Phonemic and Phonetic Errors in Conduction Aphasia

Purpose: The purpose of this study was to characterize the relationship between phonemic and phonetic errors in conduction aphasia (CA) as well as the quality of these errors. Background: CA is a type of fluent aphasia that is characterized by phonological difficulties and substantial repetition difficulties in the context of relatively spared language functions in other areas. The clinical diagnosis of CA is often based on the Western Aphasia Profile (WAB), which is one of the most popular aphasia batteries due to its ease of administration and relatively objective scoring. The most challenging subtest score for this instrument is the fluency rating. The scale takes into consideration multiple dimensions, including phrase length, grammatical competence, and paraphasias of spontaneous speech. A score of 5-10 means the patient has fluent aphasia while a score of 1-4 indicates nonfluent aphasia. Because CA is a fluent type of aphasia, it requires a fluency rating greater than 4. However, people who are recovering from other presentation profiles may also receive this rating and a WAB diagnosis of CA due to persistent repetition difficulties. This may happen even if their presentation profile is not qualitatively indicative of the CA syndrome. Further examination of phonological difficulties can help identify the subset of people who have a more classic CA profile as those who present a high frequency of phonemic errors and a low frequency of phonetic distortion errors. By definition, the relationship between distortion errors and phonemic errors should be low in this population. Methods: The speech samples for this study came from AphasiaBank (http://talkbank.org/AphasiaBank/). 41 individuals classified as having CA on the WAB were given the Boston Naming Test (BNT), which includes a list of 15 words. The author transcribed each of the 615 words using a narrow transcription protocol with 12 diacritic marks. The frequency of omissions, additions, and substitutions were then compiled and supplemented by calculation of the edit distance between broad transcription of the target and observed production. Additionally, distortion type and frequency was evaluated for the data compilation. Results The results were consistent both with the clinical characterization of and the prediction that the relationship between distortion errors and phonemic errors would be low. The mean proportion of segments with phonemic errors was 61.79% while the mean proportion of distortion errors was 5.28%. The correlation between the two was low (r=0.16). Other results to note were the mean frequency of distorted substitutions, which was very low at 1.74%, and the frequencies of substitutions (20.44%), additions (4.50%), and omissions (11.60%). Discussion: As a group, these participants produced relatively high frequencies of sound errors without the distortion quality that is considered typical of motor speech disorders, including apraxia of speech (AOS). We are currently examining the results to determine whether a subset of the 41 speakers had a classic CA profile, with high phonemic error rate and low distortion error rate, whereas others may have presented with more evidence of a motor speech disorder (especially AOS). Additionally, we anticipate that further analysis of the specific distortion qualities will advance our understanding of what is characteristic of the CA profile

Reliability Improvements for Phonetic Transcription of Lengthening

The purpose of this study was to determine ways to improve the reliability of narrow phonetic transcription of lengthening distortions in AOS. More specifically, we looked for ways to make the narrow transcription of segment lengthening more accurate and consistent among transcribers

Network Analyses Reveal Novel Aspects of ALS Pathogenesis

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of motor neurons, muscle atrophy and paralysis. Mutations in the human VAMP-associated protein B (hVAPB) cause a heterogeneous group of motor neuron diseases including ALS8. Despite extensive research, the molecular mechanisms underlying ALS pathogenesis remain largely unknown. Genetic screens for key interactors of hVAPB activity in the intact nervous system, however, represent a fundamental approach towards understanding the in vivo function of hVAPB and its role in ALS pathogenesis. Targeted expression of the disease-causing allele leads to neurodegeneration and progressive decline in motor performance when expressed in the adult Drosophila, eye or in its entire nervous system, respectively. By using these two phenotypic readouts, we carried out a systematic survey of the Drosophila genome to identify modifiers of hVAPB-induced neurotoxicity. Modifiers cluster in a diverse array of biological functions including processes and genes that have been previously linked to hVAPB function, such as proteolysis and vesicular trafficking. In addition to established mechanisms, the screen identified endocytic trafficking and genes controlling proliferation and apoptosis as potent modifiers of ALS8-mediated defects. Surprisingly, the list of modifiers was mostly enriched for proteins linked to lipid droplet biogenesis and dynamics. Computational analysis reveals that most modifiers can be linked into a complex network of interacting genes, and that the human genes homologous to the Drosophila modifiers can be assembled into an interacting network largely overlapping with that in flies. Identity markers of the endocytic process were also found to abnormally accumulate in ALS patients, further supporting the relevance of the fly data for human biology. Collectively, these results not only lead to a better understanding of hVAPB function but also point to potentially relevant targets for therapeutic intervention

Fbxw7 Acts as an E3 Ubiquitin Ligase That Targets c-Myb for Nemo-like Kinase (NLK)-induced Degradation*S⃞

The c-myb proto-oncogene product (c-Myb) is degraded in response to Wnt-1 signaling via a pathway involving TAK1 (transforming growth factor-β-activated kinase 1), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). NLK directly binds to c-Myb, which results in the phosphorylation of c-Myb at multiple sites, and induces its ubiquitination and proteasome-dependent degradation. Here, we report that Fbxw7, the F-box protein of an SCF complex, targets c-Myb for degradation in a Wnt-1- and NLK-dependent manner. Fbxw7α directly binds to c-Myb via its C-terminal WD40 domain and induces the ubiquitination of c-Myb in the presence of NLK in vivo and in vitro. The c-Myb phosphorylation site mutant failed to interact with Fbxw7α, suggesting that the c-Myb/Fbxw7α interaction is enhanced by NLK phosphorylation of c-Myb. Treatment of M1 cells with Fbxw7 small interfering RNA (siRNA) rescued the Wnt-induced c-Myb degradation and also the Wnt-induced inhibition of cell proliferation. NLK bound to Cul1, a component of the SCF complex, while HIPK2 interacted with both Fbxw7α and Cul1, suggesting that both kinases enhance the c-Myb/SCF interaction. In contrast to c-Myb, the v-myb gene product (v-Myb) encoded by the avian myeloblastosis virus was resistant to NLK/Fbxw7α-induced degradation. Thus, Fbxw7 is an E3 ubiquitin ligase of c-Myb, and the increased c-Myb levels may contribute, at least partly, to transformation induced by mutation of Fbxw7