Online Resource to Promote Vocational Interests Among Job Seekers With Multiple Sclerosis: A Randomized Controlled Trial in Australia

© 2017 American Congress of Rehabilitation Medicine Objective: To provide a preliminary evaluation of the effectiveness of an online resource for job seekers with multiple sclerosis (MS). Design: Randomized controlled design. Setting: Community-dwelling cohort. Participants: Adults (N = 95) with relapsing-remitting or progressive MS were randomly assigned to one of two groups. Forty-five accessed an email delivered, 7 module resource, Work and MS, over a 4 week period. Waitlist control participants (n=50) were offered the opportunity to access Work and MS 4 weeks postenrollment. Main Outcome Measures: Primary outcomes focused on vocational interests (My Vocational Situation Scale) and self-efficacy in job-seeking activities (Job-Procurement Self Efficacy Scale). Secondary outcomes focused on perceived workplace difficulties (Multiple Sclerosis Work Difficulties Questionnaire [MSWDQ]), optimism (Life Orientation Test – Revised), and mood (Patient Health Questionnaire-9). Results: Intention-to-treat analyses revealed pre-post gains: participants who accessed Work and MS reported improved confidence in their career goals (My Vocational Situation Scale g=.55; 95% confidence interval [CI],.14–.96; P=.008) and positively reappraised potential workplace difficulties (MSWDQ g range,.42–.47; P range,.023–.042). The effect on job self-efficacy was not significant, but changed in the expected direction (g=.17; 95% CI, –.23 to.57; P=.409). Completer data revealed larger, significant effect estimates (g range,.52–.64; P range,.009–.035). Conclusions: Findings provide preliminary support for the utility of a job information resource, Work and MS, to augment existing employment services. The results also suggest the need to test employment-ready interventions in a larger study population. This might include the addition of online peer support to increase intervention compliance

Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice

The apoptotic cysteine protease caspase-2 has been shown to suppress tumourigenesis in mice and its reduced expression correlates with poor prognosis in some human malignancies. Caspase-2-deficient mice develop normally but show ageing-related traits and, when challenged by oncogenic stimuli or certain stress, show enhanced tumour development, often accompanied by extensive aneuploidy. As stem cells are susceptible to acquiring age-related functional defects because of their self-renewal and proliferative capacity, we examined whether loss of caspase-2 promotes such defects with age. Using young and aged Casp2−/− mice, we demonstrate that deficiency of caspase-2 results in enhanced aneuploidy and DNA damage in bone marrow (BM) cells with ageing. Furthermore, we demonstrate for the first time that caspase-2 loss results in significant increase in immunophenotypically defined short-term haematopoietic stem cells (HSCs) and multipotent progenitors fractions in BM with a skewed differentiation towards myeloid progenitors with ageing. Caspase-2 deficiency leads to enhanced granulocyte macrophage and erythroid progenitors in aged mice. Colony-forming assays and long-term culture-initiating assay further recapitulated these results. Our results provide the first evidence of caspase-2 in regulating HSC and progenitor differentiation, as well as aneuploidy, in vivo.Swati Dawar, Nur Hezrin Shahrin, Nikolina Sladojevic, Richard J D, Andrea, Loretta Dorstyn, Devendra K Hiwase and Sharad Kuma

Belonging in the Online World: Older Adults' Use of Internet for Community

Objective: To explore older Australians’ experiences of using computermediated communication (CMC) to engage with their social networks and communities. Background: Use of CMC among older adults has been associated with favourable social outcomes. How older adults engage with others to foster these outcomes is less well known. Understanding this may be useful when developing programs to encourage older adults’ use of CMC for social purposes. Methods: In-depth semi-structured interviews with 12 adults (five women, seven men; aged 69 to 81) were conducted. Interview questions focused on individuals’ use of CMC to engage with online communities. Data were transcribed and thematically analysed. Results: Two overarching themes relating to a sense of Belonging and Support emerged. Belonging was most heavily emphasised, and included subthemes on how participants experienced their close social networks online, as well as their broader engagement with building interests and identity. Support arose to a lesser extent, and included subthemes relating to how CMC was used not only for the provision and receipt of such, but also to signal availability or need for support. Throughout, participants consistently weighed the benefits of CMC against the disadvantages. Conclusion: The findings highlight the importance of social networks and online communities for older adults and, in particular, how CMC facilitates feelings of belongingness and provides opportunities for reciprocal instrumental, emotional, and informational support. Future research needs to consider the importance of having a sense of belonging when describing the social functioning of digitally literate older adults.Belinda Grace Fuss, Diana Dorstyn, Lynn War

Mindfulness Therapies for Improving Mental Health in Parents of Children with a Developmental Disability: a Systematic Review

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Mindfulness offers promise as a therapy approach for parents of children with developmental disabilities (DD), however its effectiveness in managing mental health symptoms remains unclear. This review quantitatively examines the comparative effectiveness of mindfulness-based and informed interventions, drawing on the evidence base from randomised controlled trials (RCTs). Eight RCTs were identified from the Embase, PsycINFO, PubMed and Scopus databases. Risk of bias was assessed using the Cochrane Collaboration tool and Hedges’ g effect sizes, with associated 95% confidence intervals and p values calculated. Parents who completed Mindful Parenting or Mindfulness-Based Stress Reduction programs reported immediate and large to very large reductions in psychological distress (gw range:.39–1.94), with some improvements maintained up to 6 months post-treatment. A single study reported short-term benefits with Acceptance and Commitment Therapy. Evidence for the mental health benefits of mindfulness for parents of children with DD is still at an early stage. Controlled trials are needed to determine the differential effects of specific mindfulness techniques and how to best adapt this approach to best meet the unique needs of a vulnerable caregiver population

p53 accumulation following cytokinesis failure in the absence of caspase-2

Abstract not availableYoon Lim, Dylan De Bellis, Loretta Dorstyn, Sharad Kuma

Work and SCI: a pilot randomized controlled study of an online resource for job-seekers with spinal cord dysfunction.

STUDY DESIGN:A prospective, parallel randomized controlled trial (RCT). OBJECTIVES:To test the preliminary effects of an online resource targeted to job-seekers with spinal cord injury or disorder (SCI/D), and to determine the feasibility of proceeding to a full-scale RCT. SETTING:A community cohort in Australia. METHODS:Forty-eight adults (M = 42 years, SD = 10.95, 27 males) were randomized to receive 4-weeks access to the Work and SCI resource (n = 25) or to a wait-list control group (n = 23). The Work and SCI intervention involved six stand-alone learning modules which provided job-searching and career-planning information through text, videos, and interactive activities. Self-report measures were administered at baseline and after 4 weeks: Job Procurement Self-Efficacy Scale (JSES), Life Orientation Test-Revised (LOT-R), and Patient Health Questionnaire-9 (PHQ-9). RESULTS:Online usage data identified high uptake of the Work and SCI resource, although study attrition was problematic. Intention-to-treat analyses failed to reach statistical significance, whereas complete data revealed a significant interaction effect for optimism (LOT-R). CONCLUSION:Further research to develop and enhance Work and SCI is indicated. Remediable strategies to optimize recruitment and statistical power in a future definitive RCT are discussed. SPONSORSHIP:This project was funded by the auDA Foundation (project 16019)

Caspase-2-mediated cell death is required for deleting aneuploid cells

Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2-/-) mice develop normally but show premature ageing-related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2-/- mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2C320S mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy.S Dawar, Y Lim, J Puccini, M White, P Thomas, L Bouchier-Hayes, D R Green, L Dorstyn and S Kuma

A comprehensive characterization of the caspase gene family in insects from the order Lepidoptera

<p>Abstract</p> <p>Background</p> <p>The cell suicide pathway of apoptosis is a necessary event in the life of multicellular organisms. It is involved in many biological processes ranging from development to the immune response. Evolutionarily conserved proteases, called caspases, play a central role in regulating apoptosis. Reception of death stimuli triggers the activation of initiator caspases, which in turn activate the effector caspases. In Lepidoptera, apoptosis is crucial in processes such as metamorphosis or defending against baculovirus infection. The discovery of p35, a baculovirus protein inhibiting caspase activity, has led to the characterization of the first lepidopteran caspase, Sf-Caspase-1. Studies on Sf-Caspase-1 mode of activation suggested that apoptosis in Lepidoptera requires a cascade of caspase activation, as demonstrated in many other species.</p> <p>Results</p> <p>In order to get insights into this gene family in Lepidoptera, we performed an extensive survey of lepidopteran-derived EST datasets. We identified 66 sequences distributed among 27 species encoding putative caspases. Phylogenetic analyses showed that Lepidoptera possess at least 5 caspases, for which we propose a unified nomenclature. According to homology to their <it>Drosophila </it>counterparts and their primary structure, we determined that Lep-Caspase-1, -2 and -3 are putative effector caspases, whereas Lep-Caspase-5 and -6 are putative initiators. The likely function of Lep-Caspase-4 remains unclear. Lep-Caspase-2 is absent from the silkworm genome and appears to be noctuid-specific, and to have arisen from a tandem duplication of the Caspase-1 gene. In the tobacco hawkmoth, 3 distinct transcripts encoding putative Caspase-4 were identified, suggesting at least 2 duplication events in this species.</p> <p>Conclusions</p> <p>The basic repertoire of five major types of caspases shared among Lepidoptera seems to be smaller than for most other groups studied to date, but gene duplication still plays a role in lineage-specific increases in diversity, just as in Diptera and mammals.</p

Mitochondrial fusion is regulated by Reaper to modulate Drosophila programmed cell death

In most multicellular organisms, the decision to undergo programmed cell death in response to cellular damage or developmental cues is typically transmitted through mitochondria. It has been suggested that an exception is the apoptotic pathway of Drosophila melanogaster, in which the role of mitochondria remains unclear. Although IAP antagonists in Drosophila such as Reaper, Hid and Grim may induce cell death without mitochondrial membrane permeabilization, it is surprising that all three localize to mitochondria. Moreover, induction of Reaper and Hid appears to result in mitochondrial fragmentation during Drosophila cell death. Most importantly, disruption of mitochondrial fission can inhibit Reaper and Hid-induced cell death, suggesting that alterations in mitochondrial dynamics can modulate cell death in fly cells. We report here that Drosophila Reaper can induce mitochondrial fragmentation by binding to and inhibiting the pro-fusion protein MFN2 and its Drosophila counterpart dMFN/Marf. Our in vitro and in vivo analyses reveal that dMFN overexpression can inhibit cell death induced by Reaper or γ-irradiation. In addition, knockdown of dMFN causes a striking loss of adult wing tissue and significant apoptosis in the developing wing discs. Our findings are consistent with a growing body of work describing a role for mitochondrial fission and fusion machinery in the decision of cells to die

Drosophila IAP1-Mediated Ubiquitylation Controls Activation of the Initiator Caspase DRONC Independent of Protein Degradation

Ubiquitylation targets proteins for proteasome-mediated degradation and plays important roles in many biological processes including apoptosis. However, non-proteolytic functions of ubiquitylation are also known. In Drosophila, the inhibitor of apoptosis protein 1 (DIAP1) is known to ubiquitylate the initiator caspase DRONC in vitro. Because DRONC protein accumulates in diap1 mutant cells that are kept alive by caspase inhibition (“undead” cells), it is thought that DIAP1-mediated ubiquitylation causes proteasomal degradation of DRONC, protecting cells from apoptosis. However, contrary to this model, we show here that DIAP1-mediated ubiquitylation does not trigger proteasomal degradation of full-length DRONC, but serves a non-proteolytic function. Our data suggest that DIAP1-mediated ubiquitylation blocks processing and activation of DRONC. Interestingly, while full-length DRONC is not subject to DIAP1-induced degradation, once it is processed and activated it has reduced protein stability. Finally, we show that DRONC protein accumulates in “undead” cells due to increased transcription of dronc in these cells. These data refine current models of caspase regulation by IAPs