Genetic variation in HTLV-III/LAV over time in patients with AIDS or at risk for AIDS

In a study of genetic variation in the AIDS virus, HTLV-III/LAV, sequential virus isolates from persistently infected individuals were examined by Southern blot genomic analysis, molecular cloning, and nucleotide sequencing. Four to six virus isolates were obtained from each of three individuals over a 1-year or 2-year period. Changes were detected throughout the viral genomes and consisted of isolated and clustered nucleotide point mutations as well as short deletions or insertions. Results from genomic restriction mapping and nucleotide sequence comparisons indicated that viruses isolated sequentially had evolved in parallel from a common progenitor virus. The rate of evolution of HTLV-III/LAV was estimated to be at least 10(-3) nucleotide substitutions per site per year for the env gene and 10(-4) for the gag gene, values a millionfold greater than for most DNA genomes. Despite this relatively rapid rate of sequence divergence, virus isolates from any one patient were all much more related to each other than to viruses from other individuals. In view of the substantial heterogeneity among most independent HTLV-III/LAV isolates, the repeated isolation from a given individual of only highly related viruses raises the possibility that some type of interference mechanism may prevent simultaneous infection by more than one major genotypic form of the virus.     

Chloroquine: physiological basis of drug resistance in Plasmodium berghei

Mouse erythrocytes, parasitized by chloroquine-sensitive plasmodia, concentrate this drug in vivo to levels over twice as high as erythrocytes parasitized by chloroquine-resistant plasmodia; nonparasitized red cells accumulate little chloroquine. Selective toxicity of this drug may depend upon a special drug-concentrating mechanism of plasmodic impairment of such mechanism.     

Berberine: complex with DNA

A complex of calf-thymus DNA with berberine sediments in the analytical ultracentrifuge. The DNA produced systematic changes in the absorption spectrum of berberine which suggest that single alkaloid molecules bind to DNA. Flow dichroism of purines and pyrimidines and of berberine in the complex with DNA had the same signs and magnitudes. Berberine shifted the thermal strand separation profile of DNA to higher temperatures. Therefore, the alkaloid forms a complex with DNA, probably by intercalation.     

Diversity considerations in HIV-1 vaccine selection

Globally, human immunodeficiency virus-type 1 (HIV-1) is extraordinarily variable, and this diversity poses a major obstacle to AIDS vaccine development. Currently, candidate vaccines are derived from isolates, with the hope that they will be sufficiently cross-reactive to protect against circulating viruses. This may be overly optimistic, however, given that HIV-1 envelope proteins can differ in more than 30% of their amino acids. To contend with the diversity, country-specific vaccines are being considered, but evolutionary relationships may be more useful than regional considerations. Consensus or ancestor sequences could be used in vaccine design to minimize the genetic differences between vaccine strains and contemporary isolates, effectively reducing the extent of diversity by half.     

Direct determination of ionic solvation from neutron diffraction

Much information on ionic solvation in electrolyte solutions has been inferred from macroscopic thermodynamic and transport properties and from spectroscopy. These ion-water interactions can now be probed directly and unambiguously by neutron diffraction. Such measurements have been done with neodymium trichloride solutions in heavy water that are identical in every respect except the isotopic state of the neodymium ions; these experiments yield in a straightforward manner the distribution of oxygen and deuterium atoms from the water molecules in the first hydration sphere of the neodymium ion. Each ion is surrounded by 8.6 oxygen atoms at a distance of 2.48 angstroms and 16.7 deuterium atoms at 3.13 angstroms indicating a well-defined first hydration sphere of water molecules, the deuterium atoms pointing away from the cation.     

Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation

Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic PLA(2). These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.