Inhibitors of hepatitis C virus NS3.4A protease 1. Non-charged tetrapeptide variants

Tetrapeptide-based peptidomimetic compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease without the need of a charged functionality. An aldehyde is used as a prototype reversible electrophilic warhead. The SAR of the P1 and P2 inhibitor positions is discussed.     

Non-traditional Alu evolution and primate genomic diversity

Alu elements belonging to the previously identified "young" subfamilies are thought to have inserted in the human genome after the divergence of humans from non-human primates and therefore should not be present in non-human primate genomes. Polymerase chain reaction (PCR) based screening of over 500 Alu insertion loci resulted in the recovery of a few "young" Alu elements that also resided at orthologous positions in non-human primate genomes. Sequence analysis demonstrated these "young" Alu insertions represented gene conversion events of pre-existing ancient Alu elements or independent parallel insertions of older Alu elements in the same genomic region. The level of gene conversion between Alu elements suggests that it may have a significant influence on the single nucleotide diversity within the genome. All the instances of multiple independent Alu insertions within the same small genomic regions were recovered from the owl monkey genome, indicating a higher Alu amplification rate in owl monkeys relative to many other primates. This study suggests that the majority of Alu insertions in primate genomes are the products of unique evolutionary events.     

Genetic variation of recent Alu insertions in human populations

The Alu family of intersperesed repeats is comprised of ovr 500,000 members which may be divided into discrete subfamilies based upon mutations held in common between members. Distinct subfamilies of Alu sequences have amplified within the human genome in recent evolutionary history. Several individual Alu family members have amplified so recently in human evolution that they are variable as to presence and absence at specific loci within different human populations. Here, we report on the distribution of six polymorphic Alu insetions in a survey of 563 individuals from 14 human population groups across several continents. Our results indicate that these polymorphic Alu insertions probably have an African origin and that there is a much smaller amount of genetic variation between European populations than that found between other populations groups. Present address: Department of Pathology, Stanley S. Scott Cancer Center, Louisiana State University Medical Center, 1901 Perdido St., New Orleans, LA 70112 Correspondence to: M.A. Batzer     

Synthesis of Staphylococcus aureus lipoteichoic acid derivatives for determining the minimal structural requirements for cytokine induction

For the investigation of the minimal structural requirements for cytokine induction, Staphylococcus aureus lipoteichoic acid derivatives with two, three, four, and five glycerophosphate backbone moieties, carrying each a d-alanyl residue, were needed. Based on two different glycerophosphate building blocks and 6b-O-phosphitylated gentiobiosyl diacylglycerol the desired target molecules (compounds 1-4) could be readily obtained and provided for biological studies.     

Master genes in mammalian repetitive DNA amplification.

The analysis of species-specific subfamilies of both the LINE and SINE mammalian repetitive DNA families suggests that such subfamilies have arisen by amplification of an extremely small group of 'master' genes. In contrast to the master genes, the vast majority of both SINEs and LINEs appear to behave like psudogenes in their inability to undergo extensive amplification.     

Response

Summary  The posited universal cause of codon disappearance, extreme genomic % GC, is apparently not required for codon reassignment. Rigorously interpreted, this does not eliminate codon disappearance as a contributor to reassignment, but it implies that all reassignments are unlikely to be so caused. Even more significantly, the rationale for the axiom that reassigned codons must first disappear has been eliminated. That is, it has been asserted that a codon with two meanings would be lethal (Osawa and Jukes 1989). A complete inability to distinguish serine and leucine is of course lethal. However, a state of reduced ambiguity in which CUG means both serine and leucine not only stably exists in wild-type organisms in which leucine-to-serine reassignment has occurred, but such ambiguity may even have a favorable, rather than a lethal, phenotype. The potential list of possible ambiguous intermediates has been expanded by the discovery of the multiple amino acid specificity of Candida Ser- and Leu-tRNA^Ser (Suzuki et al. 1997). Other means of making codons ambiguous, such as ribosomal ambiguity or unusual concentrations or sequences of particular tRNAs, are easily envisioned. We look forward to further fossil ambiguous states and further elucidation of their phenotypes. From such data we may ultimately be able to deduce the forces that occasionally drive modern codons from one meaning to another.     

Structure and variability of recently inserted Alu family members.

The HS subfamily of Alu sequences is comprised of a group of nearly identical members. Individual subfamily members share 97.7% nucleotide identity with each other and 98.9% nucleotide identity with the HS consensus sequence. Individual subfamily members are on the average 2.8 million years old, and were probably derived from a single source 'master' gene sometime after the human/great ape divergence. The recent Alu family member insertions provide a better image of the structure of Alu retroposons before they have had the opportunity to change significantly. All of the HS subfamily members are flanked by perfect direct repeats as a result of insertion at staggered nicks. The 'master' gene from which the HS subfamily members were derived had an oligo-dA rich tail at least 40 bases long. The 'master' gene is very rich in CpG dinucleotides, but nucleotide substitutions within subfamily members accumulated in a random manner typical for Alu sequence with CpG substitutions occurring 9.2 fold faster than non-CpG substitutions.