continued federal funding. This paper describes the use and value of the application. Investigators benefit by a yearly self‐assessment of the research progress and future plans. The noncompeting continuation application is part of the important communication and interaction that should exist between the investigator and NIH staff. NIH staff members use the application to determine important scientific advances that have resulted from supported grants. Many planning activities and required reports are based on information contained in these applications. NIH staff performs scientific and budgetary review to ensure that research progress is satisfactory and that all budgetary and certification issues are in order. Detailed guidance is provided to help the grantee prepare the application. A separate significance section is suggested as a means to document key findings and their importance.— Gordon, S. L.; Watson, D. M. Use and importance of the NIH noncompeting continuation application.FASEB J.4: 2438‐2440; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2335271

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

The folate antagonists are an important class of therapeutic compounds, as evidenced by their use as antiinfective, antineoplastic, and antiinflammatory drugs. Thus far, all of the clinically useful drugs of this class have been inhibitors of dihydrofolate reductase (DHFR), a key enzyme in the synthesis of thymidylate, and therefore, of DNA. The basis of the antiinfective selectivity of these compounds is clear; the antifolates trimethoprim and pyrimethamine are potent inhibitors of bacterial and protozoal DHFRs, respectively, but are only weak inhibitors of mammalian DHFRs. These species‐selective agents apparently exploit the differences in the active site regions of the parasite and host enzymes. Methotrexate is the DHFR inhibitor used most often in a clinical setting as an anticancer drug and as an antiinflammatory and immunosuppressive agent. Considerable progress has been made recently in understanding the biochemical basis for the selectivity of this drug and the biochemical mechanism (or mechanisms) responsible for the development of resistance to treatment with the drug. This understanding has led to a new generation of DHFR inhibitors that are now in clinical trials.— Schweitzer, B. I.; Dicker, A. D.; Bertino, J. R. Dihydrofolate reductase as a therapeutic target.FASEB J.4: 2441‐2452; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2185970

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

Cytochrome P‐450 (P‐450) enzymes catalyze the oxidation of a wide variety of substrates. Although a large number of P‐450s have been characterized in different species and tissues, the mechanisms of catalysis of oxygenation may be understood in terms of a few basic principles. The chemistry is dominated by the ability of a high‐valent formal (FeO)3+species to carry out one‐electron oxidations through the abstraction of hydrogen atoms, abstraction of electrons in n or π Orbitals, or the addition to π bonds. A series of radical recombination reactions then completes the oxidation process. The protein structures are postulated to provide the axial thiolate ligand to the heme, to control the juxtaposition of the substrate (and therefore the regioand stereoselectivity of oxidation), to alter the effective oxidation potential of the (FeO)3+complex, and possibly to participate in specific acid/base catalysis in the oxidation of some substrates.—Guengerich, F. P.; Macdonald, T. L. Mechanisms of cytochrome P‐450 catalysis.FASEB J.4: 2453‐2459; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2185971

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

Four distinct macromolecular antifreezes have been isolated and characterized from different marine fish. These include the glycoprotein antifreezes (Mr2.5‐33 K), which are made up of a repeating tripeptide (Ala‐Ala‐Thr)nwith a disaccharide attached to the threonyl residues, and three antifreeze protein (AFP) types. Type I is an alanine‐rich, amphiphilic, α‐helix (Mr3‐5 K); type II is a larger protein (Mr14 K) with a high content of reverse turns and five disulfide bridges; and type III is intermediate in size (Mr6‐7 K) with no distinguishing features of secondary structure or amino acid composition. Despite their marked structural differences, all four antifreeze types appear to function in the same way by binding to the prism faces of ice crystals and inhibiting growth along the a‐axes. It is suggested that type I AFP binds preferentially to the prism faces as a result of interactions between the helix macrodipole and the dipoles on the water molecules in the ice lattice. Binding is stabilized by hydrogen bonding, and the amphiphilic character of the helix results in the hydrophobic phase of the helix being exposed to the solvent. When the solution temperature is lowered further, ice crystal growth occurs primarily on the uncoated, unordered basal plane resulting in bipyramidal‐shaped crystals. The structural features of type I AFP that could contribute to this mechanism of action are reviewed. Current challenges lie in solving the other antifreeze structures and interpreting them in light of what appears to be a common mechanism of action.— Davies, P. L.; Hew, C. L. Biochemistry of fish antifreeze proteins.FASEB J.4: 2460‐2468; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2185972

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

Cocaine can induce lethal cardiovascular events, including myocardial infarction and ventricular fibrillation. The mechanisms responsible for these cardiotoxic effects of cocaine remain largely to be determined. Cocaine has both sympathomimetic (inhibition of neuronal uptake of norepinephrine) and local anesthetic (Na+channel blockade) properties. Neurotransmitters released from cardiac sympathetic nerves bind to both α‐and β‐adrenergic receptors eliciting a cascade of intracellular responses. Stimulation of β‐adrenergic receptors activates adenylate cyclase, increasing cyclic AMP levels, whereas α‐adrenergic receptor stimulation activates phospholipase C, increasing inositol trisphosphate. These second messengers, in turn, elicit increases in cystolic calcium. Elevations in cystolic calcium can provoke oscillatory depolarizations of the cardiac membrane, triggering sustained action potential generation and extrasystoles. Cocaine also acts as a local anesthetic by inhibiting sodium influx into cardiac cells, which impairs impulse conduction and creates an ideal substrate for reentrant circuits. Thus, the adrenergic and anesthetic properties of cocaine could act synergistically to elicit and maintain ventricular fibrillation. Adrenergic receptor activation would trigger the event whereas sodium channel blockade would create the reentrant substrate to perpetuate the malignant arrhythmias.— Billman, G. E. Mechanisms responsible for the cardiotoxic effects of cocaine.FASEB J.4: 2469‐2475; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2185973

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

Making a functional nervous system involves the production of specific types of neurons in characteristic locations and their ability to find and synapse with appropriate target cells. By capitalizing on the advanced genetics and molecular biology ofDrosophila, a rapidly growing number of genes have been identified that control these events. Studies of the expression and function of these genes in single, uniquely identified cells is possible because of the relative simplicity of theDrosophilaembryonic nervous system. A class of neurogenic genes, includingN, Dl, andE(spl), controls the emergence of the entire neuronal precursor population, whereas some of the segmentation genes, such asftzandeve, control the fates of individual neurons. Later in development, genes encoding cell‐surface molecules, called fasciclins, may be involved in the ability of growing neurons to recognize and elongate axons along specific pathways to reach their synaptic targets.— Thomas, J. B.; Crews, S. T. Molecular genetics of neuronal development in theDrosophilaembryo.FASEB J.4: 2476‐2482; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2185974

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

This review considers recent information, in the following order, on complex proteins containing Fe‐S clusters together with other prosthetic groups, on hydrogenases, unexpected functions of Fe‐S clusters, novel cluster types, protein structures furnishing the cluster ligands, evolutionary aspects, and spectroscopic methods and theoretical approaches used or developed in the study of Fe‐S proteins.—Beinert, H. Recent developments in the field of iron‐sulfur proteins.FASEB J.4: 2483‐2491; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2185975

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

The effects of neurotransmitters and peptides on phosphoinositide hydrolysis were studied by measuring [3H]inositol monophosphate ([3H]IP) and protein kinase C (PKC) activity in the sympathetic and sensory neuronal cultures of the chick embryo. [3H]IP was increased in sympathetic neurons by acetylcholine (ACh), muscarine, serotonin (5‐HT), and vasoactive intestinal polypeptide. ACh, muscarine, 5‐HT, and bradykinin increased [3H]IP in sensory neuronal cultures. Dopamine, norepinephrine, histamine, and nerve growth factor did not stimulate [3H]IP formation in both cultures. ACh and phorbol 12,13‐dibutyrate (PDB) increased the PKC activity by two‐ to sevenfold in the particulate fraction of both cultures. In sympathetic neurons, PKC activity was increased in the particulate fraction; activity in the cytosolic fraction was not affected. There was a 50% decline in the protein kinase C activity of the cytosolic fraction after PDB and ACh treatment of sensory cultures. The decline in PKC activity in the cytosolic fraction was attributed to the presence of nonneuronal cells in sensory cultures. To confirm this, the enzyme activity was determined in tissues that contain a heterogeneous population of cells. PDB activated PKC in the adrenal medulla and the brain of the rat. In both tissues there was a 65% decline in the PKC activity of the cytosolic fraction and about a 75% increase in the particulate fraction. We conclude that the mechanism of activation of protein kinase C in pure cultures of sympathetic neurons is different than in tissues containing a mixed population of neurons and nonneuronal cells.— Malhotra, R. K.; Bhave, S. V.; Wakade, T. D.; Bhave, A. S.; Wakade, A. R. Effects of neurotransmitters and peptides on phospholipid hydrolysis in sympathetic and sensory neurons.FASEB J.4: 2492‐2498; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.1970791

出版商:Wiley    

年代:1990

数据来源: WILEY

摘要:

We investigated the acute adaptation of the rat femur‐medial collateral ligament‐tibia (FMT) complex to 7 days of limb unweighting by means of a hind‐limb suspension protocol. Male, young adult, Harlan Sprague‐Dawley rats were randomly assigned to either control or suspended groups. Rats deprived of hind limb‐to‐ground contact forces had a 42% decrease in soleus muscle mass compared with the control group. Medial collateral ligament (MCL) length and cross‐sectional area were measured, and each FMT complex was tension tested to failure. All failed at their tibia‐MCL insertion. The ultimate load in the FMT and the peak Kirchhoff stress in the MCL (occurring immediately before insertion site failure) were significantly reduced in the suspended group. The suspended MCLs were 9.7% larger in area and 5.7% shorter in length than the controls under the same preload (0.25 N). We found no significant differences between the control and suspended MCLs in Green strain, stretch, or deformation immediately before insertion site failure, nor did we find a significant difference in the MCL tangent modulus. This study indicates that even acute periods of limb unweighting can structurally compromise bone‐ligament insertions. Further, this study implies that the adaptations responsible for this structural compromise must involve acute changes in the intrinsic zone (or zones) of the bone‐ligament insertion.— Vanderby, R., Jr.; Vailas, A. C.; Graf, B. K.; Thielke, R. J.; Ulm, M. J.; Kohles, S. S.; Kunz, D. N. Acute modification of biomechanical properties of the bone‐ligament insertion to rat limb unweighting.FASEB J.4: 2499‐2505; 1990.

ISSN:0892-6638    

DOI:10.1096/fasebj.4.8.2335272

出版商:Wiley    

年代:1990

数据来源: WILEY