Mechanisms of anthracycline-induced dysfunction of ca2+ handling proteins in the heart

Anthracyclines, such as doxorubicin and daunorubicin, are powerful chemotherapy agents whose use is limited due to the onset of potentially fatal cardiac side effects which include arrhythmogenesis and heart failure. Several proteins important in intracellular Ca2+ signalling have been identified as drug binding targets, including the ryanodine receptor Ca2+ release channel (RyR2), the Ca2+ binding protein calsequestrin (CSQ2) and the Sarco/Endoplasmic Reticulum Ca-ATPase (SERCA2A). The drug metabolites are believed to be important in the devastating cardiac effects of anthracyclines but their actions have been poorly characterized. Previous work showed that daunorubicin modulates RyR2 and that its effects were attributable to ligand binding and thiol oxidation. The functional effect of doxorubicin and its metabolite, doxorubicinol on RyR2 was assessed by adding clinically relevant drug concentrations to single RyR2 channels in lipid bilayers. Anthracyclines caused biphasic modulation of RyR2 where there was an increase in channel activity followed by an inhibitory phase. RyR2 channel activation, but not inhibition, could be reversed by drug washout, typical of a ligand binding effect. This was supported by affinity chromatography experiments showing that doxorubicin and doxorubicinol bind to RyR2. Conversely, the irreversible nature of the inhibitory effect suggested a non-ligand binding effect. Treatment with anthracyclines reduced the number of thiols on RyR2, indicative of a drug-induced thiol-modification such as oxidation. Together, these results support the earlier hypothesis that activation of RyR2 by anthracyclines is due to ligand binding, while the inhibitory effect is due to direct thiol oxidation. In addition to modulating RyR2, doxorubicinol was found to alter other aspects of SR Ca2+ handling. For the first time, the effect of doxorubicinol on the luminal Ca2+ sensitivity of RyR2 channels has been assessed. Doxorubicinol abolished the response of RyR2 to changes in luminal Ca2+. Additional experiments revealed that the abolition of luminal Ca2+ sensing was due to an interaction between doxorubicinol and CSQ2. Furthermore, in SR vesicles, a decrease in the Ca2+ uptake rate showed that doxorubicinol inhibits the function of SERCA2A. This effect could be prevented by pre-treatment with the thiol protective agent dithiothreitol, indicating that doxorubicinol's inhibition of SERCA2A was due to thiol oxidation. Hence doxorubicinol causes substantial dysfunction of SR Ca2+ handling proteins, affecting both Ca2+ release and Ca2+ uptake pathways. To determine the effects of doxorubicinol in an intact cell, cardiomyocytes were isolated from adult mouse hearts and loaded with the Ca2+ indicator Fluo-4. Pre-treatment with doxorubicinol reduced cytoplasmic Ca2+ transients, depleted SR load and inhibited SERCA2A and the Na+- Ca2+ exchanger. Furthermore, doxorubicinol-treated myocytes exhibited more spontaneous Ca2+ release events and had a higher resting Ca2+ concentration. These effects resulted in an overall impairment in contractile function. This project provides novel insight into cellular mechanisms of anthracyclines and is the most thorough characterization of the effects of these drugs on cardiomyocyte Ca2+ handling to date. The results suggest that by targeting multiple Ca2+ handling proteins, anthracyclines severely disturb cardiomyocyte Ca2+ homeostasis and that these effects may have an important role in the onset of anthracycline-mediated arrhythmia and heart failure

Database Analysis Of State Surface Soil Regulatory Guidance Values

A 2001 study of Cleveland, Ohio brownfield surface soil contamination led to the examination of state regulatory guidance values for soils. Surface soils were of particular interest since these generally pose the greatest risk to human health at brownfield sites. This investigation initially focused on heavy metals, common contaminants at Cleveland brownfields. However, the observation of significant variability in guidance values applied to Cd, Cr, Cu, Pb, Ni, and Zn led to questions about other state-regulated components and ultimately to research examining the origins, magnitudes, and explanations for regulatory guidance value variability. The results presented here are based on the compilation of an 18,776 state surface soil database assembled from regulatory guidance for organic, inorganic, and element contaminants. All values were captured electronically from internet sources. The structure of each guidance value dataset was then standardized in a database-compatible format. Chemical Abstract Service (CAS) registry numbers were added to each record if they were not already provided. Identification of all records by CAS number resolves the problem of chemical synonyms. All value datasets were then assembled into the ACCESS database S3GVD (State Surface Soil Guidance Value Database) Statistical analysis is presented to characterize the nature and extent of variability in state surface soil guidance values. The organics, inorganics, and elements most and least commonly regulated and the range of guidance values are discussed. Log-scale Ordered Column Diagrams (LOCDs) are used to explore the nature of individual chemical guidance value distributions

Pupils protest over toilet rules : why school responses should consider children’s rights

Many people across the UK have been protesting in 2023. Teachers on strike over pay and working conditions marched through London with placards and listened to speeches on March 15. Protests against the government’s illegal migration bill took place in Glasgow, London and Cardiff. Young people have also been protesting at a number of schools. One issue has been school rules that they claim stops them from going to the toilets during lessons

Seen and not heard : students' uses and experiences of silence in school relationships at a secondary school

Silence is traditionally understood as a power deficit; yet, it creates spaces in which power works unobtrusively. In this article, I report the findings of a qualitative study examining silence in school relationships. Based on nine conceptual discussions and 33 interviews with teachers and students in a secondary school in the UK, I assert that uses of silence in relationships between students and teachers revolve around two conceptions of power: a stronghold of respect and a refuge for dignity

Kinetochore inactivation by expression of a repressive mRNA.

Differentiation programs such as meiosis depend on extensive gene regulation to mediate cellular morphogenesis. Meiosis requires transient removal of the outer kinetochore, the complex that connects microtubules to chromosomes. How the meiotic gene expression program temporally restricts kinetochore function is unknown. We discovered that in budding yeast, kinetochore inactivation occurs by reducing the abundance of a limiting subunit, Ndc80. Furthermore, we uncovered an integrated mechanism that acts at the transcriptional and translational level to repress NDC80 expression. Central to this mechanism is the developmentally controlled transcription of an alternate NDC80 mRNA isoform, which itself cannot produce protein due to regulatory upstream ORFs in its extended 5' leader. Instead, transcription of this isoform represses the canonical NDC80 mRNA expression in cis, thereby inhibiting Ndc80 protein synthesis. This model of gene regulation raises the intriguing notion that transcription of an mRNA, despite carrying a canonical coding sequence, can directly cause gene repression

Savannah Hockey Classic Attendance Motivation

The Savannah Hockey Classic has become a very successful annual university club hockey team tournament. The 21st edition of the tournament was held in January 2020 in Savannah, Ga. featuring the Georgia Institute of Technology, University of Florida, Florida State University, and University of Georgia club hockey teams—the same teams that have comprised the tournament for many years. This study utilized Personal Investment Theory (Braskamp, 1986) and the SPEED scale (Funk, Filo, Beaton, & Pritchard, 2009) for attendance motivation assessment. Social interaction motivations were significantly higher for county residents, spectators attending with friends, spectators attending with family, and past Savannah Hockey Classic attendees. Motivations related to athlete performance were significantly higher for those who had attended the event in the past. Excitement based motivations were greater for those who had attended the event in the past as well as for those who identified as a fan of one of the teams. There were significant differences related to the esteem and diversion constructs for those who had a team rooting interest. The article fills a gap in the literature by providing the first study of club hockey attendance motivations

Youth digital activism, social media and human rights education: the Fridays for Future movement

This article examines the social media activity (Twitter) of the youth-led ‘Fridays for Future’ climate movement during the transition from in-person to online strikes early in the Covid-19 pandemic. Our aim was to identify possibilities and challenges for human rights education in youth digital activism. The research question of the study was to explore whether and how the digital environment serves as an educational space for learning about, for and through human rights. Adopting a digital ethnography, we analysed over 9,400 posts in 2020 and 2022, examining the extent to which activists’ understandings of civil, political and socio-economic rights—particularly peaceful assembly, freedom of expression, the right to a healthy environment and adequate standard of living—developed. Findings reveal the responsive, inclusive, and experiential nature of peer-to-peer learning in a social movement and our discussion considers how digital activism might support future human rights-based digital learning

Cardiac ryanodine receptor activation by a high Ca2+ store load is reversed in a reducing cytoplasmic redox environment

Here, we report the impact of redox potential on isolated cardiac ryanodine receptor (RyR2) channel activity and its response to physiological changes in luminal [Ca2+]. Basal leak from the sarcoplasmic reticulum is required for normal Ca2+ handling, bu

Experiences of cancer patients in receiving dietary advice from healthcare professionals and of healthcare professionals in providing this advice– a systematic review

Purpose: This systematic review investigated qualitative and quantitative studies exploring patients and healthcare professionals’ (HCP) experience of nutrition care throughout the cancer journey. Methods: Five databases were systematically searched for studies reporting on patient and healthcare professionals’ experience of nutrition advice. Results: Fifteen studies including 374 patients and 471 healthcare professionals were included. Findings indicate that patients desire more specific nutrition advice supported by members of the multidisciplinary team and delivered in appropriate and understandable language. Healthcare professionals have highlighted a lack of time, funding, dietetic roles, and knowledge as barriers to integrating nutrition as a standard part of cancer care. Five themes were identified (current provision of nutrition advice, optimal provision of nutrition advice, tension between patient values and nutritional or HCP priorities, providing evidence-based nutrition care, and practical barriers to nutrition advice provision). Conclusions: Further work is essential to better understand and address identified barriers and improve the provision of nutrition advice to this population. Implications for Cancer Survivors: Findings from this review will guide the delivery of nutrition advice for cancer survivors.</p