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1.  Studies on Bilateral Cochlear Implants at the University of Wisconsin’s Binaural Hearing and Speech Lab 
This report highlights research projects relevant to binaural and spatial hearing in adults and children. In the past decade we have made progress in understanding the impact of bilateral cochlear implants (BiCIs) on performance in adults and children. However, BiCI users typically do not perform as well as normal hearing (NH) listeners. In this paper we describe the benefits from BiCIs compared with a single CI, focusing on measures of spatial hearing and speech understanding in noise. We highlight the fact that in BiCI listening the devices in the two ears are not coordinated, thus binaural spatial cues that are available to NH listeners are not available to BiCI users. Through the use of research processors that carefully control the stimulus delivered to each electrode in each ear, we are able to preserve binaural cues and deliver them with fidelity to BiCI users. Results from those studies are discussed as well, with a focus on the effect of age at onset of deafness and plasticity of binaural sensitivity. Our work with children has expanded both in number of subjects tested and age range included. We have now tested dozens of children ranging in age from 2-14 years. Our findings suggest that spatial hearing abilities emerge with bilateral experience. While we originally focused on studying performance in free-field, where real world listening experiments are conducted, more recently we have begun to conduct studies under carefully controlled binaural stimulation conditions with children as well. We have also studied language acquisition and speech perception and production in young CI users. Finally, a running theme of this research program is the systematic investigation of the numerous factors that contribute to spatial and binaural hearing in BiCI users. By using CI simulations (with vocoders) and studying NH listeners under degraded listening conditions, we are able to tease apart limitations due to the hardware/software of the CI systems from limitations due to neural pathology.
doi:10.3766/jaaa.23.6.9
PMCID: PMC3517294  PMID: 22668767
2.  SCA1-Like Disease in Mice Expressing Wild Type Ataxin-1 with a Serine to Aspartic Acid Replacement at Residue 776 
Neuron  2010;67(6):929-935.
SUMMARY
Glutamine tract expansion triggers nine neurodegenerative diseases by conferring toxic properties to the mutant protein. In SCA1, phosphorylation of ATXN1 at Ser776 is thought to be key for pathogenesis. Here we show that replacing Ser776 with a phospho-mimicking Asp converted ATXN1 with a wild type glutamine tract into a pathogenic protein. ATXN1[30Q]-D776-induced disease in Purkinje cells shared most features with disease caused by ATXN1[82Q] having an expanded polyglutamine tract. However, in contrast to disease induced by ATXN1[82Q] that progresses to cell death, ATXN1[30Q]-D776 failed to induce cell death. These results support a model where pathogenesis involves changes in regions of the protein in addition to the polyglutamine tract. In ATXN1, placing an Asp at residue 776 mimics this change. Moreover, disease initiation and progression to neuronal dysfunction are distinct from induction of cell death. Ser776 is critical for the pathway to neuronal dysfunction, while an expanded polyglutamine tract is essential for neuronal death.
doi:10.1016/j.neuron.2010.08.022
PMCID: PMC2946945  PMID: 20869591
3.  Relative roles of TGF-β1 and Wnt in the systemic regulation and aging of satellite cell responses 
Aging cell  2009;8(6):676-689.
Summary
Muscle stem (satellite) cells are relatively resistant to cell-autonomous aging. Instead, their endogenous signaling profile and regenerative capacity is strongly influenced by the aged, differentiated niche (Carlson and Conboy, 2007a; Carlson et al., 2008) and by the aged circulation (Brack and Rando, 2007; Carlson and Conboy, 2007a; Conboy et al., 2005). With respect to muscle fibers, we previously established that a shift from active Notch to excessive TGF-β/pSmad3 induces CDK inhibitors in satellite cells, thereby interfering with productive myogenic responses (Carlson et al., 2008; Conboy et al., 2003). In contrast, the systemic inhibitor of muscle repair, elevated in old sera, was suggested to be Wnt (Brack et al., 2007). Here, we examined the age-dependent myogenic activity of sera TGF-β1, and its potential cross-talk with systemic Wnt. We found that sera TGF-β1 becomes elevated within aged humans and mice, while systemic Wnt remained undetectable in these species. Wnt also failed to inhibit satellite cell myogenicity, while TGF-β1 suppressed regenerative potential in a biphasic fashion. Intriguingly, young levels of TGF-β1 were inhibitory and young sera suppressed myogenesis if TGF-β1 was activated. Our data suggest that platelet-derived sera TGF-β1 levels, or endocrine TGF-β1 levels, do not explain the age-dependent inhibition of muscle regeneration by this cytokine. In vivo, TGF-β neutralizing antibody, or a soluble decoy, failed to reduce systemic TGF-β1 and to rescue myogenesis in old mice. However, muscle regeneration was improved by the systemic delivery of a TGF-β receptor kinase inhibitor, which attenuated TGF-β signaling in skeletal muscle. Summarily, these findings argue against the endocrine path of a TGF-β1-dependent block on muscle regeneration, identify physiological modalities of age-imposed changes in TGF-β1, and introduce new therapeutic strategies for the broad restoration of aged organ repair.
doi:10.1111/j.1474-9726.2009.00517.x
PMCID: PMC2783265  PMID: 19732043
4.  Computational Models of the Notch Network Elucidate Mechanisms of Context-dependent Signaling 
PLoS Computational Biology  2009;5(5):e1000390.
The Notch signaling pathway controls numerous cell fate decisions during development and adulthood through diverse mechanisms. Thus, whereas it functions as an oscillator during somitogenesis, it can mediate an all-or-none cell fate switch to influence pattern formation in various tissues during development. Furthermore, while in some contexts continuous Notch signaling is required, in others a transient Notch signal is sufficient to influence cell fate decisions. However, the signaling mechanisms that underlie these diverse behaviors in different cellular contexts have not been understood. Notch1 along with two downstream transcription factors hes1 and RBP-Jk forms an intricate network of positive and negative feedback loops, and we have implemented a systems biology approach to computationally study this gene regulation network. Our results indicate that the system exhibits bistability and is capable of switching states at a critical level of Notch signaling initiated by its ligand Delta in a particular range of parameter values. In this mode, transient activation of Delta is also capable of inducing prolonged high expression of Hes1, mimicking the “ON” state depending on the intensity and duration of the signal. Furthermore, this system is highly sensitive to certain model parameters and can transition from functioning as a bistable switch to an oscillator by tuning a single parameter value. This parameter, the transcriptional repression constant of hes1, can thus qualitatively govern the behavior of the signaling network. In addition, we find that the system is able to dampen and reduce the effects of biological noise that arise from stochastic effects in gene expression for systems that respond quickly to Notch signaling.
This work thus helps our understanding of an important cell fate control system and begins to elucidate how this context dependent signaling system can be modulated in different cellular settings to exhibit entirely different behaviors.
Author Summary
The Notch signaling pathway is an evolutionarily conserved signaling system that is involved in various cell fate decisions, both during development of an organism and during adulthood. While the same core circuit functions in various different cellular contexts, it has experimentally been shown to elicit varied behaviors and responses. On the one hand, it functions as a cellular oscillator critical for somitogenesis, whereas in other situations, it can function as a cell fate switch to pattern developing tissue, for example in the Drosophila eye. Furthermore, malfunctioning of Notch signaling is implicated in various cancers. To better understand the underlying mechanisms that allow the network to function distinctly in different contexts, we have mathematically modeled the behavior of the Notch network, encompassing the Notch gene along with two of its downstream effector transcription factors, which together form a network of positive and negative feedback loops. Our results indicate that the qualitative and quantitative behavior of the system can readily be tuned based on key parameters to reflect its multiple roles. Furthermore, our results provide insights into alterations in the signaling system that lead to malfunction and hence disease, which could be used to identify potential drug targets for therapy.
doi:10.1371/journal.pcbi.1000390
PMCID: PMC2680760  PMID: 19468305
5.  Bilateral Cochlear Implants in Children: Localization Acuity Measured with Minimum Audible Angle 
Ear and hearing  2006;27(1):43-59.
Objective
To evaluate sound localization acuity in a group of children who received bilateral (BI) cochlear implants in sequential procedures and to determine the extent to which BI auditory experience affects sound localization acuity. In addition, to investigate the extent to which a hearing aid in the nonimplanted ear can also provide benefits on this task.
Design
Two groups of children participated, 13 with BI cochlear implants (cochlear implant + cochlear implant), ranging in age from 3 to 16 yrs, and six with a hearing aid in the nonimplanted ear (cochlear implant + hearing aid), ages 4 to 14 yrs. Testing was conducted in large sound-treated booths with loudspeakers positioned on a horizontal arc with a radius of 1.5 m. Stimuli were spondaic words recorded with a male voice. Stimulus levels typically averaged 60 dB SPL and were randomly roved between 56 and 64 dB SPL (±4 dB rove); in a few instances, levels were held fixed (60 dB SPL). Testing was conducted by using a “listening game” platform via computerized interactive software, and the ability of each child to discriminate sounds presented to the right or left was measured for loudspeakers subtending various angular separations. Minimum audible angle thresholds were measured in the BI (cochlear implant + cochlear implant or cochlear implant + hearing aid) listening mode and under monaural conditions.
Results
Approximately 70% (9/13) of children in the cochlear implant + cochlear implant group discriminated left/right for source separations of ≤20° and, of those, 77% (7/9) performed better when listening bilaterally than with either cochlear implant alone. Several children were also able to perform the task when using a single cochlear implant, under some conditions. Minimum audible angle thresholds were better in the first cochlear implant than the second cochlear implant listening mode for nearly all (8/9) subjects. Repeated testing of a few individual subjects over a 2-yr period suggests that robust improvements in performance occurred with increased auditory experience. Children who wore hearing aids in the nonimplanted ear were at times also able to perform the task. Average group performance was worse than that of the children with BI cochlear implants when both ears were activated (cochlear implant + hearing aid versus cochlear implant + cochlear implant) but not significantly different when listening with a single cochlear implant.
Conclusions
Children with sequential BI cochlear implants represent a unique population of individuals who have undergone variable amounts of auditory deprivation in each ear. Our findings suggest that many but not all of these children perform better on measures of localization acuity with two cochlear implants compared with one and are better at the task than children using the cochlear implant + hearing aid. These results must be interpreted with caution, because benefits on other tasks as well as the long-term benefits of BI cochlear implants are yet to be fully understood. The factors that might contribute to such benefits must be carefully evaluated in large populations of children using a variety of measures.
doi:10.1097/01.aud.0000194515.28023.4b
PMCID: PMC2651156  PMID: 16446564
6.  Relative roles of TGF-β1 and Wnt in the systemic regulation and aging of satellite cell responses 
Aging Cell  2009;8(6):676-689.
Muscle stem (satellite) cells are relatively resistant to cell-autonomous aging. Instead, their endogenous signaling profile and regenerative capacity is strongly influenced by the aged P-Smad3, differentiated niche, and by the aged circulation. With respect to muscle fibers, we previously established that a shift from active Notch to excessive transforming growth factor-beta (TGF-β) induces CDK inhibitors in satellite cells, thereby interfering with productive myogenic responses. In contrast, the systemic inhibitor of muscle repair, elevated in old sera, was suggested to be Wnt. Here, we examined the age-dependent myogenic activity of sera TGF-β1, and its potential cross-talk with systemic Wnt. We found that sera TGF-β1 becomes elevated within aged humans and mice, while systemic Wnt remained undetectable in these species. Wnt also failed to inhibit satellite cell myogenicity, while TGF-β1 suppressed regenerative potential in a biphasic fashion. Intriguingly, young levels of TGF-β1 were inhibitory and young sera suppressed myogenesis if TGF-β1 was activated. Our data suggest that platelet-derived sera TGF-β1 levels, or endocrine TGF-β1 levels, do not explain the age-dependent inhibition of muscle regeneration by this cytokine. In vivo, TGF-β neutralizing antibody, or a soluble decoy, failed to reduce systemic TGF-β1 and rescue myogenesis in old mice. However, muscle regeneration was improved by the systemic delivery of a TGF-β receptor kinase inhibitor, which attenuated TGF-β signaling in skeletal muscle. Summarily, these findings argue against the endocrine path of a TGF-β1-dependent block on muscle regeneration, identify physiological modalities of age-imposed changes in TGF-β1, and introduce new therapeutic strategies for the broad restoration of aged organ repair.
doi:10.1111/j.1474-9726.2009.00517.x
PMCID: PMC2783265  PMID: 19732043
aging; anti-aging; cytokines; skeletal muscle

Results 1-6 (6)