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 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In sharp contrast to the Darwinian theory of evolution by natural selection, the neutral theory claims that the overwhelming majority of evolutionary changes at the molecular level are caused by random fixation (due to random sampling drift in finite populations) of selectively neutral (i.e., selectively equivalent) mutants under continued inputs of mutations. The theory also asserts that most of the genetic variability within species at the molecular level (such as protein and DNA polymorphism) are selectively neutral or very nearly neutral and that they are maintained in the species by the balance between mutational input and random extinction. The neutral theory is based on simple assumptions, enabling us to develop mathematical theories based on population genetics to treat molecular evolution and variation in quantitative terms. The theory can be tested against actual observations. Neo-Darwinians continue to criticize the neutral theory, but evidence for it has accumulated over the last two decades. The recent outpouring of DNA sequence data has greatly strengthened the theory. In this paper, I review some recent observations that strongly support the neutral theory. They include such topics as pseudoglobin genes of the mouse, alpha A-crystallin genes of the blind mole rat, genes of influenza A virus and nuclear vs. mitochondrial genes of fruit flies. I also discuss such topics as the evolution of deviant coding systems in Mycoplasma, the origin of life and the unified understanding of molecular and phenotypic evolution. I conclude that since the origin of life on Earth, neutral evolutionary changes have predominated over Darwinian evolutionary changes, at least in number.
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PMID:The neutral theory of molecular evolution: a review of recent evidence. 195 33

The temperature dependence of membrane interactions between PR8 influenza virus and virus receptor (GD1a)-containing liposomes was studied. For quantitation, the octadecylrhodamine B chloride (R18) membrane marker was incorporated into liposomes at quenched concentrations. Upon interaction with target membranes, the marker gets diluted, and dequenching can be measured in a fluorescence spectrophotometer. Rate constants were calculated from the dequenching curves under low pH conditions, which allow for fusion, and at neutral pH, where no specific fusion occurs. Activation energies were determined from Arrhenius plots. The results were compared with the temperature dependence of other viral activities like infectivity, hemolysis, and fusion with erythrocytes. For the slow reaction at pH 7.4, where only non-specific lipid transfer takes place, the activation energy was about 24 kcal/mole between 15 degrees C and 45 degrees C. For the fast, hemagglutinin (HA)-specific fusion reaction (pH 5.3), a very low activation energy (approximately 7 kcal/mole) was found between 25 degrees C and 37 degrees C, whereas below 25 degrees C it was much higher (approximately 34 kcal/mole). The temperature range with low activation energy coincides with the one for optimal infectivity, hemolysis, and fusion with erythrocytes. Furthermore, it is the same range in which the conformational change of HA takes place, which in the absence of a partner membrane leads to an irreversible inactivation of the fusion protein.
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PMID:Temperature-dependent kinetics of the activities of influenza virus. 208 51

The phosphorylation of the internal and integral membrane (M1) protein of influenza virus was studied. Four points can be made based on the data: (1) The M1 contains at least two moles of phosphate per mole of M1. (2) Phosphorylation of M1 is conserved between influenza A, B and C viruses. Other characteristics of the M1 are also conserved, such as solubility in organic solvent, heterogeneity and ability to partition into lipid vesicles. (3) M1 is phosphorylated in cells infected with a vaccinia recombinant (vP273) containing only the gene of M1, either as a result of a vaccinia virus associated kinase or a cellular one. (4) The phosphate is located within or in close proximity to the major stretch of neutral and hydrophobic amino acids found in M1, as determined by analyzing cyanogen bromide fragments.
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PMID:The phosphorylation of the integral membrane (M1) protein of influenza virus. 234 33

Two naturally occurring non-enzymic glucosylceramide activator proteins (A1a and A1b activator) shown previously to be immunochemically not detectable in a new variant of human Gaucher disease (glucosylceramide lipidosis) without glucosylceramidase deficiency, were characterized by amino-acid sequence and carbohydrate content. The complete amino-acid sequence of the A1a activator was determined. The protein consists of 80 amino-acid residues including three disulfide bridges lacking arginine and tryptophan. The molecular mass is 8.95 kDa. About 20% of the polypeptide chain are shorter by two amino-acid residues at the N-terminal end. The A1b activator was characterized by the amino-acid compositions of all tryptic peptides and of the entire protein; sequencing was performed of the regions 1-34 and 42-56. Identical results were obtained for the polypeptide chains of both A1 activators. This suggests that they do not differ in their primary structures which is in agreement with the immunochemical results. The difference between A1a and A1b activator is due to the carbohydrate part. The total amount of 49% carbohydrate in A1a and 76.7% in A1b consists mainly of hexoses. Both chains contain two moles of N-acetylglucosamine per mole protein bound to asparagine in position 22. A comparison of the primary structure of the A1 activator with the sulfatide activator sequence revealed an interesting similarity, especially of the cysteine residues and the carbohydrate-binding asparagine. Sequence homology was also found between a part of the A1 activator sequence and the hemagglutinin neuraminidase of influenza virus as well as to a hypothetical glycoprotein of the Epstein-Barr virus. The comparison with human lysosomal glucosylcerebrosidase showed no sequence similarity.
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PMID:Complete amino-acid sequence and carbohydrate content of the naturally occurring glucosylceramide activator protein (A1 activator) absent from a new human Gaucher disease variant. 344

The integral membrane proteins of influenza virus, a hemagglutinin and a neuraminidase, have been incorporated into liposomes composed of either phosphatidylcholine or a mixture of phosphatidylcholine and phosphatidylethanolamine (2:1 w/w) using detergent dialysis. The virus spike glycoproteins for reconstitution were selectively solubilized by using cetyltrimethylammonium bromide to leave a "core particle", which lacked a lipid bilayer but possessed quaternary structure as observed by electron microscopy. The viral spike proteins were combined with exogenous phospholipid in excess sodium cholate followed by exhaustive dialysis for 150 h. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that only the viral glycoproteins were associated with all the complexes formed. The level of sodium cholate remaining after dialysis was shown to be reduced to less than 1 molecule per 80 protein molecules. Viral proteins reconstituted into dimyristoylphosphatidylcholine liposomes were shown to have retained hemagglutination, low-pH-dependent hemolysis, and neuraminidase activities and were associated with a lipid bilayer in two types of complexes with average lipid to protein mole ratios after sucrose density gradient purification of either 590:1 or 970:1. The bilayer vesicles formed were of similar sizes and were shown by negative-stain electron microscopy to be 150-300 nm in diameter with well-defined spikes on their surface. Reconstituted liposomes of dimyristoylphosphatidylcholine were found to be unstable with respect to their trapped volume and therefore were unsuitable for fusion studies, unlike complexes formed with phosphatidylcholine or a mixture of phosphatidylcholine/phosphatidylethanolamine derived from hen eggs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional reconstitution of the integral membrane proteins of influenza virus into phospholipid liposomes. 366 46

An N1 strain of influenza A virus neuraminidase (A/WSN/33 NA) was purified and used to screen for inhibitors. As a result, a well-known tuberculostatic, 4'-formylacetanilide thiosemicarbazone (or thiacetazone), was identified. Thiacetazone is a non-sialate compound and inhibits the enzyme in a noncompetitive manner with respect to the substrate sialic acid. Mechanistic studies indicate that the inhibition was due to the competition of thiacetazone with Ca2+, which maintains N1 neuraminidase in an active conformation. The Ki for the inhibition was estimated to be about 4 microM. Equilibrium exchange experiments revealed that when purified A/WSN/33 NA was incubated with 5 microM 45CaCl2, 2 mol of 45Ca2+ ion was exchanged into each mole of NA tetramer and subsequently displaced from the enzyme upon the introduction of the inhibitor. Inhibition of plaque formation by thiacetazone in an MDCK cell culture that had been infected with the influenza A/WSN/33 virus was demonstrated. Thiacetazone was highly specific for A/WSN/33 neuraminidase, since little effect was noted when it was tested against NAs from the other strains of influenza virus or from bacteria. This compound might represent a group of non-sialate inhibitors of influenza NA that bind to a noncatalytic or an allosteric site on the enzyme.
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PMID:Non-sialate inhibitor of influenza A/WSN/33 neuraminidase. 753 92

A wide range of biological functions of nitric oxide (NO) was analyzed using a newly discovered nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazolineoxyl-1-oxyl-3-oxide (PTIO) or its water-soluble derivative carboxy-PTIO. The chemistry is very simple in that NO was oxidized by PTIO, yielding one mole each of NO2 and 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl. Based on the potent NO-scavenging activity of PTIO derivatives, the diverse functions of NO under physiological states as well as various pathological conditions such as endotoxin shock and viral diseases are now explicated. It was found that PTIO and carboxy-PTIO showed significant inhibitory activity against a series of biological actions of NO: (1) endothelium-dependent vascular relaxation in an ex vivo system, (2) pathogenicity of NO produced excessively in endotoxin shock in rats and in influenza virus pneumonitis in mice, and (3) enhanced vascular permeability in solid tumors mediated by NO. PTIO directly extinguishes NO generated by NO synthase (NOS) without affecting NOS activity, which is a clear contrast to NOS inhibitors. Therefore, characterization of this unique mode of action of PTIO appears to be helpful not only in understanding of the pathophysiological role of NO but also in the treatment of various diseases caused by excessive production of NO.
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PMID:Multiple functions of nitric oxide in pathophysiology and microbiology: analysis by a new nitric oxide scavenger. 796 66

Reports of the antiviral activity of aliphatic alcohols led us to investigate the effects of aliphatic alcohols, from 10 to 20 carbons in length, on the phase transition behaviour of model phospholipids and on the fusion of influenza to liposomes. Contrary to the effects of many other antiviral agents, we find that alcohols are potent promoters of the inverted hexagonal phase. However, we also find that aliphatic alcohols have little effect on influenza fusion to liposomes. Eicosanol is the only aliphatic alcohol tested which substantially increases in fusion of influenza virus. We also find that long chain alcohols display multi-component bilayer to hexagonal phase transitions at higher mole fractions. This suggests that eicosanol may be facilitating fusion by creating defects between alcohol-rich and alcohol-poor regions of the lipid bilayer.
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PMID:Fusion of influenza to liposomes is not inhibited by aliphatic primary alcohols. 803 7

The binding of influenza A virus to GM3-containing monolayers at an air/water interface was quantitatively investigated by use of a quartz crystal microbalance (QCM). A QCM was horizontally attached to the monolayer from the air phase and the binding behavior of influenza virus was followed by the frequency changes of the QCM. GM3 was reconstituted in the momolayer of sphingomyelin (SM) or glucosylceramide (GlcCer). When the mole fraction of GM3 was below 30 mol%, the binding rate of the influenza A virus to the GM3/GlcCer membrane was significantly faster than that to GM3/SM membranes. When the mole fraction of GM3 in SM was below 20 mol%, specific binding of influenza virus was not observed at all. Binding of the virus to the GM3/GlcCer mixed membrane was inhibited by the addition of sialyllactose (Neu5Ac alpha 2-3Gal beta 1-4Glc). The virus binding was also visually observed by scanning electron microscopy. Viruses selectively bound to GM3/GlcCer (20:80, by mol%) membrane, but not to GM3/SM (20:80, by mol%) membrane. Furthermore, it was suggested that specific binding of influenza virus to the GM3/GlcCer membrane induced the changes in morphology of virus. It was clearly demonstrated that binding of influenza virus to GM3 was influenced by matrix lipids surrounding GM3.
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PMID:Binding of influenza A virus to monosialoganglioside (GM3) reconstituted in glucosylceramide and sphingomyelin membranes. 894 70

Low mole fractions of viral fusion peptides induce inverted cubic (Q(II)) phases in dipalmitoleoylphosphatidylethanolamine (DiPoPE), a lipid with unsaturated acyl chains that normally forms inverted hexagonal phase (H(II)) above 43 degrees C. The ability to form a Q(II) phase is relevant to the study of membrane fusion: fusion occurs in liposomal systems under conditions where Q(II) phase precursors form, and fusion may be an obligatory step in the lamellar (L(alpha))/Q(II) phase transition. We used X-ray diffraction and time-resolved cryoelectron microscopy (TRC-TEM) to study the effects of the influenza hemagglutinin fusion peptide on the phase behavior and structure of DiPoPE. X-ray diffraction data show that at concentrations of 3-7 mol%, the fusion peptide (FP) induces formation of a Q(II) phase in preference to the H(II) phase. TRC-TEM data show that the FP acts at early stages in the phase transition (i.e. within seconds): at 2-7 mol%, FP decreases or inhibits formation of the L(alpha)/H(II) intermediate morphology observed via TRC-TEM in pure DiPoPE at the same temperature. Our X-ray diffraction data imply that FP either does not affect, or slightly increases, the spontaneous curvature of the host lipid (i.e. either does not affect or tends to destabilize inverted phases, respectively). FP may act in part by affecting the relative stability of two intermediate structures in the phase transition mechanism, as suggested previously. These results indicate a new way in which hydrophobic sequences of membrane proteins may be fusogenic.
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PMID:Effect of influenza hemagglutinin fusion peptide on lamellar/inverted phase transitions in dipalmitoleoylphosphatidylethanolamine: implications for membrane fusion mechanisms. 1101 54


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