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Description
Exome sequencing was used to identify novel variants linked to amyotrophic lateral sclerosis (ALS), in a family without mutations in genes previously linked to ALS. A F115C mutation in the gene MATR3 was identified, and further examination of other ALS kindreds identified an additional three mutations in MATR3; S85C, P154S

Exome sequencing was used to identify novel variants linked to amyotrophic lateral sclerosis (ALS), in a family without mutations in genes previously linked to ALS. A F115C mutation in the gene MATR3 was identified, and further examination of other ALS kindreds identified an additional three mutations in MATR3; S85C, P154S and T622A. Matrin 3 is an RNA/DNA binding protein as well as part of the nuclear matrix. Matrin 3 interacts with TDP-43, a protein that is both mutated in some forms of ALS, and found in pathological inclusions in most ALS patients. Matrin 3 pathology, including mislocalization and rare cytoplasmic inclusions, was identified in spinal cord tissue from a patient carrying a mutation in Matrin 3, as well as sporadic ALS patients. In an effort to determine the mechanism of Matrin 3 linked ALS, the protein interactome of wild-type and ALS-linked MATR3 mutations was examined. Immunoprecipitation followed by mass spectrometry experiments were performed using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with specific TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and more specifically the mRNA of TDP-43 and FUS. Our findings identify ALS-causing mutations in the gene MATR3, as well as a potential pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.
ContributorsBoehringer, Ashley (Author) / Bowser, Robert (Thesis advisor) / Liss, Julie (Committee member) / Jensen, Kendall (Committee member) / Ladha, Shafeeq (Committee member) / Arizona State University (Publisher)
Created2018
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Description
Detecting early signs of neurodegeneration is vital for measuring the efficacy of pharmaceuticals and planning treatments for neurological diseases. This is especially true for Amyotrophic Lateral Sclerosis (ALS) where differences in symptom onset can be indicative of the prognosis. Because it can be measured noninvasively, changes in speech production have

Detecting early signs of neurodegeneration is vital for measuring the efficacy of pharmaceuticals and planning treatments for neurological diseases. This is especially true for Amyotrophic Lateral Sclerosis (ALS) where differences in symptom onset can be indicative of the prognosis. Because it can be measured noninvasively, changes in speech production have been proposed as a promising indicator of neurological decline. However, speech changes are typically measured subjectively by a clinician. These perceptual ratings can vary widely between clinicians and within the same clinician on different patient visits, making clinical ratings less sensitive to subtle early indicators. In this paper, we propose an algorithm for the objective measurement of flutter, a quasi-sinusoidal modulation of fundamental frequency that manifests in the speech of some ALS patients. The algorithm detailed in this paper employs long-term average spectral analysis on the residual F0 track of a sustained phonation to detect the presence of flutter and is robust to longitudinal drifts in F0. The algorithm is evaluated on a longitudinal speech dataset of ALS patients at varying stages in their prognosis. Benchmarking with two stages of perceptual ratings provided by an expert speech pathologist indicate that the algorithm follows perceptual ratings with moderate accuracy and can objectively detect flutter in instances where the variability of the perceptual rating causes uncertainty.
ContributorsPeplinski, Jacob Scott (Author) / Berisha, Visar (Thesis director) / Liss, Julie (Committee member) / Electrical Engineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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Description
Previous studies have found that the detection of near-threshold stimuli is decreased immediately before movement and throughout movement production. This has been suggested to occur through the use of the internal forward model processing an efferent copy of the motor command and creating a prediction that is used to cancel

Previous studies have found that the detection of near-threshold stimuli is decreased immediately before movement and throughout movement production. This has been suggested to occur through the use of the internal forward model processing an efferent copy of the motor command and creating a prediction that is used to cancel out the resulting sensory feedback. Currently, there are no published accounts of the perception of tactile signals for motor tasks and contexts related to the lips during both speech planning and production. In this study, we measured the responsiveness of the somatosensory system during speech planning using light electrical stimulation below the lower lip by comparing perception during mixed speaking and silent reading conditions. Participants were asked to judge whether a constant near-threshold electrical stimulation (subject-specific intensity, 85% detected at rest) was present during different time points relative to an initial visual cue. In the speaking condition, participants overtly produced target words shown on a computer monitor. In the reading condition, participants read the same target words silently to themselves without any movement or sound. We found that detection of the stimulus was attenuated during speaking conditions while remaining at a constant level close to the perceptual threshold throughout the silent reading condition. Perceptual modulation was most intense during speech production and showed some attenuation just prior to speech production during the planning period of speech. This demonstrates that there is a significant decrease in the responsiveness of the somatosensory system during speech production as well as milliseconds before speech is even produced which has implications for speech disorders such as stuttering and schizophrenia with pronounced deficits in the somatosensory system.
ContributorsMcguffin, Brianna Jean (Author) / Daliri, Ayoub (Thesis director) / Liss, Julie (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
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Description
Cochlear implant (CI) successfully restores hearing sensation to profoundly deaf patients, but its
performance is limited by poor spectral resolution. Acoustic CI simulation has been widely used
in normal-­hearing (NH) listeners to study the effect of spectral resolution on speech perception,
while avoiding patient-­related confounds. It is unclear how speech production may change

Cochlear implant (CI) successfully restores hearing sensation to profoundly deaf patients, but its
performance is limited by poor spectral resolution. Acoustic CI simulation has been widely used
in normal-­hearing (NH) listeners to study the effect of spectral resolution on speech perception,
while avoiding patient-­related confounds. It is unclear how speech production may change with
the degree of spectral degradation of auditory feedback as experience by CI users. In this study,
a real-­time sinewave CI simulation was developed to provide NH subjects with auditory
feedback of different spectral resolution (1, 2, 4, and 8 channels). NH subjects were asked to
produce and identify vowels, as well as recognize sentences while listening to the real-­time CI
simulation. The results showed that sentence recognition scores with the real-­time CI simulation
improved with more channels, similar to those with the traditional off-­line CI simulation.
Perception of a vowel continuum “HEAD”-­ “HAD” was near chance with 1, 2, and 4 channels,
and greatly improved with 8 channels and full spectrum. The spectral resolution of auditory
feedback did not significantly affect any acoustic feature of vowel production (e.g., vowel space
area, mean amplitude, mean and variability of fundamental and formant frequencies). There
was no correlation between vowel production and perception. The lack of effect of auditory
feedback spectral resolution on vowel production was likely due to the limited exposure of NH
subjects to CI simulation and the limited frequency ranges covered by the sinewave carriers of
CI simulation. Future studies should investigate the effects of various CI processing parameters
on speech production using a noise-­band CI simulation.
ContributorsPerez Lustre, Sarahi (Author) / Luo, Xin (Thesis director) / Daliri, Ayoub (Committee member) / Division of Teacher Preparation (Contributor) / College of Health Solutions (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2019-05