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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.

Abstract Background Black men consistently have higher rates of prostate cancer (PCA)- related mortality. Advances in PCA treatment, screening, and hereditary cancer assessment center around germline testing (GT). Of concern is the significant under-engagement of Black males in PCA GT, limiting the benefit of precision therapy and tailored cancer screening despite longstanding awareness of these disparities. To address these critical disparities, the Socioecological Model (SEM) was employed to develop comprehensive recommendations to overcome barriers and implement equitable strategies to engage Black males in PCA GT. Methods Clinical/research experts, national organization leaders, and community stakeholders spanning multiple regions in US and Africa participated in developing a framework for equity in PCA GT grounded in the SEM. A novel mixed-methods approach was employed to generate key areas to be addressed and informed statements for consensus consideration utilizing the modified Delphi model. Statements achieving strong consensus (> =75% agreement) were included in final equity frameworks addressing clinical/community engagement and research engagement. Results All societal levels of the SEM (interpersonal, institutional, community, and policy/advocacy) must deliver information about PCA GT to Black males that address benefits/limitations, clinical impact, hereditary cancer implications, with acknowledgment of mistrust (mean scores [MS] 4.57-5.00). Interpersonal strategies for information delivery included engagement of family/friends/peers/Black role models to improve education/awareness and overcome mistrust (MS 4.65-5.00). Institutional strategies included diversifying clinical, research, and educational programs and integrating community liaisons into healthcare institutions (MS 4.57-5.00). Community strategies included partnerships with healthcare institutions and visibility of healthcare providers/researchers at community events (MS 4.65–4.91). Policy/advocacy included improving partnerships between advocacy and healthcare/community organizations while protecting patient benefits (MS 4.57-5.00). Media strategies were endorsed for the first time at every level (MS 4.56-5.00). Conclusion The SEM-based equity frameworks proposed provide the first multidisciplinary strategies dedicated to increase engagement of Black males in PCA GT, which are critical to reduce disparities in PCA-mortality through informing tailored screening, targeted therapy, and cascade testing in families.

Abstract Background Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks (SFRT-GRID) or lattice radiotherapy to create areas of low or high dose exposure, may create protective reservoirs of the tumor immune microenvironment, thereby preserving anti-tumor immune responses that are pivotal for radiation success. Methods We have developed an agent-based model (ABM) of tumor-immune interactions to investigate the immunological consequences and clinical outcomes after $$2\,\text{Gy} \times 35$$ 2 Gy × 35 whole tumor radiation therapy (WTRT) and SFRT-GRID. The ABM is conceptually calibrated such that untreated tumors escape immune surveillance and grow to clinical detection. Individual ABM simulations are initialized from four distinct multiplex immunohistochemistry (mIHC) slides, and immune related parameter rates are generated using Latin Hypercube Sampling. Results In silico simulations suggest that radiation-induced cancer cell death alone is insufficient to clear a tumor with WTRT. However, explicit consideration of radiation-induced anti-tumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is successful with radiation-induced anti-tumor immunity, and, for some pre-treatment TIME compositions and modeling parameters, SFRT-GRID might be superior to WTRT in providing tumor control. Conclusion This study demonstrates the pivotal role of the radiation-induced anti-tumor immunity. Prolonged fractionated treatment schedules may counteract early immune recruitment, which may be protected by SFRT-facilitated immune reservoirs. Different biological responses and treatment outcomes are observed based on pre-treatment TIME composition and model parameters. A rigorous analysis and model calibration for different tumor types and immune infiltration states is required before any conclusions can be drawn for clinical translation.

This letter to the editor responds to comments by Sartor et al regarding recent findings on the clinical relevance of CDK12 pathogenic mutations.

Abstract Urbanization in Sub-Saharan Africa requires vast quantities of sand to meet infrastructural demands. In Accra, Ghana, sand mining occurs predominantly on farmlands at the city’s periphery. We selected three study communities to assess the effects of sand mining on agriculture using interviews with local farmers and soil analyses of mined and unmined fields. The results underscore the profound repercussions of sand mining on farmers, characterized by substantial agricultural land loss, the destruction of food crops, and the absence of compensation payments or land reclamation. The study further reveals a significant decline in soil fertility of mined fields compared to unmined fields as evidenced by reduced levels of carbon (C, by 6.3 g kg-1) and macronutrients (nitrogen (N, by 0.6 g kg-1), phosphorus (P, 12.7 mg kg-1), potassium (K, 77 mg kg-1) and magnesium (Mg, 88 mg kg-1)), and an increase in soil compaction (bulk density by 0.13 g cm-3 and penetration resistance by 0.11 MPa). Soil texture and pH were altered and sodium (Na, by 16 mg kg-1) and soil moisture (by 4%) increased. On a communal level, sand mining adversely affected water availability, road infrastructure, and the health of residents. The study fills research gaps on the effects of sand mining on agricultural productivity, soil fertility and livelihoods, emphasizing the urgent need for effective regulation, law enforcement and collaboration as well as compensation and land reclamation mechanisms to limit the adverse impacts of sand mining on ecosystem services. Further, the use of more sustainable building materials should be fostered to reduce the demand for sand in Ghana.

Most paleoclimate studies of Mainland Southeast Asia hydroclimate focus on the summer monsoon, with few studies investigating rainfall in other seasons. Here, we present a multiproxy stalagmite record (45,000 to 4,000 years) from central Vietnam, a region that receives most of its annual rainfall in autumn (September-November). We find evidence of a prolonged dry period spanning the last glacial maximum that is punctuated by an abrupt shift to wetter conditions during the deglaciation at ~14 ka. Paired with climate model simulations, we show that sea-level change drives autumn monsoon rainfall variability on glacial-orbital timescales. Consistent with the dry signal in the stalagmite record, climate model simulations reveal that lower glacial sea level exposes land in the Gulf of Tonkin and along the South China Shelf, reducing convection and moisture delivery to central Vietnam. When sea level rises and these landmasses flood at ~14 ka, moisture delivery to central Vietnam increases, causing an abrupt shift from dry to wet conditions. On millennial timescales, we find signatures of well-known Heinrich Stadials (HS) (dry conditions) and Dansgaard-Oeschger Events (wet conditions). Model simulations show that during the dry HS, changes in sea surface temperature related to meltwater forcing cause the formation of an anomalous anticyclone in the Western Pacific, which advects dry air across central Vietnam, decreasing autumn rainfall. Notably, sea level modulates the magnitude of millennial-scale dry and wet phases by muting dry events and enhancing wet events during periods of low sea level, highlighting the importance of this mechanism to autumn monsoon variability.

Black Veterans have higher a incidence of localized and metastatic prostate cancer compared to White Veterans yet are underrepresented in reports of frequencies of somatic and germline alterations. This retrospective analysis of somatic and putative germline alterations was conducted in a large cohort of Veterans with prostate cancer (N = 835 Black, 1613 White) who underwent next generation sequencing through the VA Precision Oncology Program, which facilitates molecular testing for Veterans with metastatic cancer. No differences were observed in gene alterations for FDA approved targetable therapies (13.5% in Black Veterans vs. 15.5% in White Veterans, P = .21), nor in any potentially actionable alterations (25.5% vs. 28.7%, P =.1). Black Veterans had higher rates of BRAF (5.5% vs. 2.6%, P < .001) alterations, White Veterans TMPRSS2 fusions (27.2% vs. 11.7%, P < .0001). Putative germline alteration rates were higher in White Veterans (12.0% vs. 6.1%, P < .0001). Racial disparities in outcome are unlikely attributable to acquired somatic alterations in actionable pathways.

COVID-19 has revolutionised assessment design and practices in higher education; however, there has not been a shift in the overall objective of enhancing that the association between assessments and learning promotes the holistic development of students. In this study, we provide an empirical evaluation of the perceived effects of assessment practices (invigilated examination and alternative assessments) on students’ mental wellbeing, learning processes and academic misconduct. A cross-sectional study design was employed for this study in which a self-reported survey instrument was administered to 380 social science and nursing undergraduate and postgraduate students in a public university in Australia. We explored the correlations within defined networks by path analysis via partial least square structural equation modelling (PLS-SEM) framework of SmartPLS 3. Model assessment indexes indicated acceptable convergent, divergent and construct validity scores for the instrument used. Compared to invigilated exams, students perceived alternative assessments to have significant positive direct effects on stress levels, research skills, learning process and time management (). In relation to academic misconduct, students generally perceived invigilated exams to restrain such practices; however, the perceived effect was not statistically significant when compared with alternative assessments (. Although, the popularity of alternative assessment practices may have been driven by COVID-19, the pilot findings from this study suggest these assessment designs and practices have greater potential to promote overall student success and productivity and must be encouraged and utilised in the post-COVID-19 era.

The impact of vaccine hesitancy on global health is one that carries dire consequences. This was evident during the outbreak of the COVID-19 pandemic, where numerous theories and rumours emerged. To facilitate targeted actions aimed at increasing vaccine acceptance, it is essential to identify and understand the barriers that hinder vaccine uptake, particularly regarding the COVID-19 vaccine in Ghana, one year after its introduction in the country.We conducted a cross-sectional study utilizing self-administered questionnaires to determine factors, including barriers, that predict COVID-19 vaccine uptake among clients visiting a tertiary and quaternary hospital using some machine learning algorithms. Among the findings, machine learning models were developed and compared, with the best model employed to predict and guide interventions tailored to specific populations and contexts. A random forest model was utilized for prediction, revealing that the type of facility respondents visited and the presence of underlying medical conditions were significant factors in determining an individual's likelihood of receiving the COVID-19 vaccine. The results showed that machine learning algorithms can be of great use in determining COVID-19 vaccine uptake.

Aim – This study aims to explore the intricate interplay between organizational culture, policies, and productivity within a major public institution in Ghana. The primary purpose is to investigate the relationships between organizational policies, characteristics of organizational culture, and non-financial indicators of organizational productivity. Design/methodology/approach – This study utilizes a descriptive survey design, using a sample of 119 respondents randomly selected from a population of 1489 employees. Advanced statistical techniques, including Pearson Correlation and Multiple Linear Regression, are employed to identify relationships and test hypotheses. Findings – The results indicate positive and statistically significant relationships between organizational policies, cultural characteristics, and productivity. Multiple linear regression analysis supported the hypothesis, demonstrating a substantial influence of these factors on productivity. Notably, a moderate to strong positive correlation was found, highlighting the critical role of organizational culture in fostering improved performance. Limitations – Reliance on self-reported data raises concerns about social desirability bias. Additionally, the descriptive survey design allows for the identification of correlations, but causal relationships between variables cannot be established. Practical implications – This research highlights the importance of strategic policies and a supportive culture for public sector productivity. Clear policy implementation, leadership fostering a positive work environment, and engagement in policymaking likely enhance performance, particularly within diverse workforces. However, future research should explore causal relationships between these factors and productivity for deeper understanding and continuous optimization. Originality/value – This study investigates the combined effects of organizational culture, policy clarity, and employee participation on productivity in a Ghanaian public institution. It contributes to the literature by confirming the positive influence of a supportive culture and well-defined policies, while emphasizing the importance of employee involvement in policy development. These findings offer practical insights for leaders seeking to enhance productivity in similar contexts.

Medication adherence strategies that are successful, suitable and economical are vital to the treatment outcome of persons living with mental illness. Mobile-phone-based intervention is one such strategy and is particularly critical to reducing medication non-adherence, especially in mental health disorders. This study aimed to assess the impact of telephone adherence counselling on medication adherence in persons with mental health disorders. A longitudinal study was conducted on study participants who were randomly assigned to control and intervention groups over three months. Both groups received standard medication adherence counselling for the first month and then baseline adherence levels were determined using the medication adherence rating scale (MARS). The control group received standard medication adherence counselling at the psychiatric clinic whilst the intervention group received additional telephone calls made to each member of the intervention group once a week for a total of 8 times over 2 months. Of the patients who were screened for potential participation, 149 participants passed and 87 participants participated making a response rate of 58.40 %. The t-test conducted on the participants after the first (Month 2) and second (Month 3) on those with Telephone Call Intervention inferred significant statistical differences (p < 0.001). MARS Scores appreciated in the intervention group compared to the control group in Month 2 (1.64) and Month 3 (1.79). A positive impact of Telephone Call Interventions on medication adherence was achieved. This intervention can be a medication adherence strategy to supplement the standard medication adherence counselling which could improve treatment outcomes.

Social accountability interventions have been implemented in low-and middle-income countries as a strategy to improve state-citizen engagement. However, there has been a minimal systematic attempt to document the effectiveness of social accountability initiatives, especially their ability to stimulate accountability actions by citizens. Subsequently, this paper assesses the effectiveness of a social accountability project in Ghana to build the capacity of citizens to participate in state-society engagements and how such engagements resulted in citizens’ actions. Participants were selected from eight Metropolitan, Municipal and District Assemblies (MMDAs) in Ghana using a mixed-method approach and a multi-stage sampling procedure involving simple random and purposive sampling techniques. Key informant interviews and Focus Group Discussions were used to collect data from representatives of traditional authorities, media houses and public officers from MMDAs. Structured interviews were used to collect data from 240 participants of the social accountability project to complement the qualitative data. The project was relevant in addressing national efforts to increase citizens’ participation in local governance. Furthermore, the project raised awareness and increased knowledge about participatory principles and platforms for participation among citizens. Overall, the social accountability interventions improve state-citizen engagement. The frequency of citizen-state engagements increased with the project’s inception but did not enhance the responsiveness of the MMDAs to citizens’ demands due to resource constraints and the overreliance on intermediaries to follow up on community issues at the MMDA, thereby failing to translate into agency for collective action. As a result, the paper recommends that social accountability interventions should improve cooperation between public officials and community members around the delivery of specific public services to build trust between them. Furthermore, such interventions should orient public officials to be receptive and responsive to the concerns of community members.

AbstractIn Ghana, terrestrial sand mining in rural and peri-urban areas negatively affects the livelihoods of the majority of the residents employed in land-based livelihoods. We examine the sustainability of the alternative livelihood strategies the residents in these areas adopt as they lose their original livelihoods to sand mining. Both quantitative and qualitative data were collected from 278 household heads and 23 key informants. Descriptive statistics and the chi-square test of independence were employed to analyse the quantitative data, while the qualitative data were analysed thematically. The study revealed that while more than half of the respondents had adopted alternative livelihood strategies as a survival strategy, the remaining household heads were unable to secure alternative livelihoods because of a lack of startup capital, inadequate skills, and the unattractiveness of the alternative livelihood options. Though the adoption of alternative strategies had contributed to improvements in food consumption, employment for some farmers displaced by sand mining, and the resilience of some household heads to handle shocks from sand mining, the strategies were largely unsustainable compared to the residents’ original livelihoods (farming). We recommend that the local government authorities develop policies in consultation with landowners to preserve and restore the original land-based livelihoods of the residents.

Abstract Introduction Men with African ancestry have the highest incidence and mortality rates of prostate cancer (PCa) worldwide. Methods This study aimed to identify differentially methylated genes between tumor vs. adjacent normal and aggressive vs. indolent PCa in 121 African American patients. Epigenome‐wide DNA methylation patterns in tumor DNA were assessed using the human Illumina Methylation EPIC V1 array. Results Around 5,139 differentially methylated CpG‐sites (q 0.2) were identified when comparing normal vs. tumor, with an overall trend of hypermethylation in prostate tumors. Multiple representative differentially methylated regions (DMRs), including immune‐related genes, such as CD40, Galectin3, OX40L, and STING, were detected in prostate tumors when compared to adjacent normal tissues. Based on an epigenetic clock model, we observed that tumors’ total number of stem cell divisions and the stem cell division rate were significantly higher than adjacent normal tissues. Regarding PCa aggressiveness, 2,061 differentially methylated CpG‐sites (q .05) were identified when the grade group (GG)1 was compared with GG4/5. Among these 2,061 CpG sites, 155 probes were consistently significant in more than one comparison. Among these genes, several immune system genes, such as COL18A1, S100A2, ITGA4, HLA‐C, and ADCYAP1, have previously been linked to tumor progression in PCa. Conclusion Several differentially methylated genes involved in immune‐oncologic pathways associated with disease risk or aggressiveness were identified. In addition, 261 African American‐specific differentially methylated genes related to the risk of PCa were identified. These results can shedlight on potential mechanisms contributing to PCa disparities in the African American Population.

Objectives Stereotactic body radiotherapy (SBRT) is widely used for localized prostate cancer and implementation of MR-guided radiotherapy has the advantage of tighter margins and improved sparing of organs at risk. Here we evaluate outcomes and time required to treat using non-adaptive MR-guided SBRT (MRgSBRT) for localized prostate cancer at our institution. Methods From 9/2019 to 11/2021 we conducted a retrospective review of 80 consecutive patients who were treated with MRgSBRT to the prostate. Patients included low (LR) (5%), favorable intermediate (FIR) (40%), unfavorable intermediate (UIR) (49%), and high risk (HR) (6%). Short-term androgen deprivation therapy was used in 32% of patients. Target volumes included prostate gland and proximal seminal vesicles with an isotropic 3 mm margin. Treatment was prescribed to 36.25 Gy in 5 fractions every other day with urethral sparing. Hydrogel spacer was used in 18% of patients. Time on the linac was recorded as beam on time (BOT) plus total treatment time (TTT) including gating. Analyzed outcomes included PSA response and patient reported outcomes scored by the American Urological Association (AUA) questionnaire and toxicity per CTCAE v5. General linear regression model was used to analyze factors affecting PSA and AUA in longitudinal follow up, and chi-square test was used to assess factors affecting toxicity. Results Median follow up was 19.3 months (3.8 – 36.6). Median BOT was 4.6 min (2.6 – 7.2) with a median TTT of 11 min (7.6 – 15.8). Pre-treatment vs post-RT median PSA was 6.36 (2.20 – 19.6) vs 0.85 (0.19 – 3.6), respectively ( P < 0.001). PSA decrease differed significantly when patients were stratified by risk category, favoring LR/FIR vs UIF/HR group ( P = 0.019). Four (5%) patients experienced a biochemical failure (BCF), with a median time to BCF of 20.4 months (7.9 – 34.5). Median biochemical failure free survival (BCFFS) was not reached, with 2-yr and 4-yr BCFFS of 97.1% and 72.1%, respectively. Patients with LR/FIR disease had 100% 2-yr and 4-yr BCFFS, whereas patients with UIF/HR had 95% and 41% 2-yr and 4-yr BCFFS ( P = 0.05). Mean pre-treatment AUA was 7.3 (1 - 25) vs 11.3 (1 - 26) at first follow-up; however, AUA normalized to baseline over time. Urethral Dmax ≥35 Gy trended to lower AUA score at all follow-ups ( P = 0.07). Forty-one (51%) patients reported grade 1-2 genitourinary toxicities at the 1 month follow up. Grade 3 toxicity (proctitis) was noted in 1 patient. There was no decrease in any grade rectal toxicity with use of hydrogel spacer (3 vs 6, P = 0.2). No grade ≥4 toxicities was observed. Conclusions MRgSBRT has the potential for treatment adaptation but this comes at the cost of increased resource utilization. Our experience with non-adaptive MRgSBRT of the prostate highlights its short treatment times as well as efficacy with good PSA control and low toxicity profile.

Despite advances in screening, diagnosis, and treatment for prostate cancer (PCa), Black men tend to be diagnosed at younger ages, have higher mortality rates, and are at increased risk of recurrence or metastasis compared to their White counterparts. PCa disparities among Black men are caused by a complex interaction of social, behavioral, and biological factors across the public policy, community, organizational, interpersonal, and individual levels. Key contributing factors include mistrust in the health care system, poor communication between patients and providers, low awareness of screening guidelines, and high medical costs. These disparities are further exacerbated by the low representation of Black men in clinical trials, which limits access to high-quality cancer care and generalizability for PCa treatments. In this narrative review of the existing literature, we examined the epidemiology and identified contributing factors, and propose multi-level strategies to address and mitigate disparities among Black men with PCa.

Schistosomiasis, one of the neglected tropical diseases which affects both humans and animals, is caused by trematode worms of the genus Schistosoma. The disease is caused by several species of Schistosoma which affect several organs such as urethra, liver, bladder, intestines, skin and bile ducts. The life cycle of the disease involves an intermediate host (snail) and a mammalian host. It affects people who are in close proximity to water bodies where the intermediate host is abundant. Common clinical manifestations of the disease at various stages include fever, chills, headache, cough, dysuria, hyperplasia and hydronephrosis. To date, most of the control strategies are dependent on effective diagnosis, chemotherapy and public health education on the biology of the vectors and parasites. Microscopy (Kato-Katz) is considered the golden standard for the detection of the parasite, while praziquantel is the drug of choice for the mass treatment of the disease since no vaccines have yet been developed. Most of the previous reviews on schistosomiasis have concentrated on epidemiology, life cycle, diagnosis, control and treatment. Thus, a comprehensive review that is in tune with modern developments is needed. Here, we extend this domain to cover historical perspectives, global impact, symptoms and detection, biochemical and molecular characterization, gene therapy, current drugs and vaccine status. We also discuss the prospects of using plants as potential and alternative sources of novel anti-schistosomal agents. Furthermore, we highlight advanced molecular techniques, imaging and artificial intelligence that may be useful in the future detection and treatment of the disease. Overall, the proper detection of schistosomiasis using state-of-the-art tools and techniques, as well as development of vaccines or new anti-schistosomal drugs may aid in the elimination of the disease.

PURPOSEProstate cancer disproportionately affects men of African descent, yet their representation in tissue-based studies is limited. This multinational, multicenter pilot study aims to establish the groundwork for collaborative research on prostate cancer in sub-Saharan Africa.METHODSThe Men of African Descent and Carcinoma of the Prostate network formed a pathologist working group representing eight institutions in five African countries. Formalin-fixed paraffin-embedded prostate tissue specimens were collected from Senegal, Nigeria, and Ghana. Histology slides were produced and digitally scanned. A central genitourinary pathologist (P.L.) and eight African general pathologists reviewed anonymized digital whole-slide images for International Society of Urological Pathology grade groups and other pathologic parameters. Discrepancies were re-evaluated, and consensus grading was assigned. A virtual training seminar on prostate cancer grading was followed by a second assessment on a subcohort of the same tissue set.RESULTSOf 134 tissue blocks, 133 had evaluable tissue; 13 lacked cancer evidence, and four were of insufficient quality. Post-training, interobserver agreement for grade groups improved to 56%, with a median Cohen's quadratic weighted kappa of 0.83 (mean, 0.74), compared with an initial 46% agreement and a quadratic weighted kappa of 0.77. Interobserver agreement between African pathologist groups was 40%, with a quadratic weighted kappa of 0.66 (95% CI, 0.51 to 0.76). African pathologists tended to overgrade (36%) more frequently than undergrade (18%) compared with the reference genitourinary pathologist. Interobserver variability tended to worsen with a decrease in tissue quality.CONCLUSIONTissue-based studies on prostate cancer in men of African descent are essential for a better understanding of this common disease. Standardized tissue handling protocols are crucial to ensure good tissue quality and data. The use of digital slide imaging can enhance collaboration among pathologists in multinational, multicenter studies.

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.

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 Ca2+ 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 Ca2+ 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.

Abstract 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.

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder and the fourth cause of death of end-stage renal disease. The disease has a prevalence of 1:400–1:1000 accounting for 10% of patients on dialysis. In most ADPKD patients, bilateral kidneys are similarly affected, with numerous fluid-filled cysts arising from different nephron segments. Only a few cases of ADPKD with ectopic unilateral multicystic kidney have been reported. It has been observed that the deterioration of their kidney function seemed to be quicker than their age- and sex-matched controls and siblings especially when the ectopic kidney is dysplastic. Case presentation We report a case of a 46-year-old Ghanaian male patient who presented with left flank pain and hematuria with high BP and deranged renal function. Abdominal ultrasonography showed both kidneys to be larger than normal and had multiple cysts of varying sizes with the right kidney located in the right iliac fossa. Follow up Abdominopelvic computer tomographic scan (CT–Scan) without contrast showed enlarged kidneys with the renal parenchyma replaced by innumerable cyst of varying sizes. The right kidney was ectopically located in the right aspect of the pelvis. A diagnosis of ADPKD with right pelvic ectopic multicystic kidney was made. He was put on antihypertensives, analgesia for the left flank pain and to have follow up at the urology and nephrology departments. Conclusion In most ADPKD patients, bilateral kidneys are similarly affected. Only a few cases of ADPKD with ectopic unilateral multicystic kidney have been reported. It has been observed that the deterioration of their kidney function seemed to be quicker than their age- and sex-matched controls and siblings especially when the ectopic kidney is dysplastic.