Reverse Engineering of the Spindle Assembly Checkpoint

The Spindle Assembly Checkpoint (SAC) is an intracellular mechanism that ensures proper chromosome segregation. By inhibiting Cdc20, a co-factor of the Anaphase Promoting Complex (APC), the checkpoint arrests the cell cycle until all chromosomes are properly attached to the mitotic spindle. Inhibition of Cdc20 is mediated by a conserved network of interacting proteins. The individual functions of these proteins are well characterized, but understanding of their integrated function is still rudimentary. We here describe our attempts to reverse-engineer the SAC network based on gene deletion phenotypes. We begun by formulating a general model of the SAC which enables us to predict the rate of chromosomal missegregation for any putative set of interactions between the SAC proteins. Next the missegregation rates of seven yeast strains are measured in response to the deletion of one or two checkpoint proteins. Finally, we searched for the set of interactions that correctly predicted the observed missegregation rates of all deletion mutants. Remarkably, although based on only seven phenotypes, the consistent network we obtained successfully reproduces many of the known properties of the SAC. Further insights provided by our analysis are discussed

Specialized interfaces of Smc5/6 control hinge stability and DNA association

The Structural Maintenance of Chromosomes (SMC) complexes: cohesin, condensin and Smc5/6 are involved in the organization of higher-order chromosome structure—which is essential for accurate chromosome duplication and segregation. Each complex is scaffolded by a specific SMC protein dimer (heterodimer in eukaryotes) held together via their hinge domains. Here we show that the Smc5/6-hinge, like those of cohesin and condensin, also forms a toroidal structure but with distinctive subunit interfaces absent from the other SMC complexes; an unusual ‘molecular latch’ and a functional ‘hub’. Defined mutations in these interfaces cause severe phenotypic effects with sensitivity to DNA-damaging agents in fission yeast and reduced viability in human cells. We show that the Smc5/6-hinge complex binds preferentially to ssDNA and that this interaction is affected by both ‘latch’ and ‘hub’ mutations, suggesting a key role for these unique features in controlling DNA association by the Smc5/6 complex

Packages of Care for Dementia in Low- and Middle-Income Countries

In the fifth in a series of six articles on packages of care for mental disorders in low- and middle-income countries, Martin Prince and colleagues discuss the treatment of dementia

Factors associated with willingness to take extended release naltrexone among injection drug users

BACKGROUND: Although opioid-agonist therapy with methadone or buprenorphine/naloxone is currently the mainstay of medical treatment for opioid use disorder, these medications often are not well accepted or tolerated by patients. Recently, extended release naltrexone (XR-NTX), an opioid antagonist, has been advanced as an alternative treatment. The willingness of opioid-addicted patients to take XR-NTX has not been well described. METHODS: Opioid-using persons enrolled in a community-recruited cohort in Vancouver, Canada, were asked whether or not they would be willing to take XR-NTX. Logistic regression was used to independently identify factors associated with willingness to take the medication. RESULTS: Among the 657 participants surveyed between June 1, 2013, and November 30, 2013, 342 (52.1%) were willing to take XR-NTX. One factor positively associated with willingness was daily heroin injection (adjusted odds ratio [AOR] = 1.53; 95% confidence interval [CI] = 1.02–2.31), whereas Caucasian ethnicity was negatively associated (AOR = 0.59; 95% CI = 0.43–0.82). Satisfaction with agonist therapy (13.4%) and unwillingness to stop opioids being used for pain (26.9%) were the most common reasons for being unwilling to take XR-NTX. CONCLUSIONS: A high level of willingness to take XR-NTX was observed in this setting. Interestingly, daily injection heroin use was positively associated with willingness, whereas Caucasian participants were less willing to take XR-NTX. Although explanations for unwillingness were described in this study, further research is needed to investigate real-world acceptability of XR-NTX as an additional option for the treatment of opioid use disorder