RESUMO
A simple agent-based model is presented that produces results matching the experimental data found by Lenski's group for ≤50,000 generations of Escherichia coli bacteria under continuous selective pressure. Although various mathematical models have been devised previously to model the Lenski data, the present model has advantages in terms of overall simplicity and conceptual accessibility. The model also clearly illustrates a number of features of the evolutionary process that are otherwise not obvious, such as the roles of epistasis and historical contingency in adaptation and why evolution is time irreversible ('Dollo's law'). The reason for this irreversibility is that genomes become increasingly integrated or organized, and this organization becomes a novel selective factor itself, against which future generations must compete. Selection for integrated or synergistic networks, systems or sets of mutations or traits, not for individual mutations, confers the main adaptive advantage. The result is a punctuated form of evolution that follows a logarithmic occurrence probability, in which evolution proceeds very quickly when interactomes begin to form but which slows as interactomes become more robust and the difficulty of integrating new mutations increases. Sufficient parameters exist in the game to suggest not only how equilibrium or stasis is reached but also the conditions in which it will be punctuated, the factors governing the rate at which genomic organization occurs and novel traits appear, and how population size, genome size and gene variability affect these.
RESUMO
BACKGROUND: People at risk for acquired immunodeficiency syndrome (AIDS) have high rates of cofactor infections in addition to HIV, including cytomegalovirus, hepatitis viruses, Mycobacteria, Mycoplasmas, and Staphylococcus aureus. Most people with AIDS also develop lymphocytotoxic antibodies (LCTA) and circulating immune complexes (CIC). While HIV proteins mimic HLA antigens, many cofactor agents mimic CD4 antigens. It has therefore been proposed that cofactor infections may interact with HIV by producing complementary antigens that induce LCTA and CIC, and that the resulting immunological dysfunction is part of AIDS pathogenesis. OBJECTIVES: To test (1) whether HIV and its cofactor infections elicit complementary (idiotype-anti-idiotype) antibodies, and (2) if any of these antibodies mimic anti-lymphocyte antibodies. STUDY DESIGN: Two immunological methods are employed to test for antibody complementarity: (1) double antibody diffusion, a modification of Ouchterlony immunodiffusion, in which antibodies are tested for their ability to precipitate each other; (2) double-antibody ELISA, in which an antibody against one infectious agent is adsorbed to an ELISA plate and an antibody against a second agent is used to detect the first. RESULTS: Data on over a thousand double antibody diffusion (DAD) and about 70 DA-ELISA experiments are reported. These show that only specific pairs of antibodies are complementary: HIV-CMV; HIV-HBV; HIV-tuberculosis; HIV-mycoplasmas; HIV-S. aureus; and CMV-mycoplasmas. In addition, HIV antibodies precipitate CD4 antibodies; CMV antibodies precipitate HLA-DR antibodies; while mycobacteria and mycoplasma antibodies precipitate macrophage antibodies. CONCLUSIONS: Antibodies elicited by HIV infection can interact with antibodies elicited by cofactor infections to form CIC, and some of these antibodies mimic lymphocyte antibodies so that they may function as LCTA. Since LCTA and CIC are associated with increased lymphocyte death in AIDS, the immune response against cofactors in HIV may play a significant role in AIDS pathogenesis. The fact that both HIV and cofactors elicit antibodies with LCTA characteristics may pose problems for vaccine development.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Complexo Antígeno-Anticorpo/imunologia , Soro Antilinfocitário/imunologia , Linfócitos/imunologia , Mimetismo Molecular , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Síndrome da Imunodeficiência Adquirida/complicações , Especificidade de Anticorpos/imunologia , HumanosRESUMO
Many examples of specific binding between small molecules are known that are associated with modified physiological and pharmacological activities. Conversely, the antagonism or synergism of small molecules is often correlated with specific binding between the molecules. It follows that small molecule binding can be used as a relatively quick, easy, and specific screen for functionally useful drug actions and interactions. These actions and interactions may manifest themselves as functional antagonisms; binding may correlate with enhancement or synergism; the formation of some complexes may yield clues about how drugs may be targeted to specific cell types in vivo and provide leads for the development of antidotes for drug overdoses or poisoning; the binding of one molecule to another may mimic receptor binding; and complexation may provide novel ways of protecting and delivering drugs. Relevant examples from each type of application are reviewed involving peptide-peptide interactions; peptide-aromatic compound interactions; aromatic-aromatic compound interactions; vitamin-aromatic compound interactions; and polycyclic compound interactions. We argue that screening for molecular complementarity of small molecules turns ligands such as neurotransmitters and their metabolites, hormones, and drugs themselves, into direct targets of drug development that can augment screening new compounds for activity against receptors and second messenger systems. We believe that the small molecule complementarity approach is novel, fruitful and under-utilized.
Assuntos
Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Modelos Moleculares , Interações Medicamentosas , Humanos , Ligantes , Estrutura Molecular , Peptídeos/farmacologia , Ligação ProteicaRESUMO
Ascorbate has previously been shown to enhance both alpha(1)- and beta(2)-adrenergic activity. This activity is mediated by ascorbate binding to the extracellular domain of the adrenergic receptor, which also decreases the oxidation rate of ascorbate. H1 histamine receptors have extracellular agonist or ascorbate binding sites with strong similarities to alpha(1-) and beta(2)-adrenergic receptors. Physiological concentrations of ascorbate (50 microM) significantly enhanced histamine contractions of rabbit aorta on the lower half of the histamine dose-response curve, increasing contractions of 0.1, 0.2, and 0.3 microM histamine by two- to threefold. Increases in ascorbate concentration significantly enhanced 0.2 microM histamine (5-500 microM ascorbate) and 0.3 microM histamine (15-500 microM ascorbate) in a dose-dependent manner. Histamine does not measurably oxidize over 20 h in oxygenated PSS at 37 degrees C. Thus the ascorbate enhancement is independent of ascorbate's antioxidant effects. Ascorbate in solution oxidizes rapidly. Transfected histamine receptor membrane suspension with protein concentration at >3.1 microg/ml (56 nM maximum histamine receptor) decreases the oxidation rate of 392 microM ascorbate, and virtually no ascorbate oxidation occurs at >0.0004 mol histamine receptor/mol ascorbate. Histamine receptor membrane had an initial ascorbate oxidation inhibition rate of 0.094 min.microg protein(-1).ml(-1), compared with rates for transfected ANG II membrane (0.055 min.microg protein(-1).ml(-1)), untransfected membrane (0.052 min.microg protein(-1).ml(-1)), creatine kinase (0.0082 min.microg protein(-1).ml(-1)), keyhole limpet hemocyanin (0.00092 min.microg protein(-1).ml(-1)), and osmotically lysed aortic rings (0.00057 min.microg wet weight(-1).ml(-1)). Ascorbate enhancement of seven-transmembrane-spanning membrane receptor activity occurs in both adrenergic and histaminergic receptors. These receptors may play a significant role in maintaining extracellular ascorbate in a reduced state.
Assuntos
Ácido Ascórbico/metabolismo , Receptores Histamínicos H1/metabolismo , Sequência de Aminoácidos , Animais , Células CHO , Membrana Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Histamina/farmacologia , Humanos , Dados de Sequência Molecular , Contração Miocárdica/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Coelhos , Receptores Histamínicos H1/químicaRESUMO
We have previously demonstrated the ability of electric fields to dissociate ascorbate and catecholamines and shown that the electric field generated by cell membranes is sufficient to produce dissociation of these complexes up to 8 nm from the cell membrane. We show here that this process is applicable to a wide range of biological complexes including small molecules (norepinephrine-morphine sulfate), protein-protein complexes (insulin-glucagon), and small molecule-protein complexes (epinephrine-bovine serum albumin). The extrapolation of the slope of the electric field dependence to zero electric field can be used to estimate the log of the dissociation constant (K(D)) of a complex and, by multiplying the log(K(D)) by -2.303RT, the association energy (E) of the complex. The slope of the electric field dependence is inversely related to the molecular radii, with the best fit of the slope related to E*(1/r1 + 1/r2), where r is the estimated radius of each molecule in the complementary pair. This indicates that the binding site of the pair is shielded by the remaining parts of the molecules, and the larger the molecule the greater the shielding. When the slope of the electric field dependence goes to 0 as r goes to infinity and 1/r goes to 0, the molecular shielding constant is 7.04 x 10(-8) cm2/V. Very large complexes will be minimally affected by the electric field due to molecular shielding and reduced electric field as their radius restricts approach to the membrane. Large protein receptors will deflect the membrane electric field and allow agonist binding.
Assuntos
Campos Eletromagnéticos , Potenciais da Membrana , Modelos Biológicos , Animais , Bovinos , Epinefrina/metabolismo , Glucagon/metabolismo , Insulina/metabolismo , Morfina/química , Norepinefrina/metabolismo , Ligação Proteica , Soroalbumina Bovina/metabolismoRESUMO
This paper reviews the three major theories of peptide receptor evolution: (1) Dwyer's theory that peptide receptors evolved from self-aggregating peptides; (2) Root-Bernstein's theory that peptide receptors evolved from functionally and structurally complementary peptides; and (3) Blalock's theory that receptors evolved from hydropathically complementary sequences encoded in the antisense strand of the DNA encoding each peptide. The evidence to date suggests that the co-yevolution of peptides and their receptors is strongly constrained by one or more of these physicochemically based mechanisms, which argues against a random or frozen accident' model. The data also suggest that structure and function are integrally related from the earliest steps of receptor-ligand evolution so that peptide functionality is non-random and highly conserved in its origin. The result is a molecular paleontology' that reveals the evolutionary constraints that shaped the interaction of structure and function.
Assuntos
Evolução Molecular , Modelos Químicos , Peptídeos/química , Receptores de Peptídeos/química , Receptores de Peptídeos/genética , Sequência de Aminoácidos , Animais , Humanos , Dados de Sequência Molecular , Filogenia , Receptores de Peptídeos/classificação , Homologia de Sequência de AminoácidosRESUMO
Some important vaccines, including ones against tuberculosis (Tb) and foot-and-mouth disease (FMD), are not used in many developed countries because there is no simple way to differentiate between vaccine-induced immunity and infection. Eliminating major protein antigens has not succeeded in the cases of Tb, FMD and some other vaccine preparations. Instead of eliminating antigens, novel antigens can be added to vaccines in order to induce a unique immunological response proving that the vaccine has been delivered. Methods for producing such unique antigens are presented and preliminary test results reported. The technique may also be useful for immunologically "branding" animals.
Assuntos
Antígenos/administração & dosagem , Vacinação/métodos , Vacinas/administração & dosagem , Vacinas/imunologia , Sequência de Aminoácidos , Aminoácidos/imunologia , Animais , Antígenos/química , Antígenos/genética , Biomarcadores , Reações Cruzadas , Febre Aftosa/imunologia , Febre Aftosa/prevenção & controle , Humanos , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologiaRESUMO
It is well-known that HIV-1 infection results in a gradual decline of the CD4+ T-lymphocytes, but the underlying mechanism of this decline is not completely understood. Research has shown that HIV-1 infection of CD4+ T cells results in decreased CD28 expression, but the mechanism of this repression is unknown. There is also substantial evidence demonstrating regulatory involvement of microRNA (miRNA) during protein expression in plants and some animals, and reports have recently been published confirming the existence of viral-encoded miRNAs. Based on these findings, we hypothesize that viral-encoded miRNA from HIV-1 may directly alter T cell, macrophage and dendritic cell activity. To investigate a potential correlation between the genomic complementarity of HIV-1 and host cell protein expression, a local alignment search was performed to assess for regions of complementarity between the HIV-1 proviral genome and the mRNA coding sequence of various proteins expressed by CD+ T cells and macrophages. Regions of complementarity with strong correlations to the currently established criteria for miRNA:target mRNA activity were found between HIV-1 and CD28, CTLA-4 and some interleukins, suggesting that HIV-1 may produce translational repression in host cells.