Protein-DNA charge transport: Redox activation of a DNA repair protein by guanine radical

DNA charge transport (CT) chemistry provides a route to carry out oxidative DNA damage from a distance in a reaction that is sensitive to DNA mismatches and lesions. Here, DNA-mediated CT also leads to oxidation of a DNA-bound base excision repair enzyme, MutY. DNA-bound Ru(III), generated through a flash/quench technique, is found to promote oxidation of the [4Fe-4S](2+) cluster of MutY to [4Fe-4S](3+) and its decomposition product [3Fe-4S](1+). Flash/quench experiments monitored by EPR spectroscopy reveal spectra with g = 2.08, 2.06, and 2.02, characteristic of the oxidized clusters. Transient absorption spectra of poly(dGC) and [Ru(phen)(2)dppz](3+) (dppz = dipyridophenazine), generated in situ, show an absorption characteristic of the guanine radical that is depleted in the presence of MutY with formation instead of a long-lived species with an absorption at 405 nm; we attribute this absorption also to formation of the oxidized [4Fe-4S](3+) and [3Fe4S](1+) clusters. In ruthenium-tethered DNA assemblies, oxidative damage to the 5'-G of a 5'-GG-3' doublet is generated from a distance but this irreversible damage is inhibited by MutY and instead EPR experiments reveal cluster oxidation. With ruthenium-tethered assemblies containing duplex versus single-stranded regions, MutY oxidation is found to be mediated by the DNA duplex, with guanine radical as an intermediate oxidant; guanine radical formation facilitates MutY oxidation. A model is proposed for the redox activation of DNA repair proteins through DNA CT, with guanine radicals, the first product under oxidative stress, in oxidizing the DNA-bound repair proteins, providing the signal to stimulate DNA repair

Setting an agenda for disability research in Australia: organisation-led and targeted consultation report

This report presents the results of the Phase 2b consultation conducted with 974 individuals from 21 non-government organisations (NGOs), including service providers and disabled peoples’ organisations (DPOs), the First Nations-focused National Disability Research Agenda survey and online focus groups and in-depth interviews with people with augmentative and alternative communication needs. It is part of multi-phase research agenda setting exercise that has been conducted to understand existing disability research in Australia and consult with the disability sector to understand their priorities for disability research. This research was funded by the National Disability Research Partnership (NDRP) to underpin their development of an agenda for Australian disability research over the next decade

‘I’m Just a Rare Girl’: Gender and Disability in Life Stories Produced with Young Women with Intellectual Disabilities

Submission note: A thesis submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy to the Australian Research Centre in Sex, Health and Society, Faculty of Health Sciences, La Trobe University, Victoria.This thesis was a recipient of the Nancy Millis Award for theses of exceptional merit

Access to sexual health services and support for people with intellectual and developmental disabilities: an Australian cross-sector survey

Introduction People with intellectual and developmental disabilities under the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) have the right to access sexual health services including information, education, and support. Little is known about the capacity of sexual health professionals to provide these services. Methods Using an observational research design, this study utilised a descriptive survey tool (PASH–Ext) that also encompassed a standardised measure, with a cross-sectional purposive sample of 52 Australian sexual health professionals. Data was collected in 2020. Results Just over half of the participants reported having received training in their preservice education to work with people with intellectual and developmental disabilities, of these 60% held the view that people with intellectual and developmental disabilities would not feel embarrassed receiving sexual health information and support. Conclusion The study found that training is both important to the professionals’ preparedness to work with people with intellectual and developmental disabilities, and that these professionals advocate for the continuation of this training in pre-service courses and additional training in post service education for sexual health workers. Policy Implications To progressively realise Article 25 of the UNCRPD signatory, countries need to ensure sexual health services are accessible to people with intellectual and developmental disabilities. This study recommends that sexual health policy addresses equity of access for people with intellectual and developmental disability by ensuring all staff are prepared and supported to provide these services

Starting with us: Imagining relational, co-designed policy approaches to improve healthcare access for rural people with disability

Context: Access to healthcare for rural Australians is a wicked problem, particularly for rural people with disability. Contemporary healthcare access frameworks in Australia tend to overlook geography, use a ‘one-size-fits-all approach’, and disregard the valuable relationships between key rural healthcare stakeholders, including rural people with disability, rural health services and health professionals. The United Nation's Convention on the Rights of Persons with Disabilities requires the Australian Government to engage people with disability in the design of policies that will shape their day-to-day lives, including their access to healthcare. However, the nature and extent to which rural people with disability, rural health professionals and other key rural stakeholders are involved in the design of Australian policies impacting the health of rural people with disability are unknown. Aim: This paper examines approaches taken to engage rural people with disability and health professionals in the design of Australian disability policy impacting healthcare access, and reimagines future processes which can improve healthcare access for rural people with disability. Approach: Co-design and ethics of care lenses are applied to policy design approaches in this paper. We approach this work as rural disability and health academics, rural health professionals, and as rural people with disability, neurodivergence and family members of people with disability. Conclusion: We argue future co-designed policy approaches could focus on driving change towards equity in healthcare access for rural people with disability by harnessing the relational nature of rural healthcare

DNA-Bound Redox Activity of DNA Repair Glycosylases Containing [4Fe-4S] Clusters

MutY and endonuclease III, two DNA glycosylases from Escherichia coli, and AfUDG, a uracil DNA glycosylase from Archeoglobus fulgidus, are all base excision repair enzymes that contain the [4Fe-4S]^(2+) cofactor. Here we demonstrate that, when bound to DNA, these repair enzymes become redox-active; binding to DNA shifts the redox potential of the [4Fe-4S]^(3+/2+) couple to the range characteristic of high-potential iron proteins and activates the proteins toward oxidation. Electrochemistry on DNA-modified electrodes reveals potentials for Endo III and AfUDG of 58 and 95 mV versus NHE, respectively, comparable to 90 mV for MutY bound to DNA. In the absence of DNA modification of the electrode, no redox activity can be detected, and on electrodes modified with DNA containing an abasic site, the redox signals are dramatically attenuated; these observations show that the DNA base pair stack mediates electron transfer to the protein, and the potentials determined are for the DNA-bound protein. In EPR experiments at 10 K, redox activation upon DNA binding is also evident to yield the oxidized [4Fe-4S]^(3+) cluster and the partially degraded [3Fe-4S]1+ cluster. EPR signals at g = 2.02 and 1.99 for MutY and g = 2.03 and 2.01 for Endo III are seen upon oxidation of these proteins by Co(phen)_3^(3+) in the presence of DNA and are characteristic of [3Fe-4S]^(1+) clusters, while oxidation of AfUDG bound to DNA yields EPR signals at g = 2.13, 2.04, and 2.02, indicative of both [4Fe-4S]^(3+) and [3Fe-4S]^(1+) clusters. On the basis of this DNA-dependent redox activity, we propose a model for the rapid detection of DNA lesions using DNA-mediated electron transfer among these repair enzymes; redox activation upon DNA binding and charge transfer through well-matched DNA to an alternate bound repair protein can lead to the rapid redistribution of proteins onto genome sites in the vicinity of DNA lesions. This redox activation furthermore establishes a functional role for the ubiquitous [4Fe-4S] clusters in DNA repair enzymes that involves redox chemistry and provides a means to consider DNA-mediated signaling within the cell

The Healthy Brain Initiative (HBI): A prospective cohort study protocol

BACKGROUNDThe Health Brain Initiative (HBI), established by University of Miami's Comprehensive Center for Brain Health (CCBH), follows racially/ethnically diverse older adults without dementia living in South Florida. With dementia prevention and brain health promotion as an overarching goal, HBI will advance scientific knowledge by developing novel assessments and non-invasive biomarkers of Alzheimer's disease and related dementias (ADRD), examining additive effects of sociodemographic, lifestyle, neurological and biobehavioral measures, and employing innovative, methodologically advanced modeling methods to characterize ADRD risk and resilience factors and transition of brain aging.METHODSHBI is a longitudinal, observational cohort study that will follow 500 deeply-phenotyped participants annually to collect, analyze, and store clinical, cognitive, behavioral, functional, genetic, and neuroimaging data and biospecimens. Participants are ≥50 years old; have no, subjective, or mild cognitive impairment; have a study partner; and are eligible to undergo magnetic resonance imaging (MRI). Recruitment is community-based including advertisements, word-of-mouth, community events, and physician referrals. At baseline, following informed consent, participants complete detailed web-based surveys (e.g., demographics, health history, risk and resilience factors), followed by two half-day visits which include neurological exams, cognitive and functional assessments, an overnight sleep study, and biospecimen collection. Structural and functional MRI is completed by all participants and a subset also consent to amyloid PET imaging. Annual follow-up visits repeat the same data and biospecimen collection as baseline, except that MRIs are conducted every other year after baseline.ETHICS AND EXPECTED IMPACTHBI has been approved by the University of Miami Miller School of Medicine Institutional Review Board. Participants provide informed consent at baseline and are re-consented as needed with protocol changes. Data collected by HBI will lead to breakthroughs in developing new diagnostics and therapeutics, creating comprehensive diagnostic evaluations, and providing the evidence base for precision medicine approaches to dementia prevention with individualized treatment plans

Ableism

People living with disability may face significant barriers in work, study, sport and joining in everyday activities. Community attitudes and experiences of discrimination can further impact on a person’s wellbeing, with the resultant ableism leading to perceptions of the disabled as weak and needy, and experiences of rejection and oppression. Allied health professionals are constantly called on to recognise the multi-layered impact of ableism on those who seek their help, while simultaneously challenging their own perceptions and stereotypes. The chapter starts with definitions and statistics to contextualise the concept of disability within the contemporary Australian environment. The link between ableism and mental health is critically examined, and poignantly brought to life in the personal experiences of three individuals as they navigate living with invisible and visible disabilities. Experiential activities that encourage the learner to test and challenge societal stereotypes, their own perceptions and gain a greater understanding of environmental, social and institutional barriers faced by people living with disability conclude this chapter

Issues of sexuality and relationships

Sexuality in the lives of people with intellectual disability is almost always conflated with sexual abuse, sexual behaviours, sexual knowledge and questions about capacity to “be” sexual. Rarely is sexuality discussed in a more holistic way that acknowledges pleasure, desire, identity and “self-authored” sexual expression. Writers like Michael Gill (2015) suggested this is due to sexual ableism which he defined as “the system of imbuing sexuality with determinations of qualification to be sexual based on criteria of ability, intellect, morality, physicality, appearance …” (p. 3). Through this lens, sexuality in the lives of people with intellectual disability is mediated by ideas about capacity and competence, assumptions of desirability and overshadowed by a discourse of risk and vulnerability. Foley (2017) reported that underpinning this discourse is a “paternalistic regime” whereby the sexual lives of people with intellectual disability are strongly surveilled, often by parents or other caregivers. He described this regime as being played out where people with intellectual disability, despite their chronological adulthood, “either must ask permission and/or are prevented by their parents from taking control over their social/sexual lives” (p. 6)