Kim Workman: Journey Towards Justice

Workman, Kim

doi:10.7810/9780947492533

Cited by 5 publications

(8 citation statements)

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“…To test whether I CaL,D-C window narrowing could suppress or prevent EADs, we induced EADs either by increasing the conductance of an injected I CaL,D-C having a normal window (as produced, for example, by adrenergic stimulation) (Workman, 2010) or, in myocytes then failing to generate EADs, adding the APD-prolonging influence of K + current-block from 4-AP (Workman et al 2000). These interventions should promote EADs by increasing reactivating current amplitude and dwell-time, respectively (January & Riddle, 1989;Fozzard, 1992;Devenyi et al 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Cardiomyocytes were isolated from rabbit and human atrial tissues, as described previously (Workman et al 2000;Workman et al 2001). Rabbits (New Zealand White [Envigo, Huntington, UK], male, aged 16-34 weeks, weighing 2.1-3.6 kg, feeding ad libitum; n = 36) were humanely killed by I.V.…”

Section: Atrial Cardiomyocytesmentioning

confidence: 99%

“…Rabbits (New Zealand White [Envigo, Huntington, UK], male, aged 16-34 weeks, weighing 2.1-3.6 kg, feeding ad libitum; n = 36) were humanely killed by I.V. injection of anaesthetic (100 mg kg -1 Na + -pentobarbital, via the left marginal ear vein) and removal of the heart, which was retrogradely perfused via the aorta for enzymatic dissociation of left atrial cells (Workman et al 2000). Right atrial tissues were obtained from 28 adult patients (66 ± 2 years; 20 male, eight female) undergoing cardiac surgery (82% coronary artery bypass graft, 36% aortic valve replacement).…”

Section: Atrial Cardiomyocytesmentioning

confidence: 99%

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Dynamic clamping human and rabbit atrial calcium current: narrowing I_CaL window abolishes early afterdepolarizations

Kettlewell

Saxena

Dempster

et al. 2019

The Journal of Physiology

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Key points Early‐afterdepolarizations (EADs) are abnormal action potential oscillations and a known cause of cardiac arrhythmias. Ventricular EADs involve reactivation of a Ca2+ current (ICaL) in its ‘window region’ voltage range. However, electrical mechanisms of atrial EADs, a potential cause of atrial fibrillation, are poorly understood. Atrial cells were obtained from consenting patients undergoing heart surgery, as well as from rabbits. ICaL was blocked with nifedipine and then a hybrid patch clamp/mathematical‐modelling technique, ‘dynamic clamping’, was used to record action potentials at the same time as injecting an artificial, modifiable, ICaL (ICaL,D‐C). Progressively widening the ICaL,D‐C window region produced EADs of various types, dependent on window width. EAD production was strongest upon moving the activation (vs. inactivation) side of the window. EADs were then induced by a different method: increasing ICaL,D‐C amplitude and/or K+ channel‐blockade (4‐aminopyridine). Narrowing of the ICaL,D‐C window by ∼10 mV abolished these EADs. Atrial ICaL window narrowing is worthy of further testing as a potential anti‐atrial fibrillation drug mechanism. Abstract Atrial early‐afterdepolarizations (EADs) may contribute to atrial fibrillation (AF), perhaps involving reactivation of L‐type Ca2+ current (ICaL) in its window region voltage range. The present study aimed (i) to validate the dynamic clamp technique for modifying the ICaL contribution to atrial action potential (AP) waveform; (ii) to investigate the effects of widening the window ICaL on EAD‐propensity; and (iii) to test whether EADs from increased ICaL and AP duration are supressed by narrowing the window ICaL. ICaL and APs were recorded from rabbit and human atrial myocytes by whole‐cell‐patch clamp. During AP recording, ICaL was inhibited (3 µm nifedipine) and replaced by a dynamic clamp model current, ICaL,D‐C (tuned to native ICaL characteristics), computed in real‐time (every 50 µs) based on myocyte membrane potential. ICaL,D‐C‐injection restored the nifedipine‐suppressed AP plateau. Widening the window ICaL,D‐C, symmetrically by stepwise simultaneous equal shifts of half‐voltages (V0.5) of ICaL,D‐C activation (negatively) and inactivation (positively), generated EADs (single, multiple or preceding repolarization failure) in a window width‐dependent manner, as well as AP alternans. A stronger EAD‐generating effect resulted from independently shifting activation V0.5 (asymmetrical widening) than inactivation V0.5; for example, a 15 mV activation shift produced EADs in nine of 17 (53%) human atrial myocytes vs. 0 of 18 from inactivation shift (P < 0.05). In 11 rabbit atrial myocytes in which EADs were generated either by increasing the conductance of normal window width ICaL,D‐C or subsequent 4‐aminopyridine (2 mm), window ICaL,D‐C narrowing (10 mV) abolished EADs of all types (P < 0.05). The present study validated the dynamic clamp for ICaL, which is novel in atrial cardiomyocytes, and showed that EADs of various types are generated by wide...

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Section: Discussionmentioning

confidence: 99%

Section: Atrial Cardiomyocytesmentioning

confidence: 99%

Section: Atrial Cardiomyocytesmentioning

confidence: 99%

See 1 more Smart Citation

Dynamic clamping human and rabbit atrial calcium current: narrowing I_CaL window abolishes early afterdepolarizations

Kettlewell

Saxena

Dempster

et al. 2019

The Journal of Physiology

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“…Histone tail PTMs are involved in chromatin remodeling and play important roles in transcription regulation (Mersfelder & Parthun, 2006). Among the PTMs on histone tails, acetylation on lysine residues of histones and its role in transcription regulation is well established (Clayton et al, 2006;Jenuwein & Allis, 2001;Kuo & Allis, 1998;Sterner & Berger, 2000;Struhl, 1998;Workman & Kingston, 1998). Histone acetylation neutralizes lysine residue charges, disrupting histone-DNA interactions, resulting in an open chromatin structure which aids the accessibility of transcription components to the underlying DNA for transcription activation (Clayton et al, 2006;Jenuwein & Allis, 2001;Kuo & Allis, 1998;Sterner & Berger, 2000;Struhl, 1998;Workman & Kingston, 1998).…”

Section: Introductionmentioning

confidence: 99%

TIP60 acetylates H2AZ and regulates doxorubicin-induced DNA damage sensitivity throughRAD51transcription

Lee

Zhang

Magallanes

et al. 2020

Preprint

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TIP60, a lysine acetyltransferase and H2AZ, a histone H2A variant are involved in transcription and DNA repair. Recent studies suggest that H2AZ acetylation is dependent on TIP60. Here, we show that TIP60 acetylates both isoforms of H2AZ in vitro and in cells. Utilizing ChIP-seq and RNA-seq to identify the genes regulated by TIP60-dependent acetylation of H2AZ, we find that TIP60-dependent acetylation of H2AZ correlates with the expression of genes involved in DNA damage repair, amongst several other pathways. In line with this, TIP60-depleted cells exhibit increased sensitivity to the DNA damage-inducing drug doxorubicin. Restoring the expression level of RAD51, one of the genes involved in the DNA damage repair pathway, partially rescues the doxorubicin sensitivity due to TIP60 depletion. Overall, our study uncovers a role for TIP60 in regulating doxorubicin-induced DNA damage sensitivity in a manner dependent on RAD51 transcription. LN, DN, WST, CYT conducted the experiments. KKL, YZ, LN performed protein purification and HAT assay. YZ generated samples for RNA-seq and ChIP-seq, and CYT generated samples for 1 set of RNA-seq data. YZ, KKL, LN, SSB and DR validated RNA-seq results. DR and SSB validated ChIP-seq results. KKL, YZ, DR, SSB and LN performed doxorubicin sensitivity assays. KKL performed cisplatin and camptothecin sensitivity assays. DN performed knockdown in various cell lines. WST attempted some mice experiments. RTM and SSB conducted and, TB and SJ supervised the bioinformatics analysis used in this study. MMH, ADJ, YT, CWJ and DGT helped in the better design of experiments and provided valuable intellectual input. 37

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“…The colonising powers used the law to disown the Māori people of land, language and identity and went on to use the law to remove Māori tamariki from their whānau/family in large numbers (e.g., Stanley, 2016;Workman, 2018) therefore affecting Māori people's trust in the law as a mechanism of justice.…”

Section: Historical Justicementioning

confidence: 99%

Investigating The Autobiographical Memories Of Adolescent Boys In Youth Justice Facilities

Whelan¹

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Abstract This PhD thesis used a mixed method approach to investigate the life narratives and autobiographical memories of 41 adolescent boys, while they were detained in youth justice facilities in the North Island of Aotearoa New Zealand. The overarching aim of the research was to determine how these rangatahi reflected on their important past experiences and whether the meaning they made of their experiences was associated with aspects of their wellbeing. Given the multiple challenges these rangatahi are likely to have experienced, and the likelihood that they would have received little support to help them process their life experiences, the current research hypothesised that higher levels of reflection would be associated with poorer wellbeing during adolescence. Māori and Pacific adolescents are disproportionally detained in youth justice facilities in Aotearoa New Zealand and thus, this research was placed within the historical and contemporary contexts that relate to the disproportionate number of Māori and Pacific adolescents in the justice system. This research was conducted within a Western scientific framework, but the researcher, a tauiwi/non-Māori researcher, (see Appendix A for positioning statement), was guided by the Te Ara Tika methodological framework (Hudson et al., 2010), the over-arching values of Pacific peoples (Ministry of Pacific People’s Report, 2018), and governed by academic supervisors, a Māori academic/cultural supervisor, and a Research Whānau. The three cross-sectional quantitative studies investigated how these rangatahi organised their life experiences into their life narrative (Study One), interpreted and evaluated important events in their lives (Study Two), and reflected and gained insight from those experiences (Study Three). The relationships between the way these rangatahi/adolescents organised and made meaning out of their past experiences and their self-esteem, internalising symptoms/externalising behaviour and future orientation (how much control they felt they had over and hope they felt about their future) were investigated. In addition, thematic analysis was used to analyse the rangatahi/adolesents’ recall of significant life experiences (self-defining memories) to gain a richer understanding of the participants’ reflections on their childhoods. The ‘My Life as a Film’ autobiographical memory protocol was developed for this research to elicit the participants’ life narratives and three specific self-defining memories (a time when they hurt someone, a time when an adult was especially kind or caring towards them, and a turning point event/an event that changed their life). All of the adolescents could recount their life narrative and recall a time when they hurt someone, all bar one of the rangatahi/adolescents could recall a turning point event in their lives, but 32 out of 41 of the adolescents could not recall a specific memory of a time in their life where an adult was especially kind or caring towards them. The adolescents’ ability to recall other events but not a time of adult kindness suggests this is not a memory deficit but represents a poverty of adult care across the multiple contexts of their lives (e.g., whānau/family, education, health system, justice system, system of State-care). Qualitative analyses of the narratives found the themes expressed by the rangatahi in their autobiographical narratives highlighted the significant adversity these rangatahi/adolescents have experienced. The adolescents’ memories suggest there had been a systematic failure across their childhoods to meet their needs for adult support and care. The quantitative analyses found rangatahi/adolescents who had more highly organised life narratives (greater number of lifetime periods containing specific memories), felt more positively about themselves, (higher self-esteem), than rangatahi/adolescents with poorly organised life narratives. In addition, rangatahi/adolescents who could consider the perspectives of others, when recalling events where they had hurt people, had lower levels of conduct problems than rangatahi/adolescents who did not discuss the negative emotional experiences of others in their narratives. Finally, as predicted, we found adolescents who reflected more on their past felt less confident about their capabilities and more negative about themselves than adolescents who expressed less reflection. Given that rangatahi who offend are often asked to reflect on their lives in rehabilitation and therapeutic programmes, and the importance of positive self-esteem to behavioural change, this finding highlights the need for the consideration of developmental factors when developing policy and programmes for rangatahi in the justice system. While self-reflection may support positive change for adults in the justice system, the current findings suggest that may not be the case for adolescents. Limitations, implications for the key findings and consideration of how the quantitative and qualitative findings may impact policy and future support for justice-involved adolescents are explored.

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Kim Workman: Journey Towards Justice

Cited by 5 publications

References 0 publications

Dynamic clamping human and rabbit atrial calcium current: narrowing I_CaL window abolishes early afterdepolarizations

Dynamic clamping human and rabbit atrial calcium current: narrowing I_CaL window abolishes early afterdepolarizations

TIP60 acetylates H2AZ and regulates doxorubicin-induced DNA damage sensitivity throughRAD51transcription

Investigating The Autobiographical Memories Of Adolescent Boys In Youth Justice Facilities

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Kim Workman: Journey Towards Justice

Cited by 5 publications

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Dynamic clamping human and rabbit atrial calcium current: narrowing ICaL window abolishes early afterdepolarizations

Dynamic clamping human and rabbit atrial calcium current: narrowing ICaL window abolishes early afterdepolarizations

TIP60 acetylates H2AZ and regulates doxorubicin-induced DNA damage sensitivity throughRAD51transcription

Investigating The Autobiographical Memories Of Adolescent Boys In Youth Justice Facilities

Contact Info

Product

Resources

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Dynamic clamping human and rabbit atrial calcium current: narrowing I_CaL window abolishes early afterdepolarizations

Dynamic clamping human and rabbit atrial calcium current: narrowing I_CaL window abolishes early afterdepolarizations