The Impact of the COVID-19 Pandemic on Real-world Functioning in Adult Cochlear-implant Users.

Hypothesis: As a result of COVID-19 lockdowns and the associated effects on the auditory-social environments of cochlear-implant (CI) users, we expected that adult CI users would report a decrease in real-world communication abilities, a decrease in social isolation, and a decrease in quality of life (QOL) from pre- to post-pandemic. Background: The COVID-19 pandemic brought many changes to the environments in which adults with CIs interact and communicate. However, the impact of these changes on CI users' real-world functioning is not well understood. This study investigated the impact of the COVID-19 pandemic on real-world communication abilities, social isolation, and CI-related QOL in adult CI users. Methods: Fourteen adult CI users completed self-report questionnaires assessing communication abilities, social isolation, and CI-related QOL at time points before and after the onset of the COVID-19 pandemic. Responses at the 2 time points were compared to evaluate changes in CI users' real-world functioning. Results: Adult CI users showed a significant decrease in self-reported communication ability and a nonsignificant decline in CI-related QOL from before to during COVID-19. However, a nonsignificant trend of a decline in social isolation was also observed in adult CI users. Conclusion: Findings showed a decrease in self-reported communication abilities and, to a lesser extent, CI-related QOL, suggesting that changes to the auditory-social environment brought on by the COVID-19 pandemic may have negatively impacted communication abilities in real-world, challenging environments. Yet, the potential decrease in social isolation suggests that these changes may have had an overall positive effect on social interaction, potentially with close family and friends in well-controlled environments. Assessing changes in real-world functioning in the same CI users from both before and during the COVID-19 pandemic provided a unique glimpse into how changes in the auditory-social environment may impact outcomes in adult CI users.

Effect of Cochlear Implantation on Social Life.

OBJECTIVE: Explore the effects of hearing loss on social life and identify residual social life deficits that remain after cochlear implantation. STUDY DESIGN: Retrospective review of prospectively obtained data. SETTING: Tertiary care adult neurotology center. PATIENTS: Adults between the ages of 35 and 83 years were included with either normal hearing (NH) or a cochlear implant (CI). INTERVENTIONS: CI and non-CI-specific quality-of-life (QOL) surveys focused on social and overall QOL. MAIN OUTCOME MEASURES: (1) The difference in QOL survey responses between NH and CI participants. (2) The relationship between CI-specific global and social QOL responses and non-CI-specific social QOL responses in CI users. RESULTS: A total of 51 participants were included: 31 CI users and 20 NH participants. Of the social QOL questionnaires, CI users reported significantly poorer scores on Self-Efficacy in Social Interactions than NH peers ( p = 0.049). Both Self-Efficacy in Social Interactions scores and Social Isolation Questionnaire scores were significantly correlated with the CI-specific social domain of QOL ( r = 0.64 and -0.58, respectively). Only the Self-Efficacy in Social Interactions scores had a moderate association with global CI QOL ( r = 0.47). CONCLUSIONS: CI users self-report similar social life outcomes as their NH peers with the exception of poorer self-efficacy in social situations. Moreover, self-efficacy in social interactions and social isolation were associated with social QOL in CI users, and self-efficacy in social interactions was associated with broader CI-related QOL. Findings support the relevance of individuals' perception of social life to their overall QOL with a CI.

Calmodulin regulates protease versus co-chaperone activity of a metacaspase.

Metacaspases are ancestral homologs of caspases that can either promote cell death or confer cytoprotection. Furthermore, yeast (Saccharomyces cerevisiae) metacaspase Mca1 possesses dual biochemical activity: proteolytic activity causing cell death and cytoprotective, co-chaperone-like activity retarding replicative aging. The molecular mechanism favoring one activity of Mca1 over another remains elusive. Here, we show that this mechanism involves calmodulin binding to the N-terminal pro-domain of Mca1, which prevents its proteolytic activation and promotes co-chaperone-like activity, thus switching from pro-cell death to anti-aging function. The longevity-promoting effect of Mca1 requires the Hsp40 co-chaperone Sis1, which is necessary for Mca1 recruitment to protein aggregates and their clearance. In contrast, proteolytically active Mca1 cleaves Sis1 both in vitro and in vivo, further clarifying molecular mechanism behind a dual role of Mca1 as a cell-death protease versus gerontogene.

Calcineurin stimulation by Cnb1p overproduction mitigates protein aggregation and α-synuclein toxicity in a yeast model of synucleinopathy.

The calcium-responsive phosphatase, calcineurin, senses changes in Ca2+ concentrations in a calmodulin-dependent manner. Here we report that under non-stress conditions, inactivation of calcineurin signaling or deleting the calcineurin-dependent transcription factor CRZ1 triggered the formation of chaperone Hsp100p (Hsp104p)-associated protein aggregates in Saccharomyces cerevisiae. Furthermore, calcineurin inactivation aggravated α-Synuclein-related cytotoxicity. Conversely, elevated production of the calcineurin activator, Cnb1p, suppressed protein aggregation and cytotoxicity associated with the familial Parkinson's disease-related mutant α-Synuclein A53T in a partly CRZ1-dependent manner. Activation of calcineurin boosted normal localization of both wild type and mutant α-synuclein to the plasma membrane, an intervention previously shown to mitigate α-synuclein toxicity in Parkinson's disease models. The findings demonstrate that calcineurin signaling, and Ca2+ influx to the vacuole, limit protein quality control in non-stressed cells and may have implications for elucidating to which extent aberrant calcineurin signaling contributes to the progression of Parkinson's disease(s) and other synucleinopathies. Video Abstract.

The yeast guanine nucleotide exchange factor Sec7 is a bottleneck in spatial protein quality control and detoxifies neurological disease proteins.

ER-to-Golgi trafficking partakes in the sorting of misfolded cytoplasmic proteins to reduce their cytological toxicity. We show here that yeast Sec7, a protein involved in proliferation of the Golgi, is part of this pathway and participates in an Hsp70-dependent formation of insoluble protein deposits (IPOD). Sec7 associates with the disaggregase Hsp104 during a mild heat shock and increases the rate of Hsp104 diffusion in an Hsp70-dependent manner when overproduced. Sec7 overproduction increased formation of IPODs from smaller aggregates and mitigated the toxicity of Huntingtin exon-1 upon heat stress while Sec7 depletion increased sensitivity to aẞ42 of the Alzheimer's disease and α-synuclein of the Parkinson's disease, suggesting a role of Sec7 in mitigating proteotoxicity.

Artificial Hsp104-mediated systems for re-localizing protein aggregates.

Spatial Protein Quality Control (sPQC) sequesters misfolded proteins into specific, organelle-associated inclusions within the cell to control their toxicity. To approach the role of sPQC in cellular fitness, neurodegenerative diseases and aging, we report on the construction of Hsp100-based systems in budding yeast cells, which can artificially target protein aggregates to non-canonical locations. We demonstrate that aggregates of mutant huntingtin (mHtt), the disease-causing agent of Huntington's disease can be artificially targeted to daughter cells as well as to eisosomes and endosomes with this approach. We find that the artificial removal of mHtt inclusions from mother cells protects them from cell death suggesting that even large mHtt inclusions may be cytotoxic, a trait that has been widely debated. In contrast, removing inclusions of endogenous age-associated misfolded proteins does not significantly affect the lifespan of mother cells. We demonstrate also that this approach is able to manipulate mHtt inclusion formation in human cells and has the potential to be useful as an alternative, complementary approach to study the role of sPQC, for example in aging and neurodegenerative disease.

Growth Rate Evaluation of the Budding Yeast Saccharomyces cerevisiae Cells Carrying Endogenously Expressed Fluorescent Protein Fusions.

Fluorescent proteins within fluorescent fusions have been reported to affect cellular growth fitness via altering native protein function and intracellular localization. Here we report in detail a procedure to analyze the growth characteristics of yeast cells expressing such fusions in comparison to unmodified parental strain. This approach can serve as an initial step in fluorescent protein characterization in vivo.

Preoperative Reading Efficiency as a Predictor of Adult Cochlear Implant Outcomes.

HYPOTHESES: 1) Scores of reading efficiency (the Test of Word Reading Efficiency, second edition) obtained in adults before cochlear implant surgery will be predictive of speech recognition outcomes 6 months after surgery; and 2) Cochlear implantation will lead to improvements in language processing as measured through reading efficiency from preimplantation to postimplantation. BACKGROUND: Adult cochlear implant (CI) users display remarkable variability in speech recognition outcomes. "Top-down" processing-the use of cognitive resources to make sense of degraded speech-contributes to speech recognition abilities in CI users. One area that has received little attention is the efficiency of lexical and phonological processing. In this study, a visual measure of word and nonword reading efficiency-relying on lexical and phonological processing, respectively-was investigated for its ability to predict CI speech recognition outcomes, as well as to identify any improvements after implantation. METHODS: Twenty-four postlingually deaf adult CI candidates were tested on the Test of Word Reading Efficiency, Second Edition preoperatively and again 6 months post-CI. Six-month post-CI speech recognition measures were also assessed across a battery of word and sentence recognition. RESULTS: Preoperative nonword reading scores were moderately predictive of sentence recognition outcomes, but real word reading scores were not; word recognition scores were not predicted by either. No 6-month post-CI improvement was demonstrated in either word or nonword reading efficiency. CONCLUSION: Phonological processing as measured by the Test of Word Reading Efficiency, Second Edition nonword reading predicts to a moderate degree 6-month sentence recognition outcomes in adult CI users. Reading efficiency did not improve after implantation, although this could be because of the relatively short duration of CI use.

Using reporters of different misfolded proteins reveals differential strategies in processing protein aggregates.

The accumulation of misfolded proteins is a hallmark of aging and many neurodegenerative diseases, making it important to understand how the cellular machinery recognizes and processes such proteins. A key question in this respect is whether misfolded proteins are handled in a similar way regardless of their genetic origin. To approach this question, we compared how three different misfolded proteins, guk1-7, gus1-3, and pro3-1, are handled by the cell. We show that all three are nontoxic, even though highly overexpressed, highlighting their usefulness in analyzing the cellular response to misfolding in the absence of severe stress. We found significant differences between the aggregation and disaggregation behavior of the misfolded proteins. Specifically, gus1-3 formed some aggregates that did not efficiently recruit the protein disaggregase Hsp104 and did not colocalize with the other misfolded reporter proteins. Strikingly, while all three misfolded proteins generally coaggregated and colocalized to specific sites in the cell, disaggregation was notably different; the rate of aggregate clearance of pro3-1 was faster than that of the other misfolded proteins, and its clearance rate was not hindered when pro3-1 colocalized with a slowly resolved misfolded protein. Finally, we observed using super-resolution light microscopy as well as immunogold labeling EM in which both showed an even distribution of the different misfolded proteins within an inclusion, suggesting that misfolding characteristics and remodeling, rather than spatial compartmentalization, allows for differential clearance of these misfolding reporters residing in the same inclusion. Taken together, our results highlight how properties of misfolded proteins can significantly affect processing.

Large organellar changes occur during mild heat shock in yeast.

When the temperature is increased, the heat-shock response is activated to protect the cellular environment. The transcriptomics and proteomics of this process are intensively studied, while information about how the cell responds structurally to heat stress is mostly lacking. Here, Saccharomyces cerevisiae were subjected to a mild continuous heat shock (38°C) and intermittently cryo-immobilised for electron microscopy. Through measuring changes in all distinguishable organelle numbers, sizes and morphologies in over 2100 electron micrographs, a major restructuring of the internal architecture of the cell during the progressive heat shock was revealed. The cell grew larger but most organelles within it expanded even more, shrinking the volume of the cytoplasm. Organelles responded to heat shock at different times, both in terms of size and number, and adaptations of the morphology of some organelles (such as the vacuole) were observed. Multivesicular bodies grew by almost 70%, indicating a previously unknown involvement in the heat-shock response. A previously undescribed electron-translucent structure accumulated close to the plasma membrane. This all-encompassing approach provides a detailed chronological progression of organelle adaptation throughout the cellular heat-stress response.

Biopsychosocial Factors during the Perinatal Period: Risks, Preventative Factors, and Implications for Healthcare Professionals.

Women face risks to their wellbeing during the perinatal period of pregnancy. However, there is a dearth of information on perinatal risk factors within the biopsychosocial paradigm. Emphasis is often placed on biological components associated with pregnancy and women's health. However, psychological and social determinants of health are integral during the perinatal period, and mental wellness is often a determinant for positive maternal and neonatal health outcomes. This article reviews risk factors of perinatal wellness (e.g., physical and nutritional concerns, trauma, discrimination, adverse childhood events) and highlights protective factors for women in their perinatal period. Healthcare professionals can support perinatal health by focusing on culturally and contextually appropriate research and prevention, providing equal access to sexual and reproductive healthcare information and services, providing quality education and training for helping professionals, and supporting policies for positive sexual and reproductive women's healthcare.

Comparison of endogenously expressed fluorescent protein fusions behaviour for protein quality control and cellular ageing research.

The yeast Hsp104 protein disaggregase is often used as a reporter for misfolded or damaged protein aggregates and protein quality control and ageing research. Observing Hsp104 fusions with fluorescent proteins is a popular approach to follow post stress protein aggregation, inclusion formation and disaggregation. While concerns that bigger protein tags, such as genetically encoded fluorescent tags, may affect protein behaviour and function have been around for quite some time, experimental evidence of how exactly the physiology of the protein of interest is altered within fluorescent protein fusions remains limited. To address this issue, we performed a comparative assessment of endogenously expressed Hsp104 fluorescent fusions function and behaviour. We provide experimental evidence that molecular behaviour may not only be altered by introducing a fluorescent protein tag but also varies depending on such a tag within the fusion. Although our findings are especially applicable to protein quality control and ageing research in yeast, similar effects may play a role in other eukaryotic systems.

Effectiveness of Arginine Supplementation on Wound Healing in Older Adults in Acute and Chronic Settings: A Systematic Review.

OBJECTIVE: To examine the effect of arginine supplementation on wound healing, as measured by wound size and healing rate, in older adults in acute and long-term care (LTC) settings. DATA SOURCES: PubMed, CINAHL Plus, Google Scholar, and OpenGrey databases. STUDY SELECTION: Randomized clinical trials and clinical studies were considered for this review. Selection criteria included English-language articles published after 2008 that provide data on older adults with pressure injury receiving arginine supplementation in acute care and LTC settings. DATA EXTRACTION: Data were extracted from the articles using a predefined checklist including study size and design, participant characteristics (age, pressure injury stage, relevant comorbidities), nutrition intervention and dosage, duration of study, outcomes, and publication year. Studies were appraised using the National Institutes of Health's Quality Assessment of Controlled Intervention Studies tool. DATA SYNTHESIS: A preliminary search yielded 39 articles after removing duplicates. Abstracts and titles of articles were screened, and 23 full-text articles were examined further. Ultimately, six articles met the inclusion criteria. CONCLUSIONS: Current evidence suggests that arginine supplementation in conjunction with oral nutrition supplementation may promote wound healing in older adult patients in acute care and LTC settings as evidenced by significant reductions in wound size and improvements in wound healing when compared with oral nutrition supplementation alone. A definitive conclusion about the use of arginine supplementation alone to promote wound healing cannot be drawn because of limitations in the available literature. Additional high-quality studies are needed to examine arginine supplementation alone as a potential therapy for PI.

Syntaxin 5 Is Required for the Formation and Clearance of Protein Inclusions during Proteostatic Stress.

Spatial sorting to discrete quality control sites in the cell is a process harnessing the toxicity of aberrant proteins. We show that the yeast t-snare phosphoprotein syntaxin5 (Sed5) acts as a key factor in mitigating proteotoxicity and the spatial deposition and clearance of IPOD (insoluble protein deposit) inclusions associates with the disaggregase Hsp104. Sed5 phosphorylation promotes dynamic movement of COPII-associated Hsp104 and boosts disaggregation by favoring anterograde ER-to-Golgi trafficking. Hsp104-associated aggregates co-localize with Sed5 as well as components of the ER, trans Golgi network, and endocytic vesicles, transiently during proteostatic stress, explaining mechanistically how misfolded and aggregated proteins formed at the vicinity of the ER can hitchhike toward vacuolar IPOD sites. Many inclusions become associated with mitochondria in a HOPS/vCLAMP-dependent manner and co-localize with Vps39 (HOPS/vCLAMP) and Vps13, which are proteins providing contacts between vacuole and mitochondria. Both Vps39 and Vps13 are required also for efficient Sed5-dependent clearance of aggregates.

Studying Spatial Protein Quality Control, Proteopathies, and Aging Using Different Model Misfolding Proteins in S. cerevisiae.

Protein quality control (PQC) is critical to maintain a functioning proteome. Misfolded or toxic proteins are either refolded or degraded by a system of temporal quality control and can also be sequestered into aggregates or inclusions by a system of spatial quality control. Breakdown of this concerted PQC network with age leads to an increased risk for the onset of disease, particularly neurological disease. Saccharomyces cerevisiae has been used extensively to elucidate PQC pathways and general evolutionary conservation of the PQC machinery has led to the development of several useful S. cerevisiae models of human neurological diseases. Key to both of these types of studies has been the development of several different model misfolding proteins, which are used to challenge and monitor the PQC machinery. In this review, we summarize and compare the model misfolding proteins that have been used to specifically study spatial PQC in S. cerevisiae, as well as the misfolding proteins that have been shown to be subject to spatial quality control in S. cerevisiae models of human neurological diseases.

An integrin inhibiting molecule decreases oxidative damage and improves neurological function after spinal cord injury.

Our previous studies have shown that treatment with an alpha4beta1 integrin blocking antibody after spinal cord injury (SCI) in rats decreases intraspinal inflammation and oxidative damage, improving neurological function. Here, we studied effects of a high affinity small molecule alpha4beta1 inhibitor, BIO5192. First, rats were treated intravenously with BIO5192 (10 mg/kg) or with vehicle (controls) to assess effects of integrin blockade for 24 h or 72 h after thoracic clip-compression SCI. BIO5192 treatment significantly decreased the MPO enzymatic activity (neutrophil infiltration) and ED-1 expression (macrophage density) by 40% and 38% at 24 h and by 52% and 25% at 72 h post injury, respectively. In cord homogenates, BIO5192 treatment decreased expression of the oxidative enzymes gp91(phox), inducible nitric oxide and cyclooxygenase-2 by approximately 40% at both times of analysis. Free radical concentration decreased by 30% and lipid peroxidation decreased by 34% and 46%, respectively, at 24 h and 72 h after SCI. Next, after blockade by BIO5192 for 72 h, neurological outcomes were analyzed for 1-6 weeks after SCI. Motor function significantly improved when assessed by an open-field test. Treated rats planter placed their hind paws and/or dorsal stepped, with weight support, whereas controls only swept their hindlimbs. BIO5192 treatment also decreased mechanical allodynia elicited from the trunk and hind paw by up to 35%. This improved function correlated with decreased lesion size and spared myelin-containing white matter. The neurological improvement offered by this neuroprotective strategy supports the potential for an anti-integrin treatment for SCI.