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Background: Despite global, regional, and national efforts to address intimate partner violence (IPV), physical IPV persists as a significant challenge in Kenya. This study employs geospatial analysis to examine the spatial distribution and determinants of physical intimate partner violence among women, aiming to inform targeted interventions and policies., Methods: The study used a secondary analysis of a cross-sectional study design based on the 2022 Kenya demographic and health survey. Analyses were conducted using Stata version 17.0 and ArcMap version 10.8. Spatial autocorrelation and hotspot assessment were conducted in the geospatial analysis, while a multilevel logistic regression model was used to examine determinants of physical violence among reproductive-aged women., Results: The study found 28.8% (10,477) of the surveyed women reported experiencing physical intimate partner violence. The spatial analysis identified significant clusters in the southwest and central regions, with women in sub-counties like Chepaluugu, Konion, Sotik, Bumula, and Metayos among others experiencing more violence. Conversely, women in areas in the North East and South East corners such as Kisauni, Tarabaj, Waijir North, Lafey, and Mandera North and South among others showed little or no physical intimate partner violence. Multivariable logistic regression identified age, education, wealth index, partner domineering indicators, and justification of wife beating to be associated with physical intimate partner violence. Higher education and wealth were associated with lower violence odds, while partner domineering indicators and justification of wife beating increased odds., Conclusion: Spatial variations in intimate partner violence risk for women in Kenya underscore the need for targeted government interventions. Focusing on hotspot regions, especially among women with the poorest wealth index, no formal education, and older age, is crucial. Implementing behavior change campaigns addressing violence justification and partner dominance is vital. Active involvement of male partners in programs aiming to eliminate intimate partner violence is essential for comprehensive impact., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Okyere et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally.

Background: Despite the widespread prevalence of adolescent smoking in Gambia, a West African country, there is limited research exploring the relationships between exposure to pro-tobacco and anti-tobacco media messages and events and smoking behaviour among young people. This study investigates the interplay of these exposures and smoking behaviour among 11-17-year-old adolescents in Gambia., Methods: Secondary data analysis was conducted using the 2017 Gambia Global Youth and Tobacco Survey (GYTS), which included a total of 9,127 respondents. Descriptive and inferential analyses, including proportions, Pearson's chi-squared tests, and multivariable logistic regression models, were employed to estimate adjusted odds ratios (aOR) with 95% confidence intervals (CI)., Results: The final model revealed significant associations between exposure to anti-tobacco media messages and events and smoking behaviour. Adolescents exposed to anti-tobacco media messages had a 29% increased odds of smoking (aOR 1.29,CI = 1.08,1.53) compared to those unexposed, while exposure to anti-tobacco media events showed a 31% increased odds (aOR 1.31,CI = 1.09,1.59) compared to those unexposed. Exposure to pro-tobacco messages, such as witnessing tobacco use on TV (aOR 1.41, CI = 1.17,1.69) and owning objects with tobacco brand logos (aOR 1.49,CI = 1.19,1.86), was associated with higher odds of smoking. Covariates, including sex, age, and exposure to smoking behaviour by significant others, also demonstrated associations with smoking behaviour. Notably, male respondents showed significantly higher odds of smoking (aOR = 4.01,CI = 3.28,4.89) compared to females. Respondents aged 15 years and older had increased odds of smoking (aOR = 1.47,CI = 1.22,1.76) compared to those below 15 years old. Those whose fathers smoke displayed higher odds of smoking (aOR = 1.35, CI = 1.04,1.76) compared to individuals with non-smoking parents. Additionally, those whose closest friends smoke showed remarkably higher odds of smoking (aOR = 2.87,CI = 2.37, 3.48) compared to those without such influence., Conclusion: This study underscores the significant impact of exposure to both anti-tobacco and pro-tobacco media messages and events on smoking behaviour among adolescents in Gambia. However, pro-tobacco messages had a greater influence on smoking prevalence than anti-tobacco messages and events. Understanding these associations is crucial for devising effective public health interventions aimed at reducing tobacco use in this population., (© 2024. The Author(s).)

Altered expression of peripheral myelin protein 22 (PMP22) results in demyelinating peripheral neuropathy. PMP22 exhibits a highly restricted tissue distribution with marked expression in the myelinating Schwann cells of peripheral nerves. Auditory and vestibular Schwann cells and the afferent neurons also express PMP22, suggesting a unique role in hearing and balancing. Indeed, neuropathic patients diagnosed with PMP22-linked hereditary neuropathies often present with auditory and balance deficits, an understudied clinical complication. To investigate the mechanism by which abnormal expression of PMP22 may cause auditory and vestibular deficits, we studied gene-targeted PMP22 -null mice. PMP22 -null mice exhibit an unsteady gait, have difficulty maintaining balance, and live for only ∼3-5 weeks relative to unaffected littermates. Histological analysis of the inner ear revealed reduced auditory and vestibular afferent nerve myelination and profound Na + channel redistribution without PMP22. Yet, Na + current density was unaltered, in stark contrast to increased K + current density. Atypical postsynaptic densities and a range of neuronal abnormalities in the organ of Corti were also identified. Analyses of auditory brainstem responses (ABRs) and vestibular sensory-evoked potential (VsEP) revealed that PMP22 -null mice had auditory and vestibular hypofunction. These results demonstrate that PMP22 is required for hearing and balance, and the protein is indispensable for the formation and maintenance of myelin in the peripheral arm of the eighth nerve. Our findings indicate that myelin abnormalities and altered signal propagation in the peripheral arm of the auditory nerve are likely causes of auditory deficits in patients with PMP22-linked neuropathies., (Copyright © 2024 Lee et al.)

The inner ear is the hub where hair cells (HCs) transduce sound, gravity, and head acceleration stimuli to the brain. Hearing and balance rely on mechanosensation, the fastest sensory signals transmitted to the brain. The mechanoelectrical transducer (MET) channel is the entryway for the sound-balance-brain interface, but the channel-complex composition is not entirely known. Here, we report that the mouse utilizes Piezo1 (Pz1) and Piezo2 (Pz2) isoforms as MET-complex components. The Pz channels, expressed in HC stereocilia, and cell lines are co-localized and co-assembled with MET complex partners. Mice expressing non-functional Pz1 and Pz2 at the ROSA26 locus have impaired auditory and vestibular traits that can only be explained if the Pzs are integral to the MET complex. We suggest that Pz subunits constitute part of the MET complex and that interactions with other MET complex components yield functional MET units to generate HC MET currents., (© 2024. The Author(s).)

Background: Anaemia has become a major public health concern among women in Sub-Saharan Africa (SSA). However, little is known about the spatial disparities in anaemia prevalence and their associated factors among pregnant women in the region. This study analysed the spatial disparities in anaemia and their associated factors among pregnant women in rural and urban settings in SSA., Methods: This is a secondary analysis of the most recent demographic and health surveys of 26 countries in SSA. Spatial autocorrelation and hotspot assessment were conducted, while a multivariate logistic regression model was used to identify demographic factors associated with anaemia., Results: Anaemia was reported among ~50% of pregnant women in urban and rural areas of SSA. The hotspot analysis identified the West African sub-region as having a higher concentration of anaemia cases in rural settings. In urban areas, the odds of anaemia were significantly higher among pregnant women in their second trimester (Adjusted OR = 2.39, CI = 1.99, 2.76). On the other hand, pregnant women in their third trimester (Adjusted OR = 1.98, CI = 1.77, 2.22) and those who had taken intestinal parasite drugs (Adjusted OR = 1.12 CI = 1.02, 1.23) had a higher likelihood of having anaemia in rural areas. Pregnant women aged 35-39 years (Adjusted OR = 0.52, CI = 0.33, 0.81) and those aged 40-44 years (Adjusted OR = 0.69, CI = 0.50, 0.95) had a lesser likelihood of having anaemia compared to women aged 15-19 years in urban and rural areas respectively. Compared to Congo DR, Benin (OR = 2.22, CI = 1.51, 3.28) and Mali (OR = 3.71, CI = 2.73, 5.05) had higher odds of anaemia in urban and rural areas respectively., Conclusions: Spatial disparities in anaemia persist among pregnant women in rural and urban settings in SSA. Prevailing spatial variations in anaemia may be addressed by specialised interventions considering the contextual residential settings and socio-economic factors highlighted in this study., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: This study examined the spatial distribution and factors associated with health insurance subscription among women in Ghana., Methods: We analysed a representative sample of 9380 women aged 15-49 y from the 2014 Ghana Demographic and Health Survey. Descriptive and multilevel regression analyses were performed. The study also employed spatial analysis techniques, including spatial autocorrelation, hotspot analysis, cluster and outlier analysis, as well as geographically weighted regression to explore the geographic distribution and predictors of non-subscription to health insurance., Results: The analysis revealed a moderately high prevalence of health insurance subscription among women in Ghana (62.4%). The spatial analyses indicated substantial variations in health insurance subscription across different regions in Ghana. The coastal and middle zones reported higher rates of non-subscription compared with the northern zone. We observed that young women (aged 20-24 y) had a lower likelihood of subscribing compared with adolescent girls (aged 15-19 y). Also, higher educational attainment, listening to the radio, being in a marital union and higher wealth status were positively associated with health insurance subscription., Conclusions: The study calls for targeted interventions and policies to promote equitable access to healthcare services, focusing on improving health infrastructure in coastal and middle zones, educational campaigns for individuals with lower education levels, leveraging media platforms for health insurance awareness and implementing equitable and affordable processes for individuals in poorer households., (© The Author(s) 2023. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

The development of the central auditory system, including the auditory cortex and other areas involved in processing sound, is shaped by genetic and environmental factors, enabling infants to learn how to speak. Before explaining hearing in humans, a short overview of auditory dysfunction is provided. Environmental factors such as exposure to sound and language can impact the development and function of the auditory system sound processing, including discerning in speech perception, singing, and language processing. Infants can hear before birth, and sound exposure sculpts their developing auditory system structure and functions. Exposing infants to singing and speaking can support their auditory and language development. In aging humans, the hippocampus and auditory nuclear centers are affected by neurodegenerative diseases such as Alzheimer's, resulting in memory and auditory processing difficulties. As the disease progresses, overt auditory nuclear center damage occurs, leading to problems in processing auditory information. In conclusion, combined memory and auditory processing difficulties significantly impact people's ability to communicate and engage with their societal essence.

Background: Evidence shows that intimate partner violence (IPV) occurs more frequently in sub-Saharan Africa (SSA) than in other regions of the world. However, limited empirical studies exist on the help-seeking behaviour of women who had experienced IPV in SSA. This study aimed to examine the help-seeking behaviour of women who had experienced IPV in SSA and the factors associated with their inability to seek help after experiencing IPV., Methods: This is a quantitative study based on data from the latest demographic and health surveys (DHS) of 24 SSA countries. A sample of 53,446 women aged 15-49 years was included in the study. Associations between women's background characteristics and their help-seeking behaviour after experiencing IPV were examined using proportions and multivariate logistic regression models., Results: Overall, 60.7% of the sample did not seek help after experiencing IPV. Women's inability to seek help for IPV was highest in Mali (80.4%) and lowest in Tanzania (43.1%). Women's level of education, wealth status, marital status, age, occupation, and country of residence had significant associations with 'not seeking help' for any type of IPV. Those who experienced generational violence (AOR = 1.26, CI = 1.19, 1.33) and those who justified wife-beating (AOR = 1.09, CI = 1.07, 1.15) had higher odds of not seeking help for any type of IPV compared to those who did not experience generational violence or did not justify wife beating. Women who experienced emotional violence (AOR = 0.53, CI = 0.51, 0.55) and physical violence (AOR = 0.74, CI = 0.70, 0.76) had lower odds of not seeking help for any type of IPV compared to their counterparts who did not experience these types of violence., Conclusion: Women's inability to seek help for IPV is common in many SSA countries. This study shows that several socio-demographic factors, such as women's age, educational levels, wealth status, and marital status are associated with their inability to seek help for IPV. Additionally, women's justification of wife beating and experience of generational abuse are strongly associated with their inability to seek help for IPV. These factors need to be considered critically in IPV interventions in SSA., (© 2023. The Author(s).)

Introduction: Evidence shows that most women in Ghana do not meet the minimum 8-contact model for antenatal care as recommended by WHO with only 31.2%-41.9% of them meeting the recommendation. To the best of our knowledge, no study in Ghana has examined women's noncompliance with the WHO's recommended 8-contact model for antenatal care using geospatial analysis, as this study sets out to do., Methods: We sourced data from the recent version of the Ghana Maternal Health Survey which was executed in 2017. A sample of 10,077 women with complete data participated in this study. The link between the explanatory variables and the outcome variable was investigated using binary and multivariate logistic regression models and Spatial analyses such as spatial autocorrelation (Moran's I), hotspot, cluster and outlier analysis, and geographically weighted regression were conducted using ArcMap version 10.7., Results: Districts found in the north-eastern and south-western parts of the country were more likely to experience noncompliance with ANC. Women staying within the middle belt without health insurance were more likely (17-29%) to be noncompliant with ANC. Women with low community socioeconomic status were found to be more likely (17-34%) to be noncompliant with ANC in the eastern parts of Ghana., Conclusion: The study has shown that in order to achieve targets one and three of Sustainable Development Goal 3, the government of Ghana, the Ministry of Health, together with the Ghana Health Service may have to intensify health education in the identified areas to highlight the importance of adherence to the WHO recommendations on ANC 8-contact model., (© 2023. The Author(s).)

Background: Several studies have shown that unskilled birth attendance is associated with maternal and neonatal morbidity, disability, and death in sub-Saharan Africa (SSA). However, little evidence exists on prevailing geospatial variations and the factors underscoring the patterns of unskilled birth attendance in the region. This study analysed the geospatial disparities and factors associated with unskilled birth attendance in SSA., Methods: The study is based on data from thirty (30) SSA countries captured in the latest (2010-2019) demographic and health surveys (DHS). A total of 200,736 women aged between 15-49 years were included in the study. Geospatial methods including spatial autocorrelation and hot spot analysis as well as logistic regression models were used to analyse the data., Results: There were random spatial variations in unskilled birth attendance in SSA, with the main hotspot located in Chad, whereas South Africa and the Democratic Republic of Congo showed coldspots. Residence (urban or rural), wealth status, education, maternal age at the time of the survey and age at birth, desire for birth, occupation, media exposure, distance to a health facility, antenatal care visits, and deaths of under-five children showed significant associations with unskilled birth attendance., Conclusion: Random geospatial disparities in unskilled birth attendance exist in SSA, coupled with various associated socio-demographic determinants. Specific geospatial hotspots of unskilled birth attendance in SSA can be targeted for specialised interventions to alleviate the prevailing disparities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Addo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cervical cancer significantly affects women in Sub-Saharan Africa (SSA). However, limited studies have concentrated on cervical screening behaviour among women in SSA. This study aimed to assess the interplay of distance to health facilities and socio-demographic factors with cervical screening behaviour among women in five SSA countries., Methods: The study was based on pooled data of 40,555 women included in Demographic and Health Surveys (DHS) conducted between 2013 to 2021. Proportions and logistic regression models were used in assessing the interplay of distance to health facilities and socio-demographic factors with cervical screening behaviour., Results: Approximately, 7.9% of women that saw the distance to a health facility as a big problem, tested for cervical cancer compared to 13.5% who indicated that distance to a health facility is not a big problem. More women in urban areas, with a higher level of education, of richest wealth index, aged 40-44 years and using contraceptives who also indicated that distance to a health facility was a big problem tested for cervical cancer compared to those in rural areas with no education, of poorest wealth index, aged 15-19 years and not using contraceptives. Education, age, contraceptive use, frequent exposure to mass media and Sexual Transmitted Infections (STI) had a significant relationship with testing for cervical cancer., Conclusion: The prevalence of cervical cancer screening was low in the five SSA countries largely due to distance barriers and was also significantly influenced by education, age, contraceptive use, frequent exposure to mass media, and STI status. To improve the screening for cervical cancer and its associated benefits in the five SSA countries, there is a need for policymakers, clinicians and public health workers to channel more commitment and efforts to addressing the barriers identified in this study., (© 2023. The Author(s).)

Sinoatrial node (SAN) cells are the heart's primary pacemaker. Their activity is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR pathway that catalyzes the production of cAMP. There are current gaps in our knowledge regarding the dominant AC isoforms and the specific roles of Ca2+-activated ACs in the SAN. The current study tests the hypothesis that distinct AC isoforms are preferentially expressed in the SAN and compartmentalize within microdomains to orchestrate heart rate regulation during β-AR signaling. In contrast to atrial and ventricular myocytes, SAN cells express a diverse repertoire of ACs, with ACI as the predominant Ca2+-activated isoform. Although ACI-KO (ACI-/-) mice exhibit normal cardiac systolic or diastolic function, they experience SAN dysfunction. Similarly, SAN-specific CRISPR/Cas9-mediated gene silencing of ACI results in sinus node dysfunction. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) channels form functional microdomains almost exclusively with ACI, while ryanodine receptor and L-type Ca2+ channels likely compartmentalize with ACI and other AC isoforms. In contrast, there were no significant differences in T-type Ca2+ and Na+ currents at baseline or after β-AR stimulation between WT and ACI-/- SAN cells. Due to its central characteristic feature as a Ca2+-activated isoform, ACI plays a unique role in sustaining the rise of local cAMP and heart rates during β-AR stimulation. The findings provide insights into the critical roles of the Ca2+-activated isoform of AC in sustaining SAN automaticity that is distinct from contractile cardiomyocytes.

Somatosensory, taste, vestibular, and auditory information is first processed in the brainstem. From the brainstem, the respective information is relayed to specific regions within the cortex, where these inputs are further processed and integrated with other sensory systems to provide a comprehensive sensory experience. We provide the organization, genetics, and various neuronal connections of four sensory systems: trigeminal, taste, vestibular, and auditory systems. The development of trigeminal fibers is comparable to many sensory systems, for they project mostly contralaterally from the brainstem or spinal cord to the telencephalon. Taste bud information is primarily projected ipsilaterally through the thalamus to reach the insula. The vestibular fibers develop bilateral connections that eventually reach multiple areas of the cortex to provide a complex map. The auditory fibers project in a tonotopic contour to the auditory cortex. The spatial and tonotopic organization of trigeminal and auditory neuron projections are distinct from the taste and vestibular systems. The individual sensory projections within the cortex provide multi-sensory integration in the telencephalon that depends on context-dependent tertiary connections to integrate other cortical sensory systems across the four modalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fritzsch, Elliott and Yamoah.)

Repressor element 1-silencing transcription factor (REST) is a transcriptional repressor that recognizes neuron-restrictive silencer elements in the mammalian genomes in a tissue- and cell-specific manner. The identity of REST target genes and molecular details of how REST regulates them are emerging. We performed conditional null deletion of Rest (cKO), mainly restricted to murine hair cells (HCs) and auditory neurons (aka spiral ganglion neurons [SGNs]). Null inactivation of full-length REST did not affect the development of normal HCs and SGNs but manifested as progressive hearing loss in adult mice. We found that the inactivation of REST resulted in an increased abundance of K v 7.4 channels at the transcript, protein, and functional levels. Specifically, we found that SGNs and HCs from Rest cKO mice displayed increased K v 7.4 expression and augmented K v 7 currents; SGN's excitability was also significantly reduced. Administration of a compound with K v 7.4 channel activator activity, fasudil, recapitulated progressive hearing loss in mice. In contrast, inhibition of the K v 7 channels by XE991 rescued the auditory phenotype of Rest cKO mice. Previous studies identified some loss-of-function mutations within the K v 7.4-coding gene, Kcnq4 , as a causative factor for progressive hearing loss in mice and humans. Thus, the findings reveal that a critical homeostatic K v 7.4 channel level is required for proper auditory functions., Competing Interests: HZ, HL, ML, SW, XM, FW, JL, XL, HY, FZ, HS, NB, NG, EY, PL No competing interests declared, (© 2022, Zhang et al.)

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1 Cre strategies. In the absence of Isl1 , spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca 2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria-SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria-SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload-induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9-mediated knockdown of mitofusin-2 ( Mfn2 ), the mitochondria-SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria-SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific Mfn2 knockdown led to alterations in the mitochondria-SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria-SR microdomains resulted in abnormal mitochondrial Ca 2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria-SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.

Background: Unskilled birth attendance is a major public health concern in Sub-Saharan Africa (SSA). Existing studies are hardly focused on the socio-demographic correlates and geospatial distribution of unskilled birth attendance in Chad (a country in SSA), although the country has consistently been identified as having one of the highest prevalence of maternal and neonatal deaths in the world. This study aimed to analyse the socio-demographic correlates and geospatial distribution of unskilled birth attendance in Chad., Methods: The study is based on the latest Demographic and Health Survey (DHS) data for Chad. A total of 10,745 women aged between 15 and 49 years were included in this study. A multilevel analysis based on logistic regression was conducted to estimate associations of respondents' socio-demographic characteristics with unskilled birth attendance. Geographic Information System (GIS) mapping tools, including Getis-Ord Gi hotspot analysis tool and geographically weighted regression (GWR) tool, were used to explore areas in Chad with a high prevalence of unskilled birth attendance., Results: The findings show that unskilled birth attendance was spatially clustered in four Chad departments: Mourtcha, Dar-Tama, Assoungha, and Kimiti, with educational level, occupation, birth desire, birth order, antenatal care, and community literacy identified as the spatial predictors of unskilled birth attendance. Higher educational attainment, higher wealth status, cohabitation, lowest birth order, access to media, not desiring more births, and higher antenatal care visits were associated with lower odds of unskilled birth attendance at the individual level. On the other hand, low community literacy level was associated with higher odds of unskilled birth attendance in Chad whereas the opposite was true for urban residency., Conclusions: Unskilled birth attendance is spatially clustered in some parts of Chad, and it is associated with various disadvantaged individual and community level factors. When developing interventions for unskilled birth attendance in Chad, concerned international bodies, the Chad government, maternal health advocates, and private stakeholders should consider targeting the high-risk local areas identified in this study., (© 2022. The Author(s).)

Among the features of cisplatin chemotherapy-induced peripheral neuropathy are chronic pain and innocuous mechanical hypersensitivity. The complete etiology of the latter remains unknown. Here, we show that cisplatin targets a heterogeneous population of tyrosine hydroxylase-positive (TH + ) primary afferent dorsal root ganglion neurons (DRGNs) in mice, determined using single-cell transcriptome and electrophysiological analyses. TH + DRGNs regulate innocuous mechanical sensation through C-low threshold mechanoreceptors. A differential assessment of wild-type and vitamin E deficient TH + DRGNs revealed heterogeneity and specific functional phenotypes. The TH + DRGNs comprise; fast-adapting eliciting one action potential (AP; 1-AP), moderately-adapting (≥2-APs), in responses to square-pulse current injection, and spontaneously active (SA). Cisplatin increased the input resistance and AP frequency but reduced the temporal coding feature of 1-AP and ≥2-APs neurons. By contrast, cisplatin has no measurable effect on the SA neurons. Vitamin E reduced the cisplatin-mediated increased excitability but did not improve the TH + neuron temporal coding properties. Cisplatin mediates its effect by targeting outward K + current, likely carried through K2P18.1 (Kcnk18 ), discovered through the differential transcriptome studies and heterologous expression. Studies show a potential new cellular target for chemotherapy-induced peripheral neuropathy and implicate the possible neuroprotective effects of vitamin E in cisplatin chemotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Finno, Chen, Park, Lee, Perez-Flores, Choi and Yamoah.)

Intracellular pH (pH i ) plays critical roles in the regulation of cardiac function. Methods and techniques for cardiac pH i measurement have continued to evolve since early 1960s. Fluorescent microscopy is the most recently developed technique with several advantages over other techniques including higher spatial and temporal resolutions, and feasibility for contracting cell measurement. Here, we describe detailed methods for mouse cardiomyocyte isolation, and simultaneous measurement and quantification of pH i and sarcomere length in contracting cardiomyocytes. For complete details on the use and execution of this protocol, please refer to Lyu et al. (2022)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Mechanosensation - by which mechanical stimuli are converted into a neuronal signal - is the basis for the sensory systems of hearing, balance, and touch. Mechanosensation is unmatched in speed and its diverse range of sensitivities, reaching its highest temporal limits with the sense of hearing; however, hair cells (HCs) and the auditory nerve (AN) serve as obligatory bottlenecks for sounds to engage the brain. Like other sensory neurons, auditory neurons use the canonical pathway for neurotransmission and millisecond-duration action potentials (APs). How the auditory system utilizes the relatively slow transmission mechanisms to achieve ultrafast speed, and high audio-frequency hearing remains an enigma. Here, we address this paradox and report that the mouse, and chinchilla, AN are mechanically sensitive, and minute mechanical displacement profoundly affects its response properties. Sound-mimicking sinusoidal mechanical and electrical current stimuli affect phase-locked responses. In a phase-dependent manner, the two stimuli can also evoke suppressive responses. We propose that mechanical sensitivity interacts with synaptic responses to shape responses in the AN, including frequency tuning and temporal phase locking. Combining neurotransmission and mechanical sensation to control spike patterns gives the mammalian AN a secondary receptor role, an emerging theme in primary neuronal functions., Competing Interests: MP, EV, JL, HK, PJ, EY No competing interests declared, (© 2022, Perez-Flores et al.)

Age-related hearing loss (ARHL) is a common, increasing problem for older adults, affecting about 1 billion people by 2050. We aim to correlate the different reductions of hearing from cochlear hair cells (HCs), spiral ganglion neurons (SGNs), cochlear nuclei (CN), and superior olivary complex (SOC) with the analysis of various reasons for each one on the sensory deficit profiles. Outer HCs show a progressive loss in a basal-to-apical gradient, and inner HCs show a loss in a apex-to-base progression that results in ARHL at high frequencies after 70 years of age. In early neonates, SGNs innervation of cochlear HCs is maintained. Loss of SGNs results in a considerable decrease (~50% or more) of cochlear nuclei in neonates, though the loss is milder in older mice and humans. The dorsal cochlear nuclei (fusiform neurons) project directly to the inferior colliculi while most anterior cochlear nuclei reach the SOC. Reducing the number of neurons in the medial nucleus of the trapezoid body (MNTB) affects the interactions with the lateral superior olive to fine-tune ipsi- and contralateral projections that may remain normal in mice, possibly humans. The inferior colliculi receive direct cochlear fibers and second-order fibers from the superior olivary complex. Loss of the second-order fibers leads to hearing loss in mice and humans. Although ARHL may arise from many complex causes, HC degeneration remains the more significant problem of hearing restoration that would replace the cochlear implant. The review presents recent findings of older humans and mice with hearing loss., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elliott, Fritzsch, Yamoah and Zine.)

Neuronal development in the inner ear is initiated by expression of the proneural basic Helix-Loop-Helix (bHLH) transcription factor Neurogenin1 that specifies neuronal precursors in the otocyst. The initial specification of the neuroblasts within the otic epithelium is followed by the expression of an additional bHLH factor, Neurod1. Although NEUROD1 is essential for inner ear neuronal development, the different aspects of the temporal and spatial requirements of NEUROD1 for the inner ear and, mainly, for auditory neuron development are not fully understood. In this study, using Foxg1 Cre for the early elimination of Neurod1 in the mouse otocyst, we showed that Neurod1 deletion results in a massive reduction of differentiating neurons in the otic ganglion at E10.5, and in the diminished vestibular and rudimental spiral ganglia at E13.5. Attenuated neuronal development was associated with reduced and disorganized sensory epithelia, formation of ectopic hair cells, and the shortened cochlea in the inner ear. Central projections of inner ear neurons with conditional Neurod1 deletion are reduced, unsegregated, disorganized, and interconnecting the vestibular and auditory systems. In line with decreased afferent input from auditory neurons, the volume of cochlear nuclei was reduced by 60% in Neurod1 mutant mice. Finally, our data demonstrate that early elimination of Neurod1 affects the neuronal lineage potential and alters the generation of inner ear neurons and cochlear afferents with a profound effect on the first auditory nuclei, the cochlear nuclei., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Filova, Bohuslavova, Tavakoli, Yamoah, Fritzsch and Pavlinkova.)

Background: Long QT syndrome (LQTS) is a hereditary disease that predisposes patients to life-threatening cardiac arrhythmias and sudden cardiac death. Our previous study of the human ether-à-go-go related gene (hERG)-encoded K + channel (K v 11.1) supports an association between hERG and RING finger protein 207 (RNF207) variants in aggravating the onset and severity of LQTS, specifically T613M hERG (hERG T613M ) and RNF207 frameshift (RNF207 G603fs ) mutations. However, the underlying mechanistic underpinning remains unknown., Objective: The purpose of the present study was to test the role of RNF207 in the function of hERG-encoded K + channel subunits., Methods: Whole-cell patch-clamp experiments were performed in human embryonic kidney (HEK 293) cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) together with immunofluorescent confocal and high resolution microscopy, auto-ubiquitinylation assays, and co-immunoprecipitation experiments to test the functional interactions between hERG and RNF207., Results: Here, we demonstrated that RNF207 serves as an E3 ubiquitin ligase and targets misfolded hERG T613M proteins for degradation. RNF207 G603fs exhibits decreased activity and hinders the normal degradation pathway; this increases the levels of hERG T613M subunits and their dominant-negative effect on the wild-type subunits, ultimately resulting in decreased current density. Similar findings are shown for hERG A614V , a known dominant-negative mutant subunit. Finally, the presence of RNF207 G603fs with hERG T613M results in significantly prolonged action potential durations and reduced hERG current in human-induced pluripotent stem cell-derived cardiomyocytes., Conclusion: Our study establishes RNF207 as an interacting protein serving as a ubiquitin ligase for hERG-encoded K + channel subunits. Normal function of RNF207 is critical for the quality control of hERG subunits and consequently cardiac repolarization. Moreover, our study provides evidence for protein quality control as a new paradigm in life-threatening cardiac arrhythmias in patients with LQTS., (Published by Elsevier Inc.)

The vestibular system is vital for proper balance perception, and its dysfunction contributes significantly to fall-related injuries, especially in the elderly. Vestibular ganglion neurons innervate vestibular hair cells at the periphery and vestibular nuclei and the uvula and nodule of the cerebellum centrally. During aging, these vestibular ganglion neurons degenerate, impairing vestibular function. A complete understanding of the molecular mechanisms involved in neurosensory cell survival in the vestibular system is unknown. Brain-derived neurotrophic factor (BDNF) is specifically required for the survival of vestibular ganglion neurons, as its loss leads to early neuronal death. Bdnf null mice die within 3 weeks of birth, preventing the study of the long-term effects on target cells. We use Pax2 -cre to conditionally knock out Bdnf , allowing mice survival to approximately 6 months of age. We show that a long-term loss of Bdnf leads to a significant reduction in the number of vestibular ganglion neurons and a reduction in the number of vestibular hair cells. There was no significant decrease in the central targets lateral vestibular nucleus (LVN) or the cerebellum at 6 months. This suggests that the connectivity between central target cells and other neurons suffices to prevent their loss despite vestibular hair cell and ganglion neuron loss. Whether the central neurons would undergo eventual degeneration in the absence of Bdnf remains to be determined., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Elliott, Kersigo, Lee, Yamoah and Fritzsch.)

The mammalian heart beats incessantly with rhythmic mechanical activities generating acids that need to be buffered to maintain a stable intracellular pH (pH i ) for normal cardiac function. Even though spatial pH i non-uniformity in cardiomyocytes has been documented, it remains unknown how pH i is regulated to match the dynamic cardiac contractions. Here, we demonstrated beat-to-beat intracellular acidification, termed pH i transients, in synchrony with cardiomyocyte contractions. The pH i transients are regulated by pacing rate, Cl - /HCO 3 - transporters, pH i buffering capacity, and β-adrenergic signaling. Mitochondrial electron-transport chain inhibition attenuates the pH i transients, implicating mitochondrial activity in sculpting the pH i regulation. The pH i transients provide dynamic alterations of H + transport required for ATP synthesis, and a decrease in pH i may serve as a negative feedback to cardiac contractions. Current findings dovetail with the prevailing three known dynamic systems, namely electrical, Ca 2+ , and mechanical systems, and may reveal broader features of pH i handling in excitable cells., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Prestin (Slc26a5) is a motor protein previously considered to be expressed exclusively in outer hair cells (OHCs) of the inner ear. However, we recently identified the functional expression of prestin in the heart. Nonlinear capacitance (NLC) measurement in OHCs is used to evaluate the signature function of prestin, which exhibits membrane potential-dependent conformational changes. Here, we describe detailed recording techniques and quantification methods for NLC to evaluate the prestin function in mouse ventricular myocytes. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Ca v 3 channels play a critical role in maintaining calcium homeostasis, and its dysregulation is related to age-related diseases, such as age-related hearing loss (AHL). However, the underlying mechanism of the Ca v 3 channels involved in AHL remains unknown. Previous studies have shown that the degeneration of spiral ganglion neurons (SGNs) plays a critical role in AHL. Here, we explored the involvement of Ca v 3 channels in the dysregulation of SGNs in AHL. We used C57BL/6 mice as the AHL mouse model and found that the expression of Ca v 3 channels was increased in SGNs associated with age. The three subtypes of Ca v 3 channels were present in the apical, middle, and basal SGNs from young and older (AHL) mice. The immunostaining data suggest that Ca v 3.1 and Ca v 3.2 may contribute to Ca v 3 upregulation in SGNs of AHL mice. Additionally, we found that calpain-2 and apoptosis-inducing factor (AIF) were activated in SGNs from AHL mice. The inhibition of Ca v 3 channels or calpain-2 reduced AIF-activation in SGNs may affect neuronal survival. In conclusion, the findings suggest that Ca v 3 channels are upregulated in SGNs from AHL mice that may contribute to the degeneration of SGNs through the calpain-2-AIF apoptosis pathway in AHL mice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Globally, about 810 women die every day due to pregnancy and its related complications. Although the death of women during pregnancy or childbirth has declined from 342 deaths to 211 deaths per 100,000 live births between 2000 and 2017, maternal mortality is still higher, particularly in sub-Saharan Africa and South Asia, where 86% of all deaths occur., Methods: A secondary analysis was carried out using the 2014 Ghana Demographic and Health Survey. A sample total of 4,290 women who had a live birth in the 5 years preceding the survey was included in the analysis. GIS software was used to explore the spatial distribution of unskilled birth attendance in Ghana. The Geographic Weighted Regression (GWR) was employed to model the spatial relationship of some predictor of unskilled birth attendance. Moreover, a multilevel binary logistic regression model was fitted to identify factors associated with unskilled birth attendance., Results: In this study, unskilled birth attendance had spatial variations across the country. The hotspot, cluster and outlier analysis identified the concerned districts in the north-eastern part of Ghana. The GWR analysis identified different predictors of unskilled birth attendance across districts of Ghana. In the multilevel analysis, mothers with no education, no health insurance coverage, and mothers from households with lower wealth status had higher odds of unskilled birth attendance. Being multi and grand multiparous, perception of distance from the health facility as not a big problem, urban residence, women residing in communities with medium and higher poverty level had lower odds of unskilled birth attendance., Conclusion: Unskilled birth attendance had spatial variations across the country. Areas with high levels of unskilled birth attendance had mothers who had no formal education, not health insured, mothers from poor households and communities, primiparous women, mothers from remote and border districts could get special attention in terms of allocation of resources including skilled human power, and improved access to health facilities., Competing Interests: The authors have declared that no competing interest exist.

The two types of spiral ganglion neurons (SGNs), types I and II, innervate inner hair cells and outer hair cells, respectively, within the mammalian cochlea and send another process back to cochlear nuclei in the hindbrain. Studying these two neuronal types has been made easier with the identification of unique molecular markers. One of these markers, peripherin, was shown using antibodies to be present in all SGNs initially but becomes specific to type II SGNs during maturation. We used mice with fluorescently labeled peripherin ( Prph- eGFP) to examine peripherin expression in SGNs during development and in aged mice. Using these mice, we confirm the initial expression of Prph- eGFP in both types I and II neurons and eventual restriction to only type II perikarya shortly after birth. However, while Prph- eGFP is uniquely expressed within type II cell bodies by P8, both types I and II peripheral and central processes continue to express Prph- eGFP for some time before becoming downregulated. Only at P30 was there selective type II Prph- eGFP expression in central but not peripheral processes. By 9 months, only the type II cell bodies and more distal central processes retain Prph- eGFP expression. Our results show that Prph- eGFP is a reliable marker for type II SGN cell bodies beyond P8; however, it is not generally a suitable marker for type II processes, except for central processes beyond P30. How the changes in Prph- eGFP expression relate to subsequent protein expression remains to be explored., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Elliott, Kersigo, Lee, Jahan, Pavlinkova, Fritzsch and Yamoah.)

We review the molecular basis of three related basic helix-loop-helix (bHLH) genes ( Neurog1 , Neurod1 , and Atoh1 ) and upstream regulators Eya1/Six1 , Sox2 , Pax2 , Gata3 , Fgfr2b , Foxg1 , and Lmx1a/b during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires early expression of Neurog1 , followed by its downstream target Neurod1 , which downregulates Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 and Neurog1 expression for various aspects of development. Several experiments show a partial uncoupling of Atoh1/Neurod1 (spiral ganglia and cochlea) and Atoh1/Neurog1/Neurod1 (cochlear nuclei). In this review, we integrate the cellular and molecular mechanisms that regulate the development of auditory system and provide novel insights into the restoration of hearing loss, beyond the limited generation of lost sensory neurons and hair cells., Competing Interests: The authors declare that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2021 Fritzsch B et al.)

Cardiac cells generate and amplify force in the context of cardiac load, yet the membranous sheath enclosing the muscle fibers-the sarcolemma-does not experience displacement. That the sarcolemma sustains beat-to-beat pressure changes without experiencing significant distortion is a muscle-contraction paradox. Here, we report that an elastic element-the motor protein prestin (Slc26a5)-serves to amplify actin-myosin force generation in mouse and human cardiac myocytes, accounting partly for the nonlinear capacitance of cardiomyocytes. The functional significance of prestin is underpinned by significant alterations of cardiac contractility in Prestin-knockout mice. Prestin was previously considered exclusive to the inner ear's outer hair cells; however, our results show that prestin serves a broader cellular motor function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

We review the molecular basis of several transcription factors ( Eya1 , Sox2 ), including the three related genes coding basic helix-loop-helix (bHLH; see abbreviations) proteins ( Neurog1 , Neurod1 , Atoh1 ) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1 , to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1 . Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons' fate into "hair cells", highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1 , Atoh1 is upregulated, resulting in the formation of "intraganglionic" HCs. Additional genes, such as Eya1/Six1 , Sox2, Pax2, Gata3, Fgfr2b, Foxg1 , and Lmx1a/b , play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

Populations in peri-urban communities of Sub-Saharan Africa frequently depend on shallow aquifers and on-site sanitation facilities concurrently. Routinely, domestic wells end up too close to toilet facilities, risking groundwater contamination. For coastal communities, saltwater intrusion adds to the risk of groundwater contamination. This study assessed both risks in five peri-urban communities of Cape Coast, Ghana. Groundwater samples collected from 40 domestic wells were analyzed for physicochemical and microbial constituents. Multivariate statistics including hierarchical cluster analysis (HCA) and principal component analysis (PCA) were used to classify and link contaminants to potential sources. Results indicate high enteric bacteria contamination in 98% of the samples, as well as high enrichment in physicochemical constituents, tied largely to impacts of on-site sanitation facilities. We found that wells located within 25 m of septic tanks/toilet facilities contained higher contaminant loads than those without such facilities within 25 m of their locations. Similarly, for wells located close to point sources, the closer the water table is below the land surface (within 2 m), the higher the contaminant loads. Lastly, using molar ratios of Cl - /HCO 3 - and Na + /Cl - with R-mode HCA, the study isolated a few wells, located within 2 km of the coastline, that are experiencing effects of saltwater intrusion. Overall, this study provides useful information for aiding groundwater quality mitigation policy, and the baseline data for aiding future investigations in the study area. It also has broader policy implications for other peri-urban settings throughout Ghana and the entire Sub-Saharan Africa.

Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin's ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.

Calmodulin (CaM) plays a critical role in intracellular signaling and regulation of Ca2+-dependent proteins and ion channels. Mutations in CaM cause life-threatening cardiac arrhythmias. Among the known CaM targets, small-conductance Ca2+-activated K+ (SK) channels are unique, since they are gated solely by beat-to-beat changes in intracellular Ca2+. However, the molecular mechanisms of how CaM mutations may affect the function of SK channels remain incompletely understood. To address the structural and functional effects of these mutations, we introduced prototypical human CaM mutations in human induced pluripotent stem cell-derived cardiomyocyte-like cells (hiPSC-CMs). Using structural modeling and molecular dynamics simulation, we demonstrate that human calmodulinopathy-associated CaM mutations disrupt cardiac SK channel function via distinct mechanisms. CaMD96V and CaMD130G mutants reduce SK currents through a dominant-negative fashion. By contrast, specific mutations replacing phenylalanine with leucine result in conformational changes that affect helix packing in the C-lobe, which disengage the interactions between apo-CaM and the CaM-binding domain of SK channels. Distinct mutant CaMs may result in a significant reduction in the activation of the SK channels, leading to a decrease in the key Ca2+-dependent repolarization currents these channels mediate. The findings in this study may be generalizable to other interactions of mutant CaMs with Ca2+-dependent proteins within cardiac myocytes., (© 2020 Ledford et al.)

Stem cell replacement offers a great potential for cardiac regenerative therapy. However, one of the critical barriers to stem cell therapy is a significant loss of transplanted stem cells from ischemia and inflammation in the host environment. Here, we tested the hypothesis that inhibition of the soluble epoxide hydrolase (sEH) enzyme using sEH inhibitors (sEHIs) to decrease inflammation and fibrosis in the host myocardium may increase the survival of the transplanted human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) in a murine postmyocardial infarction model. A specific sEHI (1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea [TPPU]) and CRISPR/Cas9 gene editing were used to test the hypothesis. TPPU results in a significant increase in the retention of transplanted cells compared with cell treatment alone. The increase in the retention of hiPSC-CMs translates into an improvement in the fractional shortening and a decrease in adverse remodeling. Mechanistically, we demonstrate a significant decrease in oxidative stress and apoptosis not only in transplanted hiPSC-CMs but also in the host environment. CRISPR/Cas9-mediated gene silencing of the sEH enzyme reduces cleaved caspase-3 in hiPSC-CMs challenged with angiotensin II, suggesting that knockdown of the sEH enzyme protects the hiPSC-CMs from undergoing apoptosis. Our findings demonstrate that suppression of inflammation and fibrosis using an sEHI represents a promising adjuvant to cardiac stem cell-based therapy. Very little is known regarding the role of this class of compounds in stem cell-based therapy. There is consequently an enormous opportunity to uncover a potentially powerful class of compounds, which may be used effectively in the clinical setting., (© 2020 The Authors. STEM CELLS Translational Medicine published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, ER, and plasma membrane promote regulation of multiple functions, which include intracellular Ca 2+ flux, and cellular biogenesis. Although the purposes of apposing mitochondria and ER have been described, an understanding of altered organelle connectomics related to disease states is emerging. Since inner ear outer hair cell (OHC) degeneration is a common trait of age-related hearing loss, the objective of this study was to investigate whether the structural and functional coupling of mitochondria with subsurface cisternae (SSC) was affected by aging. We applied functional and structural probes to equal numbers of male and female mice with a hearing phenotype akin to human aging. We discovered the polarization of cristae and crista junctions in mitochondria tethered to the SSC in OHCs. Aging was associated with SSC stress and decoupling of mitochondria with the SSC, mitochondrial fission/fusion imbalance, a remarkable reduction in mitochondrial and cytoplasmic Ca 2+ levels, reduced K + -induced Ca 2+ uptake, and marked plasticity of cristae membranes. A model of structure-based ATP production predicts profound energy stress in older OHCs. This report provides data suggesting that altered membrane organelle connectomics may result in progressive hearing loss., Competing Interests: The authors declare no competing financial interests., (Copyright © 2020 the authors.)

Age-related hearing loss (ARHL) is the most prevalent sensory deficit. ARHL reduces the quality of life of the growing population, setting seniors up for the enhanced mental decline. The size of the needy population, the structural deficit, and a likely research strategy for effective treatment of chronic neurosensory hearing in the elderly are needed. Although there has been profound advancement in auditory regenerative research, there remain multiple challenges to restore hearing loss. Thus, additional investigations are required, using novel tools. We propose how the (1) flat epithelium, remaining after the organ of Corti has deteriorated, can be converted to the repaired-sensory epithelium, using Sox2. This will include (2) developing an artificial gene regulatory network transmitted by (3) large viral vectors to the flat epithelium to stimulate remnants of the organ of Corti to restore hair cells. We hope to unite with our proposal toward the common goal, eventually restoring a functional human hearing organ by transforming the flat epithelial cells left after the organ of Corti loss., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The mammalian cochlea relies on active electromotility of outer hair cells (OHCs) to resolve sound frequencies. OHCs use ionic channels and somatic electromotility to achieve the process. It is unclear, though, how the kinetics of voltage-gated ionic channels operate to overcome extrinsic viscous drag on OHCs at high frequency. Here, we report ultrafast electromechanical gating of clustered K v 7.4 in OHCs. Increases in kinetics and sensitivity resulting from cooperativity among clustered-K v 7.4 were revealed, using optogenetics strategies. Upon clustering, the half-activation voltage shifted negative, and the speed of activation increased relative to solitary channels. Clustering also rendered K v 7.4 channels mechanically sensitive, confirmed in consolidated K v 7.4 channels at the base of OHCs. K v 7.4 clusters provide OHCs with ultrafast electromechanical channel gating, varying in magnitude and speed along the cochlea axis. Ultrafast K v 7.4 gating provides OHCs with a feedback mechanism that enables the cochlea to overcome viscous drag and resolve sounds at auditory frequencies., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na + -activated K + (K Na ) mRNA and channel proteins are distinctly and locally expressed in dendritic projections of primary ANs and genetic deletion of K Na channels ( Kcnt1 and Kcnt2 ) results in the loss of proper AN synaptic function, characterized as HHL, without structural synaptic alterations. We further demonstrate that the local functional synaptic alterations transition from HHL to increased hearing-threshold, which entails changes in global Ca 2+ homeostasis, activation of caspases 3/9, impaired regulation of inositol triphosphate receptor 1 (IP 3 R1), and apoptosis-mediated neurodegeneration. Thus, the present study demonstrates how local synaptic dysfunction results in an apparent latent pathological phenotype (HHL) and, if undetected, can lead to overt HL. It also highlights, for the first time, that HHL can precede structural synaptic dysfunction and AN demyelination. The stepwise cellular mechanisms from HHL to canonical HL are revealed, providing a platform for intervention to prevent lasting and irreversible age-related hearing loss (ARHL).

Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa -/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa -/- DRGNs showed marked upregulation of voltage-gated Ca 2+ and K + channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa -/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Presbycusis or age-related hearing loss (ARHL) is the most common sensory deficit in the human population. A substantial component of the etiology stems from pathological changes in sensory and non-sensory cells in the cochlea. Using a non-obese diabetic (NOD) mouse model, we have characterized changes in both hair cells and spiral ganglion neurons that may be relevant for early signs of age-related hearing loss (ARHL). We demonstrate that hair cell loss is preceded by, or in parallel with altered primary auditory neuron functions, and latent neurite retraction at the hair cell-auditory neuron synapse. The results were observed first in afferent inner hair cell synapse of type I neurites, followed by type II neuronal cell-body degeneration. Reduced membrane excitability and loss of postsynaptic densities were some of the inaugural events before any outward manifestation of hair bundle disarray and hair cell loss. We have identified profound alterations in type I neuronal membrane properties, including a reduction in membrane input resistance, prolonged action potential latency, and a decrease in membrane excitability. The resting membrane potential of aging type I neurons in the NOD, ARHL model, was significantly hyperpolarized, and analyses of the underlying membrane conductance showed a significant increase in K + currents. We propose that attempts to alleviate some forms of ARHL should include early targeted primary latent neural degeneration for effective positive outcomes.

Potassium (K + ) channels shape the response properties of neurons. Although enormous progress has been made to characterize K + channels in the primary auditory neurons, the molecular identities of many of these channels and their contributions to hearing in vivo remain unknown. Using a combination of RNA sequencing and single molecule fluorescent in situ hybridization, we localized expression of transcripts encoding the sodium-activated potassium channels K Na 1.1 (SLO2.2/Slack) and K Na 1.2 (SLO2.1/Slick) to the primary auditory neurons (spiral ganglion neurons, SGNs). To examine the contribution of these channels to function of the SGNs in vivo, we measured auditory brainstem responses in K Na 1.1/1.2 double knockout (DKO) mice. Although auditory brainstem response (wave I) thresholds were not altered, the amplitudes of suprathreshold responses were reduced in DKO mice. This reduction in amplitude occurred despite normal numbers and molecular architecture of the SGNs and their synapses with the inner hair cells. Patch clamp electrophysiology of SGNs isolated from DKO mice displayed altered membrane properties, including reduced action potential thresholds and amplitudes. These findings show that K Na 1 channel activity is essential for normal cochlear function and suggest that early forms of hearing loss may result from physiological changes in the activity of the primary auditory neurons.

Noise is the most common occupational and environmental hazard, and noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit. Although therapeutics that target the free-radical pathway have shown promise, none of these compounds is currently approved against NIHL by the United States Food and Drug Administration. The present study has demonstrated that tetrandrine (TET), a traditional Chinese medicinal alkaloid and the main chemical isolate of the Stephania tetrandra S. Moore herb, significantly attenuated NIHL in CBA/CaJ mice. TET is known to exert antihypertensive and antiarrhythmic effects through the blocking of calcium channels. Whole-cell patch-clamp recording from adult spiral ganglion neurons showed that TET blocked the transient Ca 2+ current in a dose-dependent manner and the half-blocking concentration was 0.6 + 0.1 μM. Consistent with previous findings that modulations of calcium-based signaling pathways have both prophylactic and therapeutic effects against neural trauma, NIHL was significantly diminished by TET administration. Importantly, TET has a long-lasting protective effect after noise exposure (48 weeks) in comparison to 2 weeks after noise exposure. The otoprotective effects of TET were achieved mainly by preventing outer hair cell damage and synapse loss between inner hair cells and spiral ganglion neurons. Thus, our data indicate that TET has great potential in the prevention and treatment of NIHL.

Age-related hearing loss (AHL) is the most common sensory disorder in the elderly population, and the etiologies are diverse. To understand the underlying mechanisms of AHL, one strategy is to identify correlates of the disease for comprehensive evaluation of treatment approaches. Dysfunction and degeneration of spiral ganglion neurons (SGNs) are major contributors to AHL. Previously, we showed that one of the changes in the aging auditory system is SGN excitability increase in mice. Since hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles in determining neuronal excitability, we predicted that HCN channels in SGNs are involved in AHL. To investigate the contribution of HCN channels to AHL, we examined the expression and biophysical properties of HCN channels in SGNs from adult (2-3 months) and 11-12-month-old mice. We report a dramatic increase of HCN channel current (Ih) in SGNs in old mice (11-12 months old). The results matched well with increased expression of HCN1 and HCN2 subunits, suggesting that upregulation of HCN channels in SGNs is one of the important facets of the aging SGNs. Moreover, the activity of Ih produced a major impact on the firing properties of SGNs in older mice. The upregulation of Ih may contribute to AHL by regulating SGN excitability. We assessed whether increased SGNs excitability dovetail with neurodegeneration. Apoptosis-inducing factor (AIF)-mediated apoptosis in SGNs was observed in old mice and activation of HCN channels mediates AIF activation. Thus, these findings demonstrate stark correlation between age-dependent increased expression of HCN channels and Ih, and apoptosis in SGNs, which may contribute towards the varied mechanisms of AHL.

Small-conductance Ca 2+ -activated K + (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca 2+ and membrane potentials on a beat-to-beat basis. The inextricable interplay between activation of SK channels and Ca 2+ dynamics suggests the pathology of one begets another. Yet, the exact mechanistic underpinning for the activation of cardiac SK channels remains unaddressed. Here, we investigated the intracellular Ca 2+ microdomains necessary for SK channel activation. SK currents coupled with Ca 2+ influx via L-type Ca 2+ channels (LTCCs) continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca 2+ store, suggesting that LTCCs provide the immediate Ca 2+ microdomain for the activation of SK channels in cardiomyocytes. Super-resolution imaging of SK2, Ca v 1.2 Ca 2+ channel, and ryanodine receptor 2 (RyR2) was performed to quantify the nearest neighbor distances (NND) and localized the three molecules within hundreds of nanometers. The distribution of NND between SK2 and RyR2 as well as SK2 and Ca v 1.2 was bimodal, suggesting a spatial relationship between the channels. The activation mechanism revealed by our study paved the way for the understanding of the roles of SK channels on the feedback mechanism to regulate the activities of LTCCs and RyR2 to influence local and global Ca 2+ signaling.

Background: Intracellular pH (pH i ) is critical to cardiac excitation and contraction; uncompensated changes in pH i impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pH i regulation. Our previous studies identified several isoforms of a solute carrier Slc26a6 to be highly expressed in cardiomyocytes. We show that Slc26a6 mediates electrogenic Cl - /HCO 3 - exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pH i , but also cardiac excitability., Methods and Results: To test the mechanistic role of Slc26a6 in the heart, we took advantage of Slc26a6 knockout ( Slc26a6 -/ - ) mice using both in vivo and in vitro analyses. Consistent with our prediction of its electrogenic activities, ablation of Slc26a6 results in action potential shortening. There are reduced Ca 2+ transient and sarcoplasmic reticulum Ca 2+ load, together with decreased sarcomere shortening in Slc26a6 -/ - cardiomyocytes. These abnormalities translate into reduced fractional shortening and cardiac contractility at the in vivo level. Additionally, pH i is elevated in Slc26a6 -/ - cardiomyocytes with slower recovery kinetics from intracellular alkalization, consistent with the Cl - /HCO 3 - exchange activities of Slc26a6. Moreover, Slc26a6 -/ - mice show evidence of sinus bradycardia and fragmented QRS complex, supporting the critical role of Slc26a6 in cardiac conduction system., Conclusions: Our study provides mechanistic insights into Slc26a6, a unique cardiac electrogenic Cl - /HCO 3 - transporter in ventricular myocytes, linking the critical roles of Slc26a6 in regulation of pH i , excitability, and contractility. pH i is a critical regulator of other membrane and contractile proteins. Future studies are needed to investigate possible changes in these proteins in Slc26a6 -/ - mice., (© 2017 American Heart Association, Inc.)