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Frontiers in Audiology and Otology 2024Mutations in microRNA-96 (miR-96), a microRNA expressed within the hair cells (HCs) of the inner ear, result in progressive hearing loss in both mouse models and humans....
INTRODUCTION
Mutations in microRNA-96 (miR-96), a microRNA expressed within the hair cells (HCs) of the inner ear, result in progressive hearing loss in both mouse models and humans. In this study, we present the first HC-specific RNA-sequencing (RNA-seq) dataset from newborn heterozygous, homozygous mutant, and wildtype mice.
METHODS
Bulk RNA-seq was performed on HCs of newborn heterozygous, homozygous mutant, and wildtype mice. Differentially expressed gene analysis was conducted on homozygous mutant HCs compared to wildtype littermate controls, followed by GO term and protein-protein interaction analysis on these differentially expressed genes.
RESULTS
We identify 215 upregulated and 428 downregulated genes in the HCs of the homozygous mutant mice compared to their wildtype littermate controls. Many of the significantly downregulated genes in homozygous mutant HCs have established roles in HC development and/or known roles in deafness including , and and have enrichment in gene ontology (GO) terms with biological functions such as sensory perception of sound. Interestingly, upregulated genes in homozygous mutants, including possible miR-96 direct targets, show higher wildtype expression in supporting cells compared to HCs.
CONCLUSION
Our data further support a role for miR-96 in HC development, possibly as a repressor of supporting cell transcriptional programs in HCs. The HC-specific RNA-seq data set generated from this manuscript are now publicly available in a dedicated profile in the gene expression analysis resource (gEAR-https://umgear.org/p?l=miR96).
PubMed: 38826689
DOI: 10.3389/fauot.2024.1400576 -
BioRxiv : the Preprint Server For... May 2024Prestin's voltage-driven motor activity confers sound-elicited somatic electromotility in auditory outer hair cells (OHCs) and is essential for the exquisite sensitivity...
UNLABELLED
Prestin's voltage-driven motor activity confers sound-elicited somatic electromotility in auditory outer hair cells (OHCs) and is essential for the exquisite sensitivity and frequency selectivity of mammalian hearing. Lack of prestin results in hearing threshold shifts across frequency, supporting the causal association of variants in the prestin-coding gene, , with human hearing loss, DFNB61. However, cochlear function can tolerate reductions in prestin-mediated OHC electromotility. We found that two deafness-associated prestin variants, p.A100T and p.P119S, do not deprive prestin of its fast motor function but significantly reduce membrane expression, leading to large reductions in OHC electromotility that were only ∼30% of wildtype (WT). Mice harboring these missense variants suffered congenital hearing loss that was worse at high frequencies; however, they retained WT-like auditory brainstem response thresholds at 8 kHz, which is processed at the apex of the mouse cochlea. This observation suggests the increasing importance of prestin-driven cochlear amplification at higher frequencies relevant to mammalian hearing. The observation also suggests the promising clinical possibility that small enhancements of OHC electromotility could significantly ameliorate DFNB61 hearing loss in human patients.
SIGNIFICANCE
Prestin is abundantly expressed in the auditory outer hair cells and is essential for normal cochlear operation. Hence, reduction of prestin expression is often taken as indicative of reduced cochlear function in diseased or aged ears. However, this assumption overlooks the fact that cochlear function can tolerate large reductions in prestin motor activity. DFNB61 mouse models generated and characterized in this study provide an opportunity to gauge the amount of prestin motor activity needed to sustain normal hearing sensitivity. This knowledge is crucial not only for understanding the pathogenic roles of deafness-associated variants that impair OHC electromotility but also for unraveling how prestin contributes to cochlear amplification.
PubMed: 38826260
DOI: 10.1101/2024.05.22.595389 -
Research Square May 2024Stereocilia are unidirectional F-actin-based cylindrical protrusions on the apical surface of inner ear hair cells and function as biological mechanosensors of sound and...
Live-cell single-molecule fluorescence microscopy for protruding organelles reveals regulatory mechanisms of MYO7A-driven cargo transport in stereocilia of inner ear hair cells.
Stereocilia are unidirectional F-actin-based cylindrical protrusions on the apical surface of inner ear hair cells and function as biological mechanosensors of sound and acceleration. Development of functional stereocilia requires motor activities of unconventional myosins to transport proteins necessary for elongating the F-actin cores and to assemble the mechanoelectrical transduction (MET) channel complex. However, how each myosin localizes in stereocilia using the energy from ATP hydrolysis is only partially understood. In this study, we develop a methodology for live-cell single-molecule fluorescence microscopy of organelles protruding from the apical surface using a dual-view light-sheet microscope, diSPIM. We demonstrate that MYO7A, a component of the MET machinery, traffics as a dimer in stereocilia. Movements of MYO7A are restricted when scaffolded by the plasma membrane and F-actin as mediated by MYO7A's interacting partners. Here, we discuss the technical details of our methodology and its future applications including analyses of cargo transportation in various organelles.
PubMed: 38826223
DOI: 10.21203/rs.3.rs-4369958/v1 -
Europace : European Pacing,... Jun 2024KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous...
AIMS
KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous KCNQ1 mutations cause type 1 Jervell and Lange-Nielsen syndrome (JLNS) with deafness and higher sudden cardiac death risk. KCNQ1 variants causing JLNS or LQT1 might have distinct phenotypic expressions in heterozygous patients. The aim of this study is to evaluate QTc duration and incidence of long QT syndrome-related cardiac events according to genetic presentation.
METHODS AND RESULTS
We enrolled LQT1 or JLNS patients with class IV/V KCNQ1 variants from our inherited arrhythmia clinic (September 1993 to January 2023). Medical history, ECG, and follow-up were collected. Additionally, we conducted a thorough literature review for JLNS variants. Survival curves were compared between groups, and multivariate Cox regression models identified genetic and clinical risk factors. Among the 789 KCNQ1 variant carriers, 3 groups were identified: 30 JLNS, 161 heterozygous carriers of JLNS variants (HTZ-JLNS), and 550 LQT1 heterozygous carriers of non-JLNS variants (HTZ-Non-JLNS). At diagnosis, mean age was 3.4 ± 4.7 years for JLNS, 26.7 ± 21 years for HTZ-JLNS, and 26 ± 21 years for HTZ-non-JLNS; 55.3% were female; and the mean QTc was 551 ± 54 ms for JLNS, 441 ± 32 ms for HTZ-JLNS, and 467 ± 36 ms for HTZ-Non-JLNS. Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of heterozygous KCNQ1 variant carriers and had a lower risk of cardiac events than heterozygous non-JLNS variant carriers (HTZ-Non-JLNS) [hazard ratio (HR) = 0.34 (0.22-0.54); P < 0.01]. After multivariate analysis, four genetic parameters were independently associated with events: haploinsufficiency [HR = 0.60 (0.37-0.97); P = 0.04], pore localization [HR = 1.61 (1.14-1.2.26); P < 0.01], C-terminal localization [HR = 0.67 (0.46-0.98); P = 0.04], and group [HR = 0.43 (0.27-0.69); P < 0.01].
CONCLUSION
Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other LQT1 patients.
Topics: Humans; KCNQ1 Potassium Channel; Female; Male; Risk Assessment; Romano-Ward Syndrome; Risk Factors; Child; Electrocardiography; Child, Preschool; Heterozygote; Mutation; Jervell-Lange Nielsen Syndrome; Genetic Predisposition to Disease; Infant; Adult; Adolescent; Phenotype; Retrospective Studies; Death, Sudden, Cardiac; Young Adult; Incidence
PubMed: 38825991
DOI: 10.1093/europace/euae136 -
PloS One 2024Since the early 2000's, digital reading applications have enhanced the language and literacy skills of typically hearing young children; however, no digital storybook...
Since the early 2000's, digital reading applications have enhanced the language and literacy skills of typically hearing young children; however, no digital storybook intervention currently exists to scaffold the early language and literacy skills of their peers who are deaf or hard of hearing. To address this gap, our research team developed a novel digital storybook intervention called Hear Me Read with the aim of enhancing the therapeutic, language, and literacy benefits of speech-language therapy. This prospective clinical trial (registered at clinicaltrials.gov, NCT#: 05245799) aims to determine the efficacy of adding Hear Me Read to in-person speech-language therapy for children aged three to five years who are deaf or hard of hearing. Fifty caregivers, their child, and their child's treating speech-language pathologist participate in the trial for 12 months. In the first six months, children attend standard-of-care speech-language therapy sessions. In the second six months, children continue to attend standard-of-care speech-language therapy sessions and use the Hear Me Read application, via a study supplied iPad. The primary outcome of this trial is that, compared to in-person speech-language therapy alone, in-person speech-language therapy with Hear Me Read will improve vocabulary, speech, and language outcomes in children aged three to five years who are deaf or hard of hearing. The secondary outcome is that, compared to in-person speech-language therapy alone, in-person speech-language therapy with Hear Me Read will improve literacy outcomes in children aged three to five years who are deaf or hard of hearing. The goal of this intervention is to help children who are deaf or hard of hearing achieve their vocabulary, speech, language, and literacy goals through interactive digital storybook reading.
Topics: Child, Preschool; Female; Humans; Male; Deafness; Hearing Loss; Language Therapy; Literacy; Prospective Studies; Reading; Speech Therapy; Clinical Trials as Topic
PubMed: 38820413
DOI: 10.1371/journal.pone.0302734 -
Frontiers in Genetics 2024Cross-sectional data allow the investigation of how genetics influence health at a single time point, but to understand how the genome impacts phenotype development, one...
Cross-sectional data allow the investigation of how genetics influence health at a single time point, but to understand how the genome impacts phenotype development, one must use repeated measures data. Ignoring the dependency inherent in repeated measures can exacerbate false positives and requires the utilization of methods other than general or generalized linear models. Many methods can accommodate longitudinal data, including the commonly used linear mixed model and generalized estimating equation, as well as the less popular fixed-effects model, cluster-robust standard error adjustment, and aggregate regression. We simulated longitudinal data and applied these five methods alongside naïve linear regression, which ignored the dependency and served as a baseline, to compare their power, false positive rate, estimation accuracy, and precision. The results showed that the naïve linear regression and fixed-effects models incurred high false positive rates when analyzing a predictor that is fixed over time, making them unviable for studying time-invariant genetic effects. The linear mixed models maintained low false positive rates and unbiased estimation. The generalized estimating equation was similar to the former in terms of power and estimation, but it had increased false positives when the sample size was low, as did cluster-robust standard error adjustment. Aggregate regression produced biased estimates when predictor effects varied over time. To show how the method choice affects downstream results, we performed longitudinal analyses in an adolescent cohort of African and European ancestry. We examined how developing post-traumatic stress symptoms were predicted by polygenic risk, traumatic events, exposure to sexual abuse, and income using four approaches-linear mixed models, generalized estimating equations, cluster-robust standard error adjustment, and aggregate regression. While the directions of effect were generally consistent, coefficient magnitudes and statistical significance differed across methods. Our in-depth comparison of longitudinal methods showed that linear mixed models and generalized estimating equations were applicable in most scenarios requiring longitudinal modeling, but no approach produced identical results even if fit to the same data. Since result discrepancies can result from methodological choices, it is crucial that researchers determine their model , refrain from testing multiple approaches to obtain favorable results, and utilize as similar as possible methods when seeking to replicate results.
PubMed: 38818035
DOI: 10.3389/fgene.2024.1203577 -
Health Services Management Research May 2024The sharing of information and feedback directly from service-providing staff to healthcare organisational management is vital for organisational culture and service...
The sharing of information and feedback directly from service-providing staff to healthcare organisational management is vital for organisational culture and service improvement. However, hospital doctors report feeling unable to communicate effectively with management to provide evidence and affect improvement, and this can impact job satisfaction, workplace relations, service delivery and ultimately patient safety. In this paper, we draw on data elicited from a Mobile Instant Messaging Ethnography (MIME) study involving 28 hospital doctors working in Irish hospitals, to explore the barriers preventing them from speaking up and effecting change, and the impact of this on staff morale and services. We identify three major barriers, consistent with previous literature, to effective feedback and communication: (1) organisational deafness, (2) disconnect between managers and frontline staff, and (3) denial of the narratives and issues raised. We draw these together to identify key implications from these findings for healthcare managers, and suggest policy and practice improvements.
PubMed: 38817143
DOI: 10.1177/09514848241254929 -
Nature Communications May 2024Our limited understanding of the pathophysiological mechanisms that operate during sepsis is an obstacle to rational treatment and clinical trial design. There is a...
Our limited understanding of the pathophysiological mechanisms that operate during sepsis is an obstacle to rational treatment and clinical trial design. There is a critical lack of data from low- and middle-income countries where the sepsis burden is increased which inhibits generalized strategies for therapeutic intervention. Here we perform RNA sequencing of whole blood to investigate longitudinal host response to sepsis in a Ghanaian cohort. Data dimensional reduction reveals dynamic gene expression patterns that describe cell type-specific molecular phenotypes including a dysregulated myeloid compartment shared between sepsis and COVID-19. The gene expression signatures reported here define a landscape of host response to sepsis that supports interventions via targeting immunophenotypes to improve outcomes.
Topics: Humans; Sepsis; COVID-19; Ghana; Transcriptome; Phenotype; Male; Cohort Studies; SARS-CoV-2; Female; Adult; Middle Aged; Gene Expression Profiling; Sequence Analysis, RNA
PubMed: 38816375
DOI: 10.1038/s41467-024-48821-0 -
"Congenital cytomegalovirus in Sub-Saharan Africa-a narrative review with practice recommendations".Frontiers in Public Health 2024Cytomegalovirus (CMV) is the most common cause of congenital infection internationally, occurring in 0.67% of births, and increasingly recognised as a major public... (Review)
Review
Cytomegalovirus (CMV) is the most common cause of congenital infection internationally, occurring in 0.67% of births, and increasingly recognised as a major public health burden due to the potential for long-term neurodevelopmental and hearing impairment. This burden includes estimates of 10% of childhood cerebral palsy and up to 25% of childhood deafness. In Sub-Saharan Africa, where CMV-seroprevalence is almost ubiquitous, prevalence of congenital CMV (cCMV) is higher than the global average, and yet there is a dearth of research and initiatives to improve recognition, diagnosis and treatment. This narrative review outlines the epidemiology and clinical presentation of cCMV, discusses issues of case identification and treatment in Sub-Saharan Africa, and recommends a framework of strategies to address these challenges. Considering the significant burden of cCMV disease in this setting, it is undoubtably time we embark upon improving diagnosis and care for these infants.
Topics: Humans; Cytomegalovirus Infections; Africa South of the Sahara; Cytomegalovirus; Infant, Newborn; Prevalence; Female; Pregnancy
PubMed: 38813410
DOI: 10.3389/fpubh.2024.1359663 -
Frontiers in Public Health 2024is one of the porcine pathogens that have recently emerged as a pathogen capable of causing zoonoses in some humans. Patients infected with can present with sepsis,...
INTRODUCTION
is one of the porcine pathogens that have recently emerged as a pathogen capable of causing zoonoses in some humans. Patients infected with can present with sepsis, meningitis, or arthritis. Compared to common pathogens, such as , , and , infections in humans have been reported only rarely.
METHODS
This case report described a 57-year-old man who presented with impaired consciousness and fever following several days of backache. He was a butcher who worked in an abattoir and had wounded his hands 2 weeks prior. The patient was dependent on alcohol for almost 40 years. was detected in the cerebrospinal fluid by metagenomic next-generation sequencing. Although he received adequate meropenem and low-dose steroid therapy, the patient suffered from bilateral sudden deafness after 5 days of the infection. The final diagnosis was meningitis and sepsis.
RESULTS
The patient survived with hearing loss in both ears and dizziness at the 60-day follow-up.
DISCUSSION
We reported a case of infection manifested as purulent meningitis and sepsis. Based on literature published worldwide, human meningitis shows an acute onset and rapid progression in the nervous system. Similar to bacterial meningitis, effective antibiotics, and low-dose steroids play important roles in the treatment of human meningitis.
Topics: Humans; Streptococcus suis; Male; Middle Aged; Streptococcal Infections; China; Meningitis, Bacterial; Anti-Bacterial Agents; Sepsis; Hearing Loss, Sudden
PubMed: 38808002
DOI: 10.3389/fpubh.2024.1369703