Search

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.

Emerging youth movements to promote issues reflected in the United Nations Sustainable Development Goals (SDGs) are celebrated as critical for the future attainment of societal aims. We explore the...

Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, ER, and plasma membrane promote regulation of multiple functions, which include intracellular Ca2+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 Ca2+levels, reduced K+-induced Ca2+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.

Higher education, as a service sector, offers various programs to develop the students which can add value to the society. People, knowledge and technology play vital roles in attaining high service delivery in higher education institutions (HEIs). Knowledge sharing (KS), which is an arm of knowledge management (KM), is a key factor in HEIs requires full usage of technology to disseminate knowledge from teaching and researches through e-learning. However, technology challenges are prevalent in Africa. Hence, this paper illustrates how e-learning system can be used to enhance KM in HEIs in Africa and provide the benefits of both. Characteristics of KM and e-learning system have been highlighted. The paper shows relationship among different types of KM, e-learning and blended e-learning (BEL). It has been enumerated that there is a meeting point between KM, e-learning and BEL towards enhanced service delivery in HEIs in Africa in the era of open distance learning for towards achieving mass education. Hence, African governments should step up their efforts in funding technology-enhanced training in HEIs and necessary policies to promote effective and efficient quality services in DL education using KM and BEL.

This study assesses household’s willingness to use other renewable energy alternatives to meet their households’ energy demand. Interview schedules were used to gather primary data from 400 randoml...

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., 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 demonstrate that inhibition of the soluble epoxide hydrolase (sEH) enzyme to decrease inflammation and fibrosis in the host myocardium increases the survival of the transplanted human induced pluripotent stem cell derived‐cardiomyocytes (hiPSC‐CMs) in a murine postmyocardial infarction model.

Globally, studies have provided significant facts about pedestrian demographic characteristics influencing road crossing behaviour of pedestrians. However, there seems to be an unconcluded argument about the influence of demographic characteristics on road crossing behaviour. This study aimed at examine the gender differences in road crossing behaviour of UCC students on campus. The study was done by mapping out the road conditions of pedestrian crossing sites, identifing the perceived gender prone to indulge in bad road crossing behaviour and examine the gendered perception towards drivers’ attitude on road crossing behaviour on campus. An observation checklist was used to observe the road crossing behaviour of both men and women while one Focused Group Discusions was conducted each for men and women groups on UCC campus. Results indicated that men were more prone to road crossing accidents than women. Further analysis showed differing drivers attitudes towards pedestrians and road crossing behaviours by men and women on campus. It was found that women were relatively treated better than men. It is recommended that all road users must be educated to be sensitive to all road users to reduce gender biass attitude and behaviours while using the road.

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.

Additional file 1. Moran’s I SpatialAutocorrelation of unskilled birth attendance in Chad.

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.

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+ (KNa) mRNA and channel proteins are distinctly and locally expressed in dendritic projections of primary ANs and genetic deletion of KNa 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 Ca2+ homeostasis, activation of caspases 3/9, impaired regulation of inositol triphosphate receptor 1 (IP3R1), 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).

Neuronal development in the inner ear is initiated by expression of the proneural basic Helix-Loop-Helix (bHLH) transcription factor

The study aims to shed new lights on the lead-lag relationships between the financial sector (RFSI) and economic growth (GDP) in the midst of global economic policy uncertainty (GEPU) shocks for BRICS economies. Hence, the bivariate, partial, and wavelet multiple correlations techniques are employed. From the bivariate analysis, we document positive bi-directional causality between the RFSI and economic growth over the sample period. The partial wavelet reveals that GEPU shocks distort the significance and directional comovements between the RFSI and GDP. Moreover, the outcome from the wavelet multiple cross correlations (WMCC) indicates that the RFSI is a first mover at most time scales for the BRICS economies. This is followed by GEPU which either leads or lags for most scales, especially for South Africa. The impact of GEPU on RFSI and GDP is worst for South Africa in about four cases in the medium-, and long-terms. This signifies that South Africa’s financial markets and economic growth are vulnerable to GEPU. However, the impetus for GEPU to drive the comovements between the financial sector and economic activity was less pronounced in the pre-COVID analysis conducted with the WMCC. The study supports both the supply-leading and demand-following hypotheses. Our findings also underscore the need for policymakers, investors and academics alike to incessantly observe the dynamics between finance and growth across time and periodicity while considering adverse shocks from global economic policy uncertainty in tandem.

Summary 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)., Graphical abstract, Highlights • Prestin is functionally characterized by nonlinear capacitance (NLC) in the cell • Prestin is expressed in cardiomyocytes • Prestin accounts partly for the NLC of cardiomyocytes • We describe recording techniques and quantification methods for NLC in cardiomyocytes, 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.

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 Neurod1Cre 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 compensatory plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

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.

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.

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−/HCO3− 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.

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.

There is a growing interest from e-commerce planners and other planning agencies in the Information Technology world to measure and forecast the growth of e-commerce in developing countries like Nigeria. The difficulties lie in finding the best forecasting model that can incorporate both the internal and external barriers that influence the full adoption and diffusion of e-commerce. This study attempts to identify the relevant e-commerce tools and its spread in Ogun East Senatorial District as well as formulating a mathematical model for e-commerce adoption and diffusion. A well-structured questionnaire was used to collect data from 126 respondents and analyzed using Trendline, a built-in analysis tool in Microsoft® Office Excel version 2013. The study identified PCs/laptops, ATM cards, e-mail services, mobile money transfer, e-commerce Websites, and point-of-sales (POS) terminals as e-commerce tools used by the respondents. The results of the study show that majority of the e-commerce users/adopters were single female students between the ages of 21 and 30 years, with university education owing to a proportion of 63% of the respondents while the earliest adopted e-commerce tools in descending order were tablets/smartphones, PCs/laptops, ATM cards, and email services. The results further show that the most popularly-used tools were e-commerce websites (98% responses), email services (94% responses), mobile money transfer (94% responses), POS terminals (94% responses), tablets/smartphones (93% responses), PCs/laptops (87% responses) and ATM cards (80% responses). Based on the findings of this study, it is therefore recommended that government should promote the use and development of e-commerce, notably by reducing the costs of access to technology, through the liberation of trade in software and hardware.

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 AN is 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. The combination of neurotransmission and mechanical sensation to control spike patterns gives the AN a secondary receptor role, an emerging theme in primary neuronal functions.

Current research in the energy sector has been dedicated to influencing energy policies to become more gender-sensitive. These research have concentrated on gender mainstreaming in the energy sector with only a few exploring the factors that account for gender differences with respect to clean energy choice at the household level. This paper examines the gender differences regarding clean energy choice for the home in the Cape Coast Metropolis of Ghana. The study used interview schedules to gather data from 400 randomly selected respondents in the Cape Coast Metropolis. The study found that there were several energy sources available to households within the Cape Coast Metropolis. Also, there was a significant difference in the choice of clean energy between men and women. A multilevel binary logistic regression revealed that more men chose and used clean energy than women based on their age, household size, income, educational level, energy independence and easy maintenance of clean energy equipment. It is recommended that energy policies in Ghana should be made sensitive to the gender dynamics.