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Abstract Cardiac remodelling is a key process in the development of heart failure. Reactivation of foetal cardiac genes is often associated with cardiac remodelling. Here we study the role of Pontin (Ruvbl1), which is highly expressed in embryonic hearts, in mediating adverse remodelling in adult mouse hearts. We observe that Pontin deficiency in cardiomyocytes leads to induced apoptosis, increased hypertrophy and fibrosis, whereas Pontin overexpression improves survival, increases proliferation and reduces the hypertrophic response. Moreover, RNAseq analysis show that genes involved in cell cycle regulation, cell proliferation and cell survival/apoptosis are differentially expressed in Pontin knockout. Specifically, we detect changes in the expression of Hippo pathway components in the Pontin knockout mice. Using a cellular model we show that Pontin induces YAP activity, YAP nuclear translocation, and transcriptional activity. Our findings identify Pontin as a modulator of adverse cardiac remodelling, possibly via regulation of the Hippo pathway. This study may lead to the development of a new approach to control cardiac remodelling by targeting Pontin.

Background: In the education sector, technologies are (or can be) repurposed in the Fourth Industrial Revolution (4IR) to facilitate teaching and learning. However, this shift may impact on learners' access to reading materials and reading motivation. Objectives: The aim of the study was to determine whether Grade 8 English First Additional Language (FAL) learners' motivation to read is influenced by access to reading materials in a traditional classroom setting or through online reading platforms. Method: Likert-scale survey questionnaires were used to measure this relationship. Data from 466 Grade 8 English FAL learners from six South African township schools were collected and SPSS version 25 was used to analyse the data. Results: In traditional classrooms, the findings showed that increased access positively influenced motivation, whereas this effect was not evident in online reading platforms. However, in both settings, motivation increased when learners had access to a diverse selection of reading materials. Finally, the findings indicated a parallel relationship between learners' low motivation and limited access to reading platforms. Conclusion: The study concluded that while traditional classrooms continue to play an important role in global education, the ongoing evolution of technology-based learning platforms has compelled a shift in reading practices toward online platforms, which are reshaping the educational landscape, demonstrating the increasing significance of technology-mediated learning in modern education. Contribution: The authors recommend enhanced collaboration between teachers and learners to devise innovative methods for motivating online reading, ensuring learners' inclusion in the 4IR literacy pedagogy evolution.

Prime editing is a powerful means of introducing precise changes to specific locations in mammalian genomes. However, the widely varying efficiency of prime editing across target sites of interest has limited its adoption in the context of both basic research and clinical settings. Here, we set out to exhaustively characterize the impact of the cis- chromatin environment on prime editing efficiency. Using a newly developed and highly sensitive method for mapping the genomic locations of a randomly integrated "sensor", we identify specific epigenetic features that strongly correlate with the highly variable efficiency of prime editing across different genomic locations. Next, to assess the interaction of trans -acting factors with the cis -chromatin environment, we develop and apply a pooled genetic screening approach with which the impact of knocking down various DNA repair factors on prime editing efficiency can be stratified by cis -chromatin context. Finally, we demonstrate that we can dramatically modulate the efficiency of prime editing through epigenome editing, i.e. altering chromatin state in a locus-specific manner in order to increase or decrease the efficiency of prime editing at a target site. Looking forward, we envision that the insights and tools described here will broaden the range of both basic research and therapeutic contexts in which prime editing is useful.

Critical reading comprehension is a crucial skill for lifelong learning, but many learners struggle with effectively extracting meaning from texts. This study aimed to address this issue by investigating how a strategy-based instruction intervention could impact learners' critical reading comprehension competence. The study employed a quantitative approach with a quasi-experimental pre- and post-test control group design. The participants were 155 Grade 9 English first additional language (FAL) learners from two high schools in Gauteng, South Africa. The intervention programme was based on Bloom's taxonomy categories for learning, teaching and assessing, modified into six strategies: (1) knowledge (pre-reading), (2) comprehension (extracting meaning), (3) application (asking questions), (4) analysis (reflection), (5) evaluation (outlining key concepts and decision-making) and (6) synthesis (summarising). Using a two-way mixed analysis of variance (ANOVA) paired sample t-tests, the study found that while both groups' critical reading comprehension competence increased, the experimental group that received the strategy-based instruction intervention performed significantly better in the post-test, showing a significant improvement compared to the control group. The findings demonstrated that providing clear explanations, instruction and support on reading strategies can enhance learners' critical reading comprehension, highlighting the mutual reliance between teaching and learning. The teacher's instructional approach in guiding learners to effectively use reading strategies is crucial for enhancing critical reading comprehension in the English FAL classroom. In conclusion, the results suggest that the intervention effectively enhanced critical reading comprehension competence, and if implemented by teachers, it could potentially help break the cycle of poor critical reading comprehension among English FAL learners. Contribution The contribution of this study lies in its provision of empirically supported perspectives and insights into the effectiveness of strategy-based instruction interventions. It emphasises the necessity of employing explicit reading comprehension pedagogies and targeted interventions, along with explicit instructional strategies, to address the reading comprehension challenges encountered by English FAL learners in South Africa and beyond., Author(s): Florence M. Olifant (corresponding author) [1] Introduction Reading is essential for lifelong learning (Koch & Spörer 2017), with comprehension being critical to this process (Klapwijk 2015). In today's economically [...]

Purpose: The purpose of this study is to examine the relationship between telehealth use, telehealth satisfaction, and chronic medical conditions among residents living in Appalachian and non-Appalachian communities. Sample: A COVID-19 public health survey was distributed via social media and healthcare clinics in the tri-state region of central Appalachia. Survey responses were limited to adults aged ≥18 years who consented to participate in the survey that self-identified as an individual with one or more chronic medical conditions (n=195). Method: Simple descriptive statistics including frequencies, percentages, means, and standard deviations (SDs) were calculated for variables of interest both overall and by subgroups of interest. Chi-squared tests were used to compare categorical outcomes between groups of interest, while two-sample t-tests were used for continuous outcomes. Significance for all tests was determined using an α level of 0.05. Findings: There is no statistically significant relationship between respondents with regard to using telehealth services, satisfaction rates related to telehealth use, or reasons for electing not to use telehealth services during the COVID-19 pandemic. However, there was a trending statistical relationship between county status and the use of telehealth services in Appalachia with those counties doing economically better being more likely to use telehealth services as compared to those fairing less well (p=0.053). Findings also suggest that people living in urban areas of Appalachia were more likely to be satisfied using telehealth services than those living in non-urban areas of Appalachia (p=0.01). Conclusions: Research is still limited as to how the expansion of broadband capabilities during the COVID-19 pandemic has benefited those residing in Appalachia in terms of managing chronic health conditions. Future research should focus on expanding participation among Appalachian respondents looking for specific differences related to location within Appalachia, age, gender, ethnicity, and socioeconomic status. Keywords: Telehealth, Satisfaction, Rural, Appalachian, COVID-19 DOI: https://doi.org/10.14574/ojrnhc.v22i2.715

Abstract Background We have a limited understanding on how to best integrate technologies to support antiretroviral therapy (ART) adherence in routine HIV care. Methods We conducted semi-structured interviews with multidisciplinary providers caring for pregnant and postpartum people with HIV and asked providers about their perspectives on utilizing adherence support technologies such as text messages, video check-ins with providers or automated with facial recognition for directly-observed-therapy, signaling pill bottle, and signaling pill to support ART adherence. Each approach generated an adherence report. The interview instrument was guided by the Consolidated Framework for Implementation Research and included questions on the implementation climate, barriers, and facilitators to the clinical integration of the adherence approach and strategies that could be used to maximize this integration. The order of adherence support technologies was randomized to minimize bias. We used a modified grounded theory to develop the coding structure and two coders applied the codebook to the transcripts after establishing strong inter-rater reliability with 20% of interviews (kappa = 0.82). Results Between March and December 2020, we conducted 26 in-depth, semi-structured interviews with providers who weighed several factors when considering each approach, including the approach’s effect on patient-provider interaction in and outside of the clinic visit, timing for and duration of the approach’s utility, threat of disclosing status, and added burden to providers (e.g., needing to act on generated information) or to patients (e.g., needing to hide the signaling pills, responding to text messages). Providers’ most preferred approach was text-messages, and the least preferred was the signaling pill. Barriers to acceptability varied by approach and included perceived surveillance, violation of privacy, added time demand for providers, potential inaccuracy of the adherence data generated, and negative impact on the patient-provider relationship, particularly if the approach was perceived as coercive. Payers anticipated regulatory hurdles with unfamiliar approaches, particularly the signaling pill and signaling pill bottle. Facilitators included strengthened therapeutic alliance, predictable reminder mechanisms, and options for customization according to patient preference. Conclusions Our study elucidates barriers and facilitators to integrating technology-based adherence support approaches in clinical care to support adherence of pregnant and postpartum people with HIV.

Cardiac remodelling is a key process in the development of heart failure. Reactivation of foetal cardiac genes is often associated with cardiac remodelling. Here we study the role of Pontin (Ruvbl1), which is highly expressed in embryonic hearts, in mediating adverse remodelling in adult mouse hearts. We observe that Pontin deficiency in cardiomyocytes leads to induced apoptosis, increased hypertrophy and fibrosis, whereas Pontin overexpression improves survival, increases proliferation and reduces the hypertrophic response. Moreover, RNAseq analysis show that genes involved in cell cycle regulation, cell proliferation and cell survival/apoptosis are differentially expressed in Pontin knockout. Specifically, we detect changes in the expression of Hippo pathway components in the Pontin knockout mice. Using a cellular model we show that Pontin induces YAP activity, YAP nuclear translocation, and transcriptional activity. Our findings identify Pontin as a modulator of adverse cardiac remodelling, possibly via regulation of the Hippo pathway. This study may lead to the development of a new approach to control cardiac remodelling by targeting Pontin. Adverse cardiac remodelling is a key process leading to heart failure. Here, the authors show that expression of foetal gene Pontin (Ruvbl1) is protective against pathological remodelling and cardiomyopathy via modulation of the Hippo pathway. [ABSTRACT FROM AUTHOR]

Which contralesional circuits adapt after traumatic brain injury (TBI) is unclear. Here the authors used in vivo imaging, retrograde labeling, rabies tracing, clearing and functional imaging to demonstrate that callosal neurons selectively adapt after TBI in mice.

The chemotherapeutic agent temozolomide (TMZ) kills tumor cells preferentially via alkylation of the O6-position of guanine. However, cells that express the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), or harbor deficient DNA mismatch repair (MMR) function, are profoundly resistant to this drug. TMZ is in clinical use for melanoma, but objective response rates are low, even when TMZ is combined with O6-benzylguanine (O6BG), a potent MGMT inhibitor. We used in vitro and in vivo models of melanoma to characterize the early events leading to cellular TMZ resistance. Melanoma cell lines were exposed to a single treatment with TMZ, at physiologically relevant concentrations, in the absence or presence of O6BG. Surviving clones and mass cultures were analyzed by Western blot, colony formation assays, and DNA methylation studies. Mice with melanoma xenografts received TMZ treatment, and tumor tissue was analyzed by immunohistochemistry. We found that MGMT-negative melanoma cell cultures, before any drug treatment, already harbored a small fraction of MGMT-positive cells, which survived TMZ treatment and promptly became the dominant cell type within the surviving population. The MGMT-negative status in individual cells was not stable, as clonal selection of MGMT-negative cells again resulted in a mixed population harboring MGMT-positive, TMZ-resistant cells. Blocking the survival advantage of MGMT via the addition of O6BG still resulted in surviving clones, although at much lower frequency and independent of MGMT, and the resistance mechanism of these clones was based on a common lack of expression of MSH6, a key MMR enzyme. TMZ treatment of mice implanted with MGMT-negative melanoma cells resulted in effective tumor growth delay, but eventually tumor growth resumed, with tumor tissue having become MGMT positive. Altogether, these data reveal stochastic expression of MGMT as a pre-existing, key determinant of TMZ resistance in melanoma cell lines. Although MGMT activity can effectively be eliminated by pharmacologic intervention with O6BG, additional layers of TMZ resistance, although considerably rarer, are present as well and minimize the cytotoxic impact of TMZ/O6BG combination treatment. Our results provide rational explanations regarding clinical observations, where the TMZ/O6BG regimen has yielded mostly disappointing outcomes in melanoma patients.

Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, resulting in a median survival time of about 12 to 15 months. Despite these therapeutic efforts, the tumor returns in the vast majority of patients. When relapsing, statistics suggest an imminent death dependent on the size of the tumor, the Karnofsky Performance Status, and the tumor localization. Following the standard of care, the administration of Bevacizumab, inhibiting the growth of the tumor vasculature, is an approved medicinal treatment option approved in the United States, but not in the European Union, as well as the recently approved alternating electric fields (AEFs) generator NovoTTF/Optune. However, it is clear that regardless of the current treatment regimens, glioma patients continue to have dismal prognosis and novel treatments are urgently needed. Here, we describe different approaches of recently developed therapeutic glioma brain cancer vaccines, which stimulate the patient's immune system to recognize tumor-associated antigens (TAA) on cancer cells, aiming to instruct the immune system to eventually attack and destroy the brain tumor cells, with minimal bystander damage to normal brain cells. These distinct immunotherapies may target particular glioma TAAs which are molecularly defined, but they may also target broad patient-derived tumor antigen preparations intentionally evoking a very broad polyclonal antitumor immune stimulation.

AimERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine - composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors.MethodsIn this double-blinded, randomized, Phase II study bevacizumab-naive patients with recurrent GBM were randomized to receive either ERC1671 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine® or sargramostim) and cyclophosphamide plus bevacizumab, or placebo plus bevacizumab. Interim results: Median overall survival (OS) of patients treated with ERC1671 plus bevacizumab was 12 months. In the placebo plus bevacizumab group, median OS was 7.5 months. The maximal CD4+ T-lymphocyte count correlated with OS in the ERC1671 but not in the placebo group.ConclusionThe addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.