Reconstituting the spindle assembly checkpoint and the signalling roles of Mad1

Cell division allows the passage of genetic information to a new cell. During this process, maintaining chromosome transmission fidelity is important in preventing diseases such as cancer and Down’s syndrome. To ensure accurate chromosome segregation, eukaryotes have developed a cell cycle control mechanism that monitors kinetochore-microtubule attachments, known as the spindle assembly checkpoint (SAC). The SAC is active in metaphase and is able to sense a lack of tension and incorrect attachments between kinetochores and microtubules. This leads to a metaphase arrest, allowing time for error correction to take place before anaphase onset. The Mad and Bub proteins, along with Mps1 kinase are central to this signalling pathway which leads to the formation of the mitotic checkpoint complex (MCC) — the key inhibitor of the anaphase promoting complex/cyclosome (APC/C). APC/C inhibition prevents proteolytic degradation of Securin and Cyclin B, blocking cells in metaphase. Although we are familiar with the components of the SAC pathway, the mechanism by which they interact to form the MCC remains unclear. It is well established that SAC signalling is initiated at kinetochores. These are complex structures that are involved in key mitotic functions such as microtubule attachment and biorientation of sister chromatids. To study the checkpoint without interfering with kinetochore function, we have devised a minimalist approach. This study describes an ectopic reconstitution of SAC activation and silencing in S. pombe. Using abscisic acid induced dimerisation, we are able to control the co-recruitment of the checkpoint proteins KNL1 and Mps1 to recapitulate robust SAC arrest and silencing. Additionally, we provide insight into how S. pombe and HeLa cells respond to a prolonged ectopic arrest. It is widely accepted that Mad1 recruits Mad2 to unattached kinetochores, enabling MCC formation. However, recent findings point towards a more active role of Mad1 in checkpoint activation. This study shows that Mad1 interacts with Bub1 in S. pombe to form a scaffold complex that is essential for SAC function. We also investigate Mad1 C-terminal mutants to further dissect the roles of Mad1 and find that it forms a complex with the APC/C coactivator Cdc20. As a result, this study provides evidence in support of the hypothesis that the C-terminus of Mad1 has additional roles in SAC signalling aside from Mad2 kinetochore recruitment

Study protocol for the Multimodal Approach to Preventing Suicide in Schools (MAPSS) project: a regionally based randomised trial of an integrated response to suicide risk among secondary school students

Background Suicide is the leading cause of death among young Australians, accounting for one-third of all deaths in those under 25. Schools are a logical setting for youth suicide prevention activities, with universal, selective and indicated approaches all demonstrating efficacy. Given that international best practice recommends suicide prevention programmes combine these approaches, and that to date this has not been done in school settings, this study aims to evaluate a suicide prevention programme incorporating universal, selective and indicated components in schools. Methods This study is a trial of a multimodal suicide prevention programme for young people. The programme involves delivering universal psychoeducation (safeTALK) to all students, screening them for suicide risk, and delivering internet-based Cognitive Behavioural Therapy (Reframe IT) to those students identified as being at high risk for suicide. The programme will be trialled in secondary schools in Melbourne, Australia, and target year 10 students (15 and 16 year-olds). safeTALK and screening will be evaluated using a single group pre-test/post-test case series, and Reframe IT will be evaluated in a Randomised Controlled Trial. The primary outcome is change in suicidal ideation; other outcomes include help-seeking behaviour and intentions, and suicide knowledge and stigma. The programme’s cost-effectiveness will also be evaluated. Discussion This study is the first to evaluate a suicide prevention programme comprising universal, selective and indicated components in Australian schools. If the programme is found to be efficacious and cost-effective, it could be more widely disseminated in schools and may ultimately lead to reduced rates of suicide and suicidal behaviour in school students across the region

Nutritional interventions to ameliorate the effect of endocrine disruptors on human reproductive health: A semi-structured review from FIGO

Background: Endocrine disrupting chemicals have harmful effects on reproductive, perinatal, and obstetric outcomes. Objective: To analyze the evidence on nutritional interventions to reduce the negative effects of endocrine disruptors on reproductive, perinatal, and obstetric outcomes. Search strategy: A search of MEDLINE (PubMed), Allied Health Literature (CINAHL), EMBASE, Web of Science, and the Cochrane Database was conducted from inception to May 2021. Selection criteria: Experimental studies on human populations. Data collection and analysis: Data were collected from eligible studies. Risk of bias assessment was completed using the Cochrane risk of bias tool and the ROBINS-I Tool. Results: Database searches yielded 15 362 articles. Removing 11 181 duplicates, 4181 articles underwent abstract screening, 26 articles were eligible for full manuscript review, and 16 met full inclusion criteria. Several Interventions were found to be effective in reducing exposure to endocrine disruptors: avoidance of plastic containers, bottles, and packaging; avoidance of canned food/beverages; consumption of fresh and organic food; avoidance of fast/processed foods; and supplementation with vitamin C, iodine, and folic acid. There were some interventional studies examining therapies to improve clinical outcomes related to endocrine disruptors. Conclusion: Dietary alterations can reduce exposure to endocrine disruptors, with limited data on interventions to improve endocrine-disruptor–related clinical outcomes. This review provides useful instruction to women, their families, healthcare providers, and regulatory bodie

Nutritional interventions to ameliorate the effect of endocrine disruptors on human reproductive health: A semi-structured review from FIGO.

BackgroundEndocrine disrupting chemicals have harmful effects on reproductive, perinatal, and obstetric outcomes.ObjectiveTo analyze the evidence on nutritional interventions to reduce the negative effects of endocrine disruptors on reproductive, perinatal, and obstetric outcomes.Search strategyA search of MEDLINE (PubMed), Allied Health Literature (CINAHL), EMBASE, Web of Science, and the Cochrane Database was conducted from inception to May 2021.Selection criteriaExperimental studies on human populations.Data collection and analysisData were collected from eligible studies. Risk of bias assessment was completed using the Cochrane risk of bias tool and the ROBINS-I Tool.ResultsDatabase searches yielded 15 362 articles. Removing 11 181 duplicates, 4181 articles underwent abstract screening, 26 articles were eligible for full manuscript review, and 16 met full inclusion criteria. Several interventions were found to be effective in reducing exposure to endocrine disruptors: avoidance of plastic containers, bottles, and packaging; avoidance of canned food/beverages; consumption of fresh and organic food; avoidance of fast/processed foods; and supplementation with vitamin C, iodine, and folic acid. There were some interventional studies examining therapies to improve clinical outcomes related to endocrine disruptors.ConclusionDietary alterations can reduce exposure to endocrine disruptors, with limited data on interventions to improve endocrine-disruptor-related clinical outcomes. This review provides useful instruction to women, their families, healthcare providers, and regulatory bodies

Transforming knowledge systems for life on Earth : Visions of future systems and how to get there

Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.Peer reviewe

Transforming knowledge systems for life on Earth: Visions of future systems and how to get there

Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent