Misfolded proteins are recognized in the endoplasmic reticulum (ER), transported back to the cytoplasm and degraded by the proteasome. Processing intermediates of N-linked oligosaccharides on incompletely folded glycoproteins have an important role in their folding/refolding, and also in their targeting to proteolytic degradation. In Saccharomyces cerevisiae, we have identified a gene coding for a non-essential protein that is homologous to mannosidase I (HTM1) and that is required for degradation of glycoproteins. Deletion of the HTM1 gene does not affect oligosaccharide trimming. However, deletion of HTM1 does reduce the rate of degradation of the mutant glycoproteins such as carboxypeptidase Y, ABCtransporter Pdr5-26p and oligosaccharyltransferase subunit Stt3-7p, but not of mutant Sec61-2p, a non-glycoprotein. Our results indicate that although Htm1p is not involved in processing of N-linked oligosaccharides, it is required for their proteolytic degradation. We propose that this mannosidase homolog is a lectin that recognizes Man 8 GlcNAc 2 oligosaccharides that serve as signals in the degradation pathway.

The purpose of this study was to investigate the efficiency of the Swiss hearing aid dispensing system, and to determine factors contributing to successful hearing aid provision. A national cross sectional survey was performed using a postal questionnaire with 8707 adult hearing aid owners (response rate 62%). To correct results for a potential non-response bias, 193 randomly selected non-respondents were contacted by telephone. Data on hearing loss and type of hearing aid were provided by the hearing aid dispensing practice. Logistic regression analyses were performed to identify determinants of non-regular use and dissatisfaction. Eighty-five percent used their device(s) regularly, 12% only occasionally and 3% never. Eighty percent were satisfied with their aids. Non-regular use of hearing aids was significantly associated with age, gender, regional language, total duration of use, type of amplification, hearing aid category, hearing loss, and dissatisfaction with and difficulties in managing the aid. Dissatisfaction was associated with regional language, total duration of use, difficulties in managing the aid, and non-regular use. It was concluded that rates of regular hearing aid use and satisfaction are high in Switzerland. AbstractThe purpose of this study was to investigate the efficiency of the Swiss hearing aid dispensing system, and to determine factors contributing to successful hearing aid provision.A national cross sectional survey was performed using a postal questionnaire with 8 707 adult hearing aid owners (response rate 62%). To correct results for a potential nonresponse bias, 193 randomly selected non-respondents were contacted by telephone. Data on hearing loss and type of hearing aid were provided by the hearing aid dispensing practice.Logistic regression analyses were performed to identify determinants of non-regular use and dissatisfaction. Eighty-five percent used their device(s) regularly, 12% only occasionally and 3% never. Eighty percent were satisfied with their aids. Non-regular use of hearing aids was significantly associated with age, gender, regional language, total duration of use, type of amplification, hearing aid category, hearing loss, dissatisfaction with and difficulties in managing the aid. Dissatisfaction was associated with regional language, total duration of use, difficulties in managing the aid, and non-regular use. It was concluded that rates of regular hearing aid use and satisfaction are high in Switzerland.

Nerve growth factor (NGF) is a potent survival and axon growth factor for neuronal populations in the peripheral nervous system. Although the mechanisms by which target-derived NGF influences survival of innervating neurons have been extensively investigated, its regulation of axonal growth and target innervation are just being elucidated. Here, we identify Wnt5a, a member of the Wnt family of secreted growth factors, as a key downstream effector of NGF in mediating axonal branching and growth in developing sympathetic neurons. Wnt5a is robustly expressed in sympathetic neurons when their axons are innervating NGF-expressing targets. NGF:TrkA signaling enhances neuronal expression of Wnt5a. Wnt5a rapidly induces axon branching while it has a long-term effect on promoting axon extension. Loss of Wnt5a function revealed that it is necessary for NGF-dependent axonal branching and growth, but not survival, in vitro. Furthermore, Wnt5a Ϫ/Ϫ mice display reduced innervation of NGF-expressing target tissues, and a subsequent increase in neuronal apoptosis, in vivo. Wnt5a functions in developing sympathetic neurons by locally activating protein kinase C in axons. Together, our findings define a novel regulatory pathway in which Wnt5a, expressed in sympathetic neurons in response to target-derived NGF, regulates innervation of peripheral targets.

Summary Endocytic events are critical for neuronal survival in response to target-derived neurotrophic cues, but whether local axon growth is mediated by endocytosis-dependent signaling mechanisms remains unclear. Here, we report that Nerve Growth Factor (NGF) promotes endocytosis of its TrkA receptors and axon growth by calcineurin-mediated dephosphorylation of the endocytic GTPase, dynamin1. Conditional deletion of calcineurin in sympathetic neurons disrupts NGF-dependent innervation of peripheral target tissues. Calcineurin signaling is required locally in sympathetic axons to support NGF-mediated growth in a manner independent of transcription, during the initial phase of axonal outgrowth. We show that calcineurin associates with dynamin1 via a PxIxIT interaction motif found only in specific dynamin1 splice variants. PxIxIT-containing dynamin1 isoforms co-localize with surface TrkA receptors, and their phosphoregulation is selectively required for NGF-dependent TrkA internalization and axon growth in sympathetic neurons. Thus, NGF-dependent phosphoregulation of dynamin1 is a critical event coordinating neurotrophin receptor endocytosis and initial axonal growth.