Transfer RNAs from all organisms contain many modi®ed nucleosides. Their vastly different chemical structures, their presence in different tRNAs, their occurrence in different locations in tRNA and their in¯uence on different reactions in which tRNA participates suggest that each modi®ed nucleoside may have its own speci®c function. However, since the frequency of frameshifting in several different mutants [mnmA, mnmE, tgt, truA (hisT), trmD, miaA, miaB and miaE] defective in tRNA modi®cation was higher compared with the corresponding wild-type controls, these modi®cations have a common function: they all improve reading frame maintenance. Frameshifting occurs by peptidyl-tRNA slippage, which is in¯uenced by the hypomodi®ed tRNA in two ways: (i) a hypomodi®ed tRNA in the ternary complex may decrease the rate by which the complex is recruited to the A-site and thereby increasing peptidyl-tRNA slippage; or (ii) a hypomodi®ed peptidyl-tRNA may be more prone to slip than its fully modi®ed counterpart. We propose that the improvement of reading frame maintenance has been and is the major selective factor for the emergence of new modi®ed nucleosides. Keywords: frameshift/modi®ed nucleoside/tRNA/ translation IntroductionThe capacity of the translation apparatus has evolved to read long messages and thereby to make sophisticated proteins required for life as we see it today. Although the translation apparatus has the ability to decode faithfully, errors occur with frequencies of 10 ±3 ±10 ±4 per codon (Kurland et al., 1996). Most missense errors are not harmful to proteins, since many amino acids can be substituted without affecting the stability or the activity of the protein. In sharp contrast to the missense errors, almost all of the frameshift errors are detrimental to the synthesis of a functional protein, since following such a shift in frame the amino acid sequence becomes completely different and eventually the ribosome usually encounters a stop codon. This results in a truncated, usually unstable or inactive, peptide. Clearly, during evolution, features of the translation apparatus that are pivotal for reading frame maintenance have evolved. To understand the mechanism by which the ribosome traverses the mRNA in a faithful manner, one has to unravel the features of the translation apparatus that are important for maintaining the correct reading frame.There are several examples of how frameshift errors occur by peptidyl-tRNA slippage induced by a pause occurring in the A-site (reviewed in Farabaugh, 1997;Farabaugh and Bjo Èrk, 1999; see also Figure 1). The length of the pause in the A-site, the ®tness of the tRNA in the P-site and the mRNA sequence determine the frequency of slippage by the peptidyl-tRNA and thus the frequency of frameshift. Changes in the tRNA structure, such as that induced by a de®ciency of a modi®ed nucleoside, may therefore affect reading frame maintenance. Modi®ed nucleosides are derivatives of the four major nucleosides U, C, A and G, and at present 81 different modi®ed nucleosides have ...

According to the prevailing model, frameshift-suppressing tRNAs with an extra nucleotide in the anticodon loop suppress +1 frameshift mutations by recognizing a four-base codon and promoting quadruplet translocation. We present three sets of experiments that suggest a general alternative to this model. First, base modification should actually block such a four-base interaction by two classical frameshift suppressors. Second, for one Salmonella suppressor tRNA, it is not mutant tRNA but a structurally normal near cognate that causes the +1 shift in-frame. Finally, frameshifting occurs in competition with normal decoding of the next in-frame codon, consistent with an event that occurs in the ribosomal P site after the translocation step. These results suggest an alternative model involving peptidyl-tRNA slippage at the classical CCC-N and GGG-N frameshift suppression sites.

The oxidative dehydrogenation of cyclohexane by cobalt oxide nanoparticles was studied via temperature programmed reaction combined with in situ grazing incidence X-ray absorption spectroscopy and grazing incidence smallangle X-ray scattering and theoretical calculations on model Co 3 O 4 substrates. Both 6 and 12 nm Co 3 O 4 nanoparticles were made through a surfactant-free preparation and dispersed on an Al 2 O 3 surface formed by atomic layer deposition. Under reaction conditions the nanoparticles retained their oxidation state and did not sinter. They instead underwent an assembly/ disassembly process and could reorganize within their assemblies. The selectivity of the catalyst was found to be size-and temperature-dependent, with larger particles preferentially producing cyclohexene at lower temperatures and smaller particles predominantly resulting in benzene at higher temperatures. The mechanistic features thought to control the oxidative dehydrogenation of cyclohexane and other light alkanes on cobalt oxide were established by carrying out density functional theory calculations on the activation of propane, a surrogate model alkane, over model Co 3 O 4 surfaces. The initial activation of the alkane (propane) proceeds via hydrogen abstraction over surface oxygen sites. The subsequent activation of the resulting alkoxide intermediate occurs at a second surface oxygen site to form the alkene (propene) which then desorbs from the surface. Hydroxyl recombination results in the formation of water which desorbs from the surface. Oxygen is necessary to regenerate the surface oxygen sites, catalyze C−H activation steps, and minimize catalyst degradation.

Transfer RNA modification improves the rate of aatRNA selection at the A-site and the fitness in the P-site and thereby prevents frameshifting according to a new model how frameshifting occurs [Qian et al. (1998)

The modified nucleoside 2-thiocytidine (s 2 C) has so far been found in tRNA from organisms belonging to the phylogenetic domains Archaea and Bacteria. In the bacteria Escherichia coli and Salmonella enterica serovar

Translational frameshifting is a ubiquitous, if rare, form of alternative decoding in which ribosomes spontaneously shift reading frames during translation elongation. In studying +1 frameshifting in Ty retrotransposons of the yeast S. cerevisiae, we previously showed that unusual P site tRNAs induce frameshifting. The frameshift-inducing tRNAs we show here are near-cognates for the P site codon. Their abnormal decoding induces frameshifting in either of two ways: weak codon-anticodon pairing allows the tRNA to disengage from the mRNA and slip +1, or an unusual codon-anticodon structure interferes with cognate in-frame decoding allowing out-of-frame decoding in the A site. We draw parallels between this mechanism and a proposed mechanism of frameshift suppression by mutant tRNAs.

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The authors demonstrate that adolescents assign more disutility (lower valuations) than parents for HRQL and three of five of the TTO assessments for PID-related health states. Future economic evaluations using patient-specific preferences to determine resource allocation for PID management in adolescents should include adolescent health outcomes and utilities.