A Preliminary Study of Voluntary Cough Motor Performance and Learning With Skill Training and Biofeedback.

PURPOSE: Sensorimotor cough skill training (CST) has been shown to improve cough strength, as well as facilitate changes during training (i.e., motor performance) and generalization to untrained tasks (i.e., motor learning). However, there is a gap in our understanding of the effects of voluntary CST (without sensory stimuli) on motor performance and learning. Furthermore, the contribution of physiologic factors, such as lung volume, a driver of cough strength in healthy adults, and treatment-specific factors, such as biofeedback, remains unexamined. METHOD: Twenty individuals with Parkinson's disease (PD) completed pre- and post-CST single voluntary, sequential voluntary, and reflex cough testing. Participants were randomized to biofeedback or no biofeedback groups. They completed one CST session involving 25 trials of voluntary coughs, with the treatment target set 25% above baseline peak flow. Participants were instructed to "cough hard" to exceed the target. In the biofeedback group, participants received direct visualization of the target line in real time. RESULTS: Cough peak flow showed positive improvements in motor performance (ß = .02; 95% credible interval [CI]: 0.01, 0.03) and learning (ß = .26; 95% CI: 0.03, 0.47). Changes in lung volume from pre- to post-CST did not predict treatment response. No differences in treatment response were detected between the biofeedback groups. CONCLUSIONS: A single session of voluntary CST improved voluntary cough motor performance and learning. Although lung volume increased during CST, changes to lung volume did not predict treatment response. These findings demonstrate the potential of voluntary CST to improve motor performance and motor learning among individuals with PD and cough dysfunction. SUPPLEMENTAL MATERIAL AND OPEN SCIENCE FORM: https://doi.org/10.23641/asha.25447444.

An Examination of Cognitive Heterogeneity in Parkinson Disease: The Dual-Syndrome Hypothesis.

PURPOSE: Cognitive impairment is one of the most debilitating nonmotor symptoms in Parkinson disease (PD), and its presentation is heterogeneous. One proposed model to explain cognitive variability in PD is the dual-syndrome hypothesis. This hypothesis delineates two cognitive profiles, a "fronto-striatal" profile and a "posterior cortical" profile according to symptom presentation, associated motor phenotype, and risk for dementia. The current study examined the dual-syndrome hypothesis in individuals with idiopathic PD to evaluate the existence of these profiles, determine the association with the motor phenotype (tremor dominant vs. postural instability/gait disorder), and assess the relative risk for dementia. METHOD: A retrospective examination was conducted using data from the Parkinson's Progression Markers Initiative database at baseline (within 2 years of diagnosis) and 5 years after baseline. Descriptive categorizations, cluster analyses, generalized linear mixed models, and logistic regressions were used to address the research questions. RESULTS: There was emerging evidence of cognitive profiles; however, these were not fully supported by cluster analyses. Baseline cognitive profile was associated with later motor phenotype, and as predicted, dementia risk was greatest in persons with baseline posterior cortical impairments. CONCLUSION: The current results provide mixed support for the dual-syndrome hypothesis, with some evidence that the posterior cortical cognitive profile is associated with postural instability and gait disorder as well as greater dementia risk.

Behavioral Management of Respiratory/Phonatory Dysfunction for Dysarthria Associated With Neurodegenerative Disease: A Systematic Review.

PURPOSE: This systematic review represents an update to previous reviews of the literature addressing behavioral management of respiratory/phonatory dysfunction in individuals with dysarthria due to neurodegenerative disease. METHOD: Multiple electronic database searches and hand searches of prominent speech-language pathology journals were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. RESULTS: The search yielded 1,525 articles, from which 88 met inclusion criteria and were reviewed by two blinded co-investigators. A large range of therapeutic approaches have been added to the evidence base since the last review, including expiratory muscle strength training, singing, and computer- and device-driven programs, as well as a variety of treatment modalities, including teletherapy. Evidence for treatment in several different population groups-including cerebellar ataxia, myotonic dystrophy, autosomal recessive spastic ataxia of Charlevoix-Saguenay, Huntington's disease, multiple system atrophy, and Lewy body dementia-were added to the current review. Synthesis of evidence quality provided strong evidence in support of only one behavioral intervention: Lee Silverman Voice Treatment Program (LSVT LOUD) in people with Parkinson's disease. No other treatment approach or population included in this review demonstrated more than limited evidence, reflecting that these approaches/populations require urgent further examination. CONCLUSION: Suggestions about where future research efforts could be significantly strengthened and how clinicians can apply research findings to their practice are provided. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24964473.

The Effects of Speech Task on Lexical Stress in Parkinson's Disease.

PURPOSE: Hypokinetic dysarthria associated with Parkinson's disease (PD) is characterized by dysprosody, yet the literature is mixed with respect to how dysprosody affects the ability to mark lexical stress, possibly due to differences in speech tasks used to assess lexical stress. The purpose of this study was to compare how people with and without PD modulate acoustic dimensions of lexical stress-fundamental frequency, intensity, and duration-to mark lexical stress across three different speech tasks. METHOD: Twelve individuals with mild-to-moderate idiopathic PD and 12 age- and sex-matched older adult controls completed three speech tasks: picture description, word production in isolation, and word production in lists. Outcome measures were the fundamental frequency, intensity, and duration of the vocalic segments of two trochees (initial stress) and two iambs (final stress) spoken in all three tasks. RESULTS: There were very few group differences. Both groups marked trochees by modulating intensity and fundamental frequency and iambs by modulating duration. Task had a significant impact on the stress patterns used by both groups. Stress patterns were most differentiated in words produced in isolation and least differentiated in lists of words. CONCLUSIONS: People with PD did not demonstrate impairments in the production of lexical stress, suggesting that dysprosody associated with PD does not impact all types of prosody in the same way. However, there were reduced distinctions in stress marking that were more apparent in trochees than iambs. In addition, the task used to assess prosody has a significant effect on all acoustic measures. Future research should focus on the use of connected speech tasks to obtain more generalizable measures of prosody in PD.

Telehealth Management of Dysphagia in Adults: A Survey of Speech Language Pathologists' Experiences and Perceptions.

The goal of this study was to explore telehealth use for dysphagia management in response to COVID-19 to understand variables associated with clinician confidence and perceived effectiveness of this service delivery model and determine clinician-perceived benefits and challenges of managing dysphagia via telehealth. Speech-language pathologists (SLPs, n = 235) completed a web-based survey, providing information on demographics, telehealth use during the pandemic, and perspectives on current and future tele-management of dysphagia. Analyses included descriptive statistics to examine usage patterns; logistic regression to determine which variables were associated with telehealth use, clinician confidence, and perceived-effectiveness; and conventional content analysis to analyze responses to open-ended questions. Results revealed a sharp increase in the tele-management of dysphagia during the pandemic. Years of experience with dysphagia management (p = .031) and pre-pandemic use of telehealth (p < .001) were significantly associated with current use patterns. Working in the outpatient setting was associated with greater clinician confidence (p = .003) and perceived effectiveness (p = .007), and use of guidelines (p = .042) was also associated with greater clinician confidence. Key challenges identified included inadequate technological infrastructure, inadequate patient digital literacy, and reimbursement restrictions. Key benefits were treatment continuity, improving access to care, and time savings. The majority (67%) of respondents reported that they would use telehealth in the future. These findings demonstrate SLPs' abilities and desire to expand their practice patterns to include telehealth for dysphagia management. Therefore, clinician training and more research on best practices for assessment and treatment of dysphagia via telehealth is warranted to refine models of care for dysphagia tele-management.

Respiratory Responses to Two Voice Interventions for Parkinson's Disease.

PURPOSE: The purpose of this study was to examine the respiratory strategies used by persons with Parkinson's disease (PD) to support louder speech in response to two voice interventions. Contrasting interventions were selected to investigate the role of internal and external cue strategies on treatment outcomes. LSVT LOUD, which uses an internal cueing framework, and the SpeechVive prosthesis, which employs an external noise cue to elicit louder speech, were studied. METHOD: Thirty-four persons with hypophonia secondary to idiopathic PD were assigned to one of three groups: LSVT LOUD (n = 12), SpeechVive (n = 12), or a nontreatment clinical control (n = 10). The LSVT LOUD and SpeechVive participants received 8 weeks of voice intervention. Acoustic and respiratory kinematic data were simultaneously collected at pre-, mid- and posttreatment during a monologue speech sample. Intervention outcomes included sound pressure level (SPL), utterance length, lung volume initiation, lung volume termination, and lung volume excursion. RESULTS: As compared to controls, the LSVT LOUD and SpeechVive participants significantly increased SPL at mid- and posttreatment, thus confirming a positive intervention effect. Treatment-related changes in speech breathing were further identified, including significantly longer utterance lengths (syllables per breath group) at mid- and posttreatment, as compared to pretreatment. The respiratory strategies used to support louder speech varied by group. The LSVT LOUD participants terminated lung volume at significantly lower levels at mid- and posttreatment, as compared to pretreatment. This finding suggests the use of greater expiratory muscle effort by the LSVT LOUD participants to support louder speech. Participants in the SpeechVive group did not significantly alter their respiratory strategies across the intervention period. Single-subject effect sizes highlight the variability in respiratory strategies used across speakers to support louder speech. CONCLUSIONS: This study provides emerging evidence to suggest that the LSVT LOUD and SpeechVive therapies elicit different respiratory adjustments in persons with PD. The study highlights the need to consider respiratory function when addressing voice targets in persons with PD.

Speech, Facial and Fine Motor Features for Conversation-Based Remote Assessment and Monitoring of Parkinson's Disease.

We present a cloud-based multimodal dialogue platform for the remote assessment and monitoring of speech, facial and fine motor function in Parkinson's Disease (PD) at scale, along with a preliminary investigation of the efficacy of the various metrics automatically extracted by the platform. 22 healthy controls and 38 people with Parkinson's Disease (pPD) were instructed to complete four interactive sessions, spaced a week apart, on the platform. Each session involved a battery of tasks designed to elicit speech, facial movements and finger movements. We find that speech, facial kinematic and finger movement dexterity metrics show statistically significant differences between controls and pPD. We further investigate the sensitivity, specificity, reliability and generalisability of these metrics. Our results offer encouraging evidence for the utility of automatically-extracted audiovisual analytics in remote mon-itoring of PD and other movement disorders.

Perception of Physical Demand, Mental Demand, and Performance: A Comparison of Two Voice Interventions for Parkinson's Disease.

PURPOSE: The purpose of the study was to examine the effect of two voice intervention approaches for hypophonia secondary to Parkinson's disease (PD) on self-reported measures of physical demand, mental demand, and vocal performance. METHOD: Thirty-four persons with hypophonia secondary to PD were assigned to one of three groups: Lee Silverman Voice Treatment (LSVT) LOUD (n = 12), SpeechVive (n = 12), and nontreatment clinical control (n = 10). The LSVT LOUD and the SpeechVive participants received 8 weeks of voice intervention following the standardized protocol previously described for each approach. To confirm the effectiveness of each voice intervention, sound pressure level (dB SPL) data were analyzed for the experimental and control participants for a monologue sample obtained pretreatment, midtreatment, and posttreatment. During the voice intervention period, the LSVT LOUD and the SpeechVive participants were instructed to complete a modified version of the National Aeronautics and Space Administration Task Load Index rating scale to indicate the mental and physical demand required to complete the intervention activities, and to indicate how well they performed in completing the assigned vocal tasks. RESULTS: The LSVT LOUD and the SpeechVive participants demonstrated a significant posttreatment increase in SPL (dB), in comparison to the clinical controls, thus confirming a positive intervention effect. The LSVT LOUD participants reported significantly higher ratings of physical and mental demand over the course of treatment, in comparison to the SpeechVive participants. CONCLUSION: Consideration of the mental and physical demand associated with two voice intervention approaches, commonly used for PD, may help to foster improved therapeutic compliance and treatment outcomes.

The effects of vocal exertion on lung volume measurements and acoustics in speakers reporting high and low vocal fatigue.

PURPOSE: Vocal exertion is common and often results in reduced respiratory and laryngeal efficiency. It is unknown, however, whether the respiratory kinematic and acoustic adjustments employed during vocal exertion differ between speakers reporting vocal fatigue and those who do not. This study compared respiratory kinematics and acoustic measures in individuals reporting low and high levels of vocal fatigue during a vocal exertion task. METHODS: Individuals reporting low (N = 20) and high (N = 10) vocal fatigue participated in a repeated measures design study over 2 days. On each day, participants completed a 10-minute vocal exertion task consisting of repeated, loud vowel productions at elevated F0 sustained for maximum phonation time. Respiratory kinematic and acoustic measures were analyzed on the 1st vowel production (T0), and the vowels produced 2 minutes (T2), 5 minutes (T5), 7 minutes (T7), and 10 minutes (T10) into the vocal exertion task. Vowel durations were also measured at each time point. RESULTS: No differences in respiratory kinematics were observed between low and high vocal fatigue groups at T0. As the vocal exertion task progressed (T2-T10), individuals reporting high vocal fatigue initiated phonation at lower lung volumes while individuals with low vocal fatigue initiated phonation at higher lung volumes. As the exertion task progressed, total lung volume excursion decreased in both groups. Differences in acoustic measures were observed, as individuals reporting high vocal fatigue produced softer, shorter vowels from T0 through T10. CONCLUSIONS: Individuals reporting high vocal fatigue employed less efficient respiratory strategies during periods of increased vocal demand when compared with individuals reporting low vocal fatigue. Individuals reporting high vocal fatigue had shorter maximum phonation time on loud vowels. Further study should examine the potential screening value of loud maximum phonation time, as well as the clinical implications of the observed respiratory patterns for managing vocal fatigue.

Longitudinal Effects of Parkinson's Disease on Speech Breathing During an Extemporaneous Connected Speech Task.

PURPOSE: A critical component to the development of any type of intervention to improve speech production in individuals with Parkinson's disease (PD) is a complete understanding of the speech impairments present at each stage of the disease and how these impairments change with disease progression. The purpose of this longitudinal study was to examine the impact of disease on speech production and speech breathing during an extemporaneous speech task in individuals with PD over the course of approximately 3.5 years. METHOD: Eight individuals with PD and eight age- and sex-matched control participants produced an extemporaneous connected speech task on two occasions (Time 1 and Time 2) an average of 3 years 7 months apart. Dependent variables included sound pressure level; utterance length; speech rate; lung volume initiation, termination, and excursion; and percent vital capacity per syllable. RESULTS: From Time 1 to Time 2, individuals with PD demonstrated decreased utterance length and lung volume initiation, termination, and excursion and increased speech rate. Control participants demonstrated decreased utterance length and lung volume termination and increased lung volume excursion and percent vital capacity per syllable from Time 1 to Time 2. CONCLUSIONS: Changes in speech production and speech breathing variables experienced by individuals with PD over the course of several years are related to their disease process and not typical aging. Changes to speech breathing highlight the need to provide intervention focused on increasing efficient respiratory patterning for speech production.

Effects of Bolus Holding on Respiratory-Swallow Coordination in Parkinson's Disease.

PURPOSE: The aim of this study was to examine the effects of bolus holding on respiratory-swallow coordination (RSC) in people with Parkinson's disease (PD). METHOD: People with PD were prospectively recruited to undergo RSC assessment using simultaneous respiratory inductive plethysmography and flexible laryngoscopy. During RSC assessment, participants swallowed 5-ml thin liquid boluses during held and nonheld swallowing tasks. Measures of RSC were analyzed for each swallow, which included respiratory pause duration, lung volume at swallow initiation, respiratory phase patterning, and the presence of paradoxical respiratory movements. Multilevel statistical modeling was used to determine if differences in RSC were present between the held and nonheld tasks. RESULTS: Thirty-three participants were enrolled. When compared to the nonheld swallows, the held swallows exhibited shorter respiratory pauses (p = .001, R 2 = .019), lower lung volumes at swallow initiation (p < .001, R 2 = .116), more frequent exhale-swallow-exhale patterns (p < .001, OR = 4.30), and less frequent paradoxical respiratory movements (p = .001, OR = 0.43). CONCLUSIONS: Findings from this study revealed that bolus holding significantly influences RSC in people with PD. This demonstrates that bolus holding may be an efficacious strategy to immediately improve RSC in PD. However, clinicians and researchers should consider avoiding bolus holding during swallowing evaluations if attempting to assess RSC behaviors that are most typical for the examinee.

Pediatric Health Promotion in the Community Setting: A Learning Experience for Nursing Students and Elementary School Students.

This article describes a health teaching initiative as a community-based experience for junior-level baccalaureate nursing students in their pediatric course. The students created and taught health promotion education sessions, along with an activity involving developmentally appropriate gross and fine motor skills, to elementary school students ages 4-9 years. The nursing students were able to reinforce their understanding of developmentally appropriate education techniques and activities. The elementary students had opportunities to learn about various health promotion topics and had an opportunity to practice their gross and fine motor skills.

Restoration Strategies Following Short-Term Vocal Exertion in Healthy Young Adults.

Purpose This study aims to investigate the effects of a 10-min vocal exertion task on voice and respiratory measures, to determine whether restorative strategies can mitigate these effects after cessation of exertion, and to assess whether these strategies continue to reduce these detrimental effects when vocal exertion is resumed. Method A prospective, repeated-measures design was used. On consecutive days, 20 participants (equal men and women) completed two vocal exertion tasks separated by 10 min of restoration strategies: vocal rest or controlled phonation (low-level tissue mobilization using straw phonation). Voice and respiratory data were collected at baseline, following the first exertion task, after restoration strategies, and after the second exertion task. Outcome measures included (a) vocal effort, (b) phonation threshold pressure, (c) maximum and minimum fundamental frequencies, (d) cepstral peak prominence of connected speech, (e) lung volume initiation and termination, (f) percent vital capacity expended per syllable, and (g) number of syllables per breath group. Results A worsening of phonation threshold pressure (p < .001), vocal effort (p < .001), and increase of minimum fundamental frequency (p = .007) were observed after vocal exertion. Lung volume initiation (p < .001) and lung volume termination (p < .001) increased. These changes were largely reversed by restoration strategies, but only controlled phonation prevented exertion-induced changes in respiratory kinematic measures on a subsequent vocal exertion task. Conclusions Exertion-induced voice changes occur rapidly and may be mitigated by either controlled phonation or vocal rest. Controlled phonation is recommended as a superior strategy due to evidence of a protective effect on a successive vocal exertion task.

Mitigating the Effects of Acute Vocal Exertion in Individuals With Vocal Fatigue.

OBJECTIVES/HYPOTHESIS: To investigate the effects of acute vocal exertion on individuals with vocal fatigue and to determine whether semi-occluded vocal tract exercises (SOVTEs) are more effective than vocal rest in mitigating acute effects. STUDY DESIGN: Prospective, repeated-measures design. METHODS: On consecutive days, 10 individuals (6 males, 4 females) with scores indicating vocal fatigue on the Vocal Fatigue Index completed two 10-minute vocal exertion tasks. Vocal rest or SOVTEs were interspersed in counterbalanced order between exertion tasks. Respiratory kinematic, acoustic, aerodynamic, and self-perceptual measures were collected at baseline, following vocal exertion, following SOVTE/vocal rest, and following the second exertion task. RESULTS: Acute vocal exertion worsened phonation threshold pressure (P < .001) and vocal effort (P < .001) and reduced maximum fundamental frequency (P < .001). Speech was terminated at lower lung volumes following vocal exertion (decreased lung volume termination [LVT], P < .001). Exertion-induced changes in vocal effort and LVT were significantly reversed by both vocal rest and SOVTE. Detrimental changes in voice measures reoccurred following the second vocal exertion task. SOVTE and vocal rest protected against changes in respiratory kinematics when vocal exertion was resumed. CONCLUSIONS: Vocal exertion impacted laryngeal, respiratory, and self-perceptual measures in individuals with vocal fatigue. Both SOVTE and vocal rest partially mitigated changes in voice measures and prompted more efficient respiratory strategies that were maintained when vocal exertion resumed. These data increase our understanding of how individuals with vocal fatigue respond to vocal exertion tasks and offer preliminary guidance for optimal clinical recommendations. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2732-2739, 2021.

Demonstrating Ligandability of the LC3A and LC3B Adapter Interface.

Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).

Obtaining Objective Clinical Measures During Telehealth Evaluations of Dysarthria.

Purpose COVID-19 has shifted models of health care delivery, requiring the rapid adoption of telehealth, despite limited evidence and few resources to guide speech-language pathologists. Management of dysarthria presents specific challenges in the telehealth modality. Evaluations of dysarthria typically rely heavily on perceptual judgments, which are difficult to obtain via telehealth given a variety of technological factors such as inconsistencies in mouth-to-microphone distance, changes to acoustic properties based on device settings, and possible interruptions in connection that may cause video freezing. These factors limit the validity, reliability, and clinicians' certainty of perceptual speech ratings via telehealth. Thus, objective measures to supplement the assessment of dysarthria are essential. Method This tutorial outlines how to obtain objective measures in real time and from recordings of motor speech evaluations to support traditional perceptual ratings in telehealth evaluations of dysarthria. Objective measures include pause patterns, utterance length, speech rate, diadochokinetic rates, and overall speech severity. We demonstrate, through clinical case vignettes, how these measures were completed following three clinical telehealth evaluations of dysarthria conducted via Zoom during the COVID-19 pandemic. This tutorial describes how each of these objective measures were utilized, in combination with subjective perceptual analysis, to determine deviant speech characteristics and their etiology, develop a patient-specific treatment plan, and track change over time. Conclusion Utilizing objective measures as an adjunct to perceptual ratings for telehealth dysarthria evaluations is feasible under real-world pandemic conditions and can be used to enhance the quality and utility of these evaluations.

The Impact of Parkinson's Disease on Breath Pauses and Their Relationship to Speech Impairment: A Longitudinal Study.

Purpose The purposes of this longitudinal study were to (a) examine the impact of Parkinson's disease (PD) progression on breath pause patterns and speech and linguistic errors and (b) determine the extent to which breath pauses and speech and linguistic errors contribute to speech impairment. Method Eight individuals with PD and eight age- and sex-matched control participants produced a reading passage on two occasions (Time 1 and Time 2) 3 years and 7 months apart on average. Two speech-language pathologists rated the severity of speech impairment for all participants at each time. Dependent variables included the location of each breath pause relative to syntax and punctuation as well as the number of disfluencies and mazes. Results At Time 1, there were no significant differences between the groups regarding breath pause patterns. At Time 2, individuals with PD produced significantly fewer breath pauses at major syntactic boundaries and periods as well as significantly more breath pauses at locations with no punctuation than control participants. Individuals with PD produced a significantly greater number of disfluencies than control participants at both time points. There were no significant differences between the groups in the number of mazes produced at either time point. Together, the number of mazes and the percentage of breath pauses at locations with no punctuation explained 50% of the variance associated with the ratings of severity of speech impairment. Conclusion These results highlight the importance of targeting both respiratory physiological and cognitive-linguistic systems in order to improve speech production in individuals with PD.

Oxygen-dependent asparagine hydroxylation of the ubiquitin-associated (UBA) domain in Cezanne regulates ubiquitin binding.

Deubiquitinases (DUBs) are vital for the regulation of ubiquitin signals, and both catalytic activity of and target recruitment by DUBs need to be tightly controlled. Here, we identify asparagine hydroxylation as a novel posttranslational modification involved in the regulation of Cezanne (also known as OTU domain-containing protein 7B (OTUD7B)), a DUB that controls key cellular functions and signaling pathways. We demonstrate that Cezanne is a substrate for factor inhibiting HIF1 (FIH1)- and oxygen-dependent asparagine hydroxylation. We found that FIH1 modifies Asn35 within the uncharacterized N-terminal ubiquitin-associated (UBA)-like domain of Cezanne (UBACez), which lacks conserved UBA domain properties. We show that UBACez binds Lys11-, Lys48-, Lys63-, and Met1-linked ubiquitin chains in vitro, establishing UBACez as a functional ubiquitin-binding domain. Our findings also reveal that the interaction of UBACez with ubiquitin is mediated via a noncanonical surface and that hydroxylation of Asn35 inhibits ubiquitin binding. Recently, it has been suggested that Cezanne recruitment to specific target proteins depends on UBACez Our results indicate that UBACez can indeed fulfill this role as regulatory domain by binding various ubiquitin chain types. They also uncover that this interaction with ubiquitin, and thus with modified substrates, can be modulated by oxygen-dependent asparagine hydroxylation, suggesting that Cezanne is regulated by oxygen levels.

An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5.

Short linear motifs, known as LC3-interacting regions (LIRs), interact with mactoautophagy/autophagy modifiers (Atg8/LC3/GABARAP proteins) via a conserved universal mechanism. Typically, this includes the occupancy of 2 hydrophobic pockets on the surface of Atg8-family proteins by 2 specific aromatic and hydrophobic residues within the LIR motifs. Here, we describe an alternative mechanism of Atg8-family protein interaction with the non-canonical UBA5 LIR, an E1-like enzyme of the ufmylation pathway that preferentially interacts with GABARAP but not LC3 proteins. By solving the structures of both GABARAP and GABARAPL2 in complex with the UBA5 LIR, we show that in addition to the binding to the 2 canonical hydrophobic pockets (HP1 and HP2), a conserved tryptophan residue N-terminal of the LIR core sequence binds into a novel hydrophobic pocket on the surface of GABARAP proteins, which we term HP0. This mode of action is unique for UBA5 and accompanied by large rearrangements of key residues including the side chains of the gate-keeping K46 and the adjacent K/R47 in GABARAP proteins. Swapping mutations in LC3B and GABARAPL2 revealed that K/R47 is the key residue in the specific binding of GABARAP proteins to UBA5, with synergetic contributions of the composition and dynamics of the loop L3. Finally, we elucidate the physiological relevance of the interaction and show that GABARAP proteins regulate the localization and function of UBA5 on the endoplasmic reticulum membrane in a lipidation-independent manner.Abbreviations: ATG: AuTophaGy-related; EGFP: enhanced green fluorescent protein; GABARAP: GABA-type A receptor-associated protein; ITC: isothermal titration calorimetry; KO: knockout; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NMR: nuclear magnetic resonance; RMSD: root-mean-square deviation of atomic positions; TKO: triple knockout; UBA5: ubiquitin like modifier activating enzyme 5.

The Accuracy of Respiratory Calibration Methods for Estimating Lung Volume During Speech Breathing: A Comparison of Four Methods Across Three Adult Cohorts.

Purpose This study evaluated the accuracy of respiratory calibration methods for estimating lung volume during speech breathing. Method Respiratory kinematic data were acquired via inductance plethysmography in 32 young adults, 22 older adults, and 13 older adults with Parkinson's disease (PD). Raw rib cage (RC) and abdomen (AB) signals (V) were calibrated to liters using 4 correction methods: (a) isovolume maneuvers, (b) a constant 2:1 RC-to-AB ratio, (c) least squares method with RC correction only (LsqRC), and (d) least squares method with both RC and AB corrections (LsqRC/AB). Mean percent error, the absolute difference between estimated and actual lung volumes then normalized to each speaker's vital capacity, was calculated for each method. Results For young adults, the LsqRC/AB method significantly reduced mean percent error compared to all other methods. Although LsqRC/AB also resulted in smaller errors for older adults and adults with PD, LsqRC/AB and LsqRC were not significantly different from one another in these groups. Conclusion The LsqRC/AB method reduces errors across all cohorts, but older adults and adults with PD also have reduced errors when using LsqRC. Further research should investigate both least squares methods across larger age and disease severity ranges.