Digital plethysmography for assessing erythrityl tetranitrate bioavailability.

The bioavailability or oral, sublingual, and chewable tablets or erythrityl tetranitrate (ETN) was evaluated in 15 normal men. In a randomized, complete crossover investigation with nitroglycerin and placebo controls, drug-induced changes in the diastolic amplitude response intensity were measured with a digital plethysmogram. Values for area under the response intensity curve (AUC), maximum response intensity (Imax), and time lapse from dosing to peak response (tmax) were obtained by computer processing and converted to intensity values and AUC segments for specific time intervals. Sublingual nitroglycerin induced a response (p less than 0.05) from placebo within the first hour. Although somewhat slower in reaching peak intensity, all forms of ETN induced significant responses over placebo (p less than 0.05) for 2 hr, with oral (swallowed) ETN different 6 hr. Our results indicate that all the ETN dosage forms were bioavailable, with the longest duration of effect by the oral form.

Compositional similarities between the human immunodeficiency virus and surface antigens of pathogens.

The genome of the human immunodeficiency virus (HIV) is rich in A but not U and deficient in C but not G. This asymmetric nucleotide bias is the major factor in determining the unusual composition of HIV proteins. In this report, we have identified the cellular genes in the GenBank database that are compositionally similar to HIV in order to further understand the significance of the nucleotide bias of the viral genome. A total of 101 genes in the bacterial and invertebrate subdivisions of the database were found to have a base composition that is similar to the composition of the HIV genome. The identified cellular sequences represent a discrete subset of the database since 81 of the 101 entries code for antigens from pathogens and nearly all of these organisms infect humans. The amino acid compositions of these surface antigens are also similar to the unusual composition of HIV proteins, which are deficient in proline and rich in lysine and other polar residues encoded by A-rich codons. The similarities between the HIV proteins and the immunodominant antigens from other pathogens may indicate a common pathogenic strategy for the promotion of immune dysregulation.

Short-term longitudinal effects of the transcendental meditation technique on EEG power and coherence.

EEG alpha coherence and slow alpha power were recorded from frontal and occipital derivations during relaxation or the Transcendental Meditation (TM) technique in fifteen subjects. Subjects were tested before and after a two-week baseline period in which half practiced twice daily relaxation and half did not change their schedule. All subjects were then instructed in the TM technique and retested after a two-week period of twice daily practice of the technique. During the first two-week period there were no group differences or group by session interactions, but there was a significant effect of repeated measurement, indicating a decrease in occipital power independent of group. After the two-week TM technique period, subjects showed a significant increase in frontal alpha coherence above a 0.95 threshold. Frontal alpha coherence was found to be a more sensitive discriminator of the TM technique than alpha power, which may clarify previously reported nonsignificant EEG differences between the TM technique and general relaxation.

Nucleotide composition as a driving force in the evolution of retroviruses.

All complete retrovirus sequences in the GenEMBL database were examined with the goal of assessing possible relationships between the nucleotide composition of retroviral genomes, the amino acid composition of retroviral proteins, and evolutionary strategies used by retroviruses. The results demonstrated that the genome of each viral lineage has a characteristic base composition and that the variations between groups are related to retroviral phylogeny. By analogy to microbial species, we suggest that the variations arise from group-specific patterns of directional mutations where the bias can be exerted on any of the four nucleotides. It is most likely that the mutational patterns are introduced during reverse transcription, and a direct participation of reverse transcriptase in the process is suspected. A straightforward strategy was used to analyze the compositional relationship between nucleotides and encoded amino acids. The procedure entailed calculations of amino acid frequencies from nucleotide content and the comparison of the calculated values to the observed amino acid frequencies in retroviruses. The results revealed an excellent correspondence between variation in genomic base composition and variation in amino acid composition of proteins with the compositional differences extending into all major coding regions of the viruses. Because of the magnitude and dispersion of these effects, and because of the nonconservative nature of many of the substitutions between groups with different genomic biases, we suggest that the variations in protein composition driven by biased nucleotide frequencies are an important factor in shaping the characteristic phenotypes of the different viral lineages. A clue to the nature of the evolutionary forces that are responsible for the generation of nucleotide biases was provided by the observation that viruses with radically different base frequencies most often inhabit the same cell type. This observation, along with analysis of amino acid and nucleotide replacement patterns between and within reverse transcriptase sequences from the various groups, permitted us to advance a model for the evolution of retroviruses. According to the model, speciation could initiate when daughter virions from a single progenitor vary in the direction of their mutational bias. These variations would exert a pleiotropic effect on the frequencies of nucleotides in all viral genes and consequently on the frequencies of amino acids in the encoded proteins. The variants with the most extreme compositional differences would have a selective advantage because their different precursor requirements would enable them to occupy different ecological niches within a single cell.(ABSTRACT TRUNCATED AT 400 WORDS)

Species-specific patterns of DNA bending and sequence.

Nucleotide sequences in the GenEMBL database were analyzed using strategies designed to reveal species-specific patterns of DNA bending and DNA sequence. The results uncovered striking species-dependent patterns of bending with more variations among individual organisms than between prokaryotes and eukaryotes. The frequency of bent sites in sequences from different bacteria was related to genomic A + T content and this relationship was confirmed by electrophoretic analysis of genomic DNA. However, base composition was not an accurate predictor for DNA bending in eukaryotes. Sequences from C. elegans exhibited the highest frequency of bent sites in the database and the RNA polymerase II locus from the nematode was the most bent gene in GenEMBL. Bent DNA extended throughout most introns and gene flanking segments from C.elegans while exon regions lacked A-tract bending characteristics. Independent evidence for the strong bending character of this genome was provided by electrophoretic studies which revealed that a large number of the fragments from C.elegans DNA exhibited anomalous gel mobilities when compared to genomic fragments from over 20 other organisms. The prevalence of bent sites in this genome enabled us to detect selectively C.elegans sequences in a computer search of the database using as probes C.elegans introns, bending elements, and a 20 nucleotide consensus sequence for bent DNA. This approach was also used to provide additional examples of species-specific sequence patterns in eukaryotes where it was shown that (A) greater than or equal to 10 and (A.T) greater than or equal to 5 tracts are prevalent throughout the untranslated DNA of D.discodium and P.falciparum, respectively. These results provide new insight into the organization of eukaryotic DNA because they show that species-specific patterns of simple sequences are found in introns and in other untranslated regions of the genome.

Circular structures in retroviral and cellular genomes.

A computer program for predicting DNA bending from nucleotide sequence was used to identify circular structures in retroviral and cellular genomes. An 830-base pair circular structure was located in a control region near the center of the genome of the human immunodeficiency virus type I (HIV-I). This unusual structure displayed relatively smooth planar bending throughout its length. The structure is conserved in diverse isolates of HIV-I, HIV-II, and simian immunodeficiency viruses, which implies that it is under selective constraints. A search of all sequences in the GenBank data base was carried out in order to identify similar circular structures in cellular DNA. The results revealed that the structures are associated with a wide range of sequences that undergo recombination, including most known examples of DNA inversion and subtelomeric translocation systems. Circular structures were also associated with replication and transposition systems where DNA looping has been implicated in the generation of large protein-DNA complexes. Experimental evidence for the structures was provided by studies which demonstrated that two sequences detected as circular by computer preferentially formed covalently closed circles during ligation reactions in vitro when compared to nonbent fragments, bent fragments with noncircular shapes, and total genomic DNA. In addition, a single T-->C substitution in one of these sequences rendered it less planar as seen by computer analysis and significantly reduced its rate of ligase-catalyzed cyclization. These results permit us to speculate that intrinsically circular structures facilitate DNA looping during formation of the large protein-DNA complexes that are involved in site- and region-specific recombination and in other genomic processes.

Conserved patterns of bending in satellite and nucleosome positioning DNA.

Intrinsic DNA curvature has previously been implicated in the condensation of satellite DNA in chromatin. In this article, electrophoretic methods and computer programs for predicting DNA structure from nucleotide sequence were used to determine if curvature is a conserved feature of satellite DNA. The results revealed that satellite sequences display wide variation in magnitude of intrinsic bending. Less than half of the satellites examined were strongly bent when compared with control DNA. However, a conserved pattern of bending was seen in all 57 satellite sequences that were studied. The pattern consisted of repeating units of two 50-60-base pair bending elements which were separated by a 20-30-base pair region of low curvature. This pattern resembles qualitatively the bending of DNA in the nucleosome where the helix is folded approximately two turns around the histone octomer with the turns interrupted by a less bent segment in the center of the particle. The distance between successive pairs of bending elements was also similar to the average spacing of nucleosomes in chromatin. Thus, the conserved structures could play some role in the positioning of nucleosomes along satellite chromatin. In order to strengthen the correlation between DNA structure and nucleosome positioning, sequences were examined which have been shown to position nucleosomes at single major sites. This analysis revealed a conserved pattern of DNA structure resembling the two peak units seen in satellites. In addition, the nucleotide sequence patterns responsible for the conserved patterns of bending were similar in both satellite and nucleosome positioning DNA. Likewise, nucleotide sequence patterns that are thought to direct the rotational orientation of DNA in the nucleosome were similar in both sequence sets. These results are considered in terms of a general model for the role of DNA bending and nucleotide sequence in the control of nucleosome positioning and chromatin condensation in eukaryotes.