[show abstract][hide abstract] ABSTRACT: Cochlear implants have enabled many congenitally or prelingually deaf children to acquire their native language and communicate successfully on the basis of electrical rather than acoustic input. Nevertheless, degraded spectral input provided by the device reduces the ability to perceive emotion in speech. We compared the vocal imitations of 5- to 7-year-old deaf children who were highly successful bilateral implant users with those of a control sample of children who had normal hearing. First, the children imitated several happy and sad sentences produced by a child model. When adults in Experiment 1 rated the similarity of imitated to model utterances, ratings were significantly higher for the hearing children. Both hearing and deaf children produced poorer imitations of happy than sad utterances because of difficulty matching the greater pitch modulation of the happy versions. When adults in Experiment 2 rated electronically filtered versions of the utterances, which obscured the verbal content, ratings of happy and sad utterances were significantly differentiated for deaf as well as hearing children. The ratings of deaf children, however, were significantly less differentiated. Although deaf children's utterances exhibited culturally typical pitch modulation, their pitch modulation was reduced relative to that of hearing children. One practical implication is that therapeutic interventions for deaf children could expand their focus on suprasegmental aspects of speech perception and production, especially intonation patterns.
[show abstract][hide abstract] ABSTRACT: Proteasome inhibition is used as a treatment strategy for multiple types of cancers. Although proteasome inhibition can induce apoptotic cell death in actively proliferating cells, it is less effective in quiescent cells. In this study, we used primary human fibroblasts as a model system to explore the link between the proliferative state of a cell and proteasome inhibition-mediated cell death. We found that proliferating and quiescent fibroblasts have strikingly different responses to MG132, a proteasome inhibitor; proliferating cells rapidly apoptosed, whereas quiescent cells maintained viability. Moreover, MG132 treatment of proliferating fibroblasts led to increased superoxide anion levels, juxtanuclear accumulation of ubiquitin- and p62/SQSTM1-positive protein aggregates, and apoptotic cell death, whereas MG132-treated quiescent cells displayed fewer juxtanuclear protein aggregates, less apoptosis, and higher levels of mitochondrial superoxide dismutase. In both cell states, reducing reactive oxygen species with N-acetylcysteine lessened protein aggregation and decreased apoptosis, suggesting that protein aggregation promotes apoptosis. In contrast, increasing cellular superoxide levels with 2-methoxyestradiol treatment or inhibition of autophagy/lysosomal pathways with bafilomycin A1 sensitized serum-starved quiescent cells to MG132-induced apoptosis. Thus, antioxidant defenses and the autophagy/lysosomal pathway protect serum-starved quiescent fibroblasts from proteasome inhibition-induced cytotoxicity.
Molecular biology of the cell 08/2012; 23(18):3566-81. · 5.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Changes in microRNA expression have been linked to a wide array of pathological states. However, little is known about the regulation of microRNA expression. The let-7 microRNA is a tumor suppressor that inhibits cellular proliferation and promotes differentiation, and is frequently lost in tumors. We investigated the transcriptional regulation of two let-7 family members, let-7a-3 and let-7b, which form a microRNA cluster and are located 864 bp apart on chromosome 22q13.31. Previous reports present conflicting data on the role of the NF-κB transcription factor in regulating let-7. We cloned three fragments upstream of the let-7a-3/let-7b miRNA genomic region into a plasmid containing a luciferase reporter gene. Ectopic expression of subunits of NF-κB (p50 or p65/RelA) significantly increased luciferase activity in HeLa, 293, 293T and 3T3 cells, indicating that the let-7a-3/let-7b promoter is highly responsive to NF-κB. Mutation of a putative NF-κB binding site at bp -833 reduced basal promoter activity and decreased promoter activity in the presence of p50 or p65 overexpression. Mutation of a second putative binding site, at bp -947 also decreased promoter activity basally and in response to p65 induction, indicating that both sites contribute to NF-κB responsiveness. While the levels of the endogenous primary let-7a and let-7b transcript were induced in response to NF-κB overexpression in 293T cells, the levels of fully processed, mature let-7a and let-7b miRNAs did not increase. Instead, levels of Lin-28B, a protein that blocks let-7 maturation, were induced by NF-κB. Increased Lin-28B levels could contribute to the lack of an increase in mature let-7a and let-7b. Our results suggest that the final biological outcome of NF-κB activation on let-7 expression may vary depending upon the cellular context. We discuss our results in the context of NF-κB activity in repressing self-renewal and promoting differentiation.
PLoS ONE 01/2012; 7(2):e31240. · 3.73 Impact Factor