In Saccharomyces cerevisiae, non-coding RNAs, including cryptic unstable transcripts (CUTs), are subject to degradation by the exosome. The Trf4/5-Air1/2-Mtr4 polyadenylation (TRAMP) complex in S. cerevisiae is a nuclear exosome cofactor that recruits the exosome to degrade RNAs. Trf4/5 are poly(A) polymerases, Mtr4 is an RNA helicase, and Air1/2 are putative RNA-binding proteins that contain five CCHC zinc knuckles (ZnKs). One central question is how the TRAMP complex, especially the Air1/2 protein, recognizes its RNA substrates. To characterize the function of the Air1/2 protein, we used random mutagenesis of the AIR1/2 gene to identify residues critical for Air protein function. We identified air1-C178R and air2-C167R alleles encoding air1/2 mutant proteins with a substitution in the second cysteine of ZnK5. Mutagenesis of the second cysteine in AIR1/2 ZnK1-5 reveals that Air1/2 ZnK4 and -5 are critical for Air protein function in vivo. In addition, we find that the level of CUT, NEL025c, in air1 ZnK1-5 mutants is stabilized, particularly in air1 ZnK4, suggesting a role for Air1 ZnK4 in the degradation of CUTs. We also find that Air1/2 ZnK4 and -5 are critical for Trf4 interaction and that the Air1-Trf4 interaction and Air1 level are critical for TRAMP complex integrity. We identify a conserved IWRXY motif in the Air1 ZnK4-5 linker that is important for Trf4 interaction. We also find that hZC-CHC7, a putative human orthologue of Air1 that contains the IWRXY motif, localizes to the nucleolus in human cells and interacts with both mammalian Trf4 orthologues, PAPD5 and PAPD7 (PAP-associated domain containing 5 and 7), suggesting that hZCCHC7 is the Air component of a human TRAMP complex.Production of mature RNAs in eukaryotes requires a complex set of processing steps, including 5Ј-end capping, splicing, 3Ј-end cleavage, polyadenylation, nucleolytic cleavage/trimming, and base modifications, by numerous processing components. Incorrectly processed RNAs are rapidly degraded by RNA quality control machinery to prevent deleterious effects on the cell. Processing and degradation of multiple classes of RNA are performed by RNA endo/exoribonucleases that are recruited to their RNA substrates by specific protein cofactors. These nucleases and their cofactors are highly regulated and evolutionarily conserved.In Saccharomyces cerevisiae, non-coding RNAs (ncRNAs), 2 including precursors of rRNAs, snoRNAs, and snRNAs, are processed and/or degraded by the nuclear exosome, an evolutionarily conserved ringlike riboexonuclease complex containing two active 3Ј-5Ј-riboexonucleases, Rrp44/Dis3 and Rrp6 (1-8). Hypomodified initiator tRNAs (tRNA i Met ) from cells with an impaired tRNA methyltransferase and aberrant pre-mRNAs from cells with defective 3Ј-end processing, splicing, or nuclear export factors are also degraded by the nuclear exosome (9 -13). More recently, a novel class of small (250 -300-nucleotide) intergenic RNA polymerase II transcripts, termed cryptic unstable transcripts (CUTs), was discovered in cells that lack ...

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Highlights d Early-life starvation and unrestricted feeding result in reproductive abnormalities d Maternal dietary restriction protects progeny from starvationinduced abnormalities d Maternal diet and insulin/IGF signaling affect vitellogenin oocyte provisioning d Vitellogenin oocyte provisioning affects progeny insulin/IGF signaling

Temporally sparse stimuli have been found to produce larger multifocal visual evoked potentials than rapid contrast-reversal stimuli. We compared the contrast-response functions of conventional contrast-reversing (CR) stimuli and three grades of temporally sparse stimuli, examining both the changes in response amplitude and signal-to-noise ratio (SNR). All stimuli were presented dichoptically to normal adult human subjects. One stimulus variant, the slowest pattern pulse, had interleaved monocular and binocular stimuli. Response amplitudes and SNRs were similar for all stimuli at contrast 0.4 but grew faster with increasing contrast for the sparser stimuli. The best sparse stimulus provided an SNR improvement that corresponded to a recording time improvement of 2.6 times relative to that required for contrast reversing stimuli. Multiple regression of log-transformed response metrics characterized the contrast-response functions by fitting power-law relationships. The exponents for the two sparsest stimuli were significantly larger (P < 0.001) than for the CR stimuli, as were the mean response amplitudes and signal-to-noise ratios for these stimuli. The contrast-dependent response enhancement is discussed with respect to the possible influences of rapid retinal contrast gain control, or intracortical and cortico-geniculate feedback.