Triple Thread

Program listing performers and works performed

Oboe Studio Recital

Program listing performers and works performed

ANIA:ANnotation and Integrated Analysis of the 14-3-3 interactome

The dimeric 14-3-3 proteins dock onto pairs of phosphorylated Ser and Thr residues on hundreds of proteins, and thereby regulate many events in mammalian cells. To facilitate global analyses of these interactions, we developed a web resource named ANIA: ANnotation and Integrated Analysis of the 14-3-3 interactome, which integrates multiple data sets on 14-3-3-binding phosphoproteins. ANIA also pinpoints candidate 14-3-3-binding phosphosites using predictor algorithms, assisted by our recent discovery that the human 14-3-3-interactome is highly enriched in 2R-ohnologues. 2R-ohnologues are proteins in families of two to four, generated by two rounds of whole genome duplication at the origin of the vertebrate animals. ANIA identifies candidate ‘lynchpins’, which are 14-3-3-binding phosphosites that are conserved across members of a given 2R-ohnologue protein family. Other features of ANIA include a link to the catalogue of somatic mutations in cancer database to find cancer polymorphisms that map to 14-3-3-binding phosphosites, which would be expected to interfere with 14-3-3 interactions. We used ANIA to map known and candidate 14-3-3-binding enzymes within the 2R-ohnologue complement of the human kinome. Our projections indicate that 14-3-3s dock onto many more human kinases than has been realized. Guided by ANIA, PAK4, 6 and 7 (p21-activated kinases 4, 6 and 7) were experimentally validated as a 2R-ohnologue family of 14-3-3-binding phosphoproteins. PAK4 binding to 14-3-3 is stimulated by phorbol ester, and involves the ‘lynchpin’ site phosphoSer99 and a major contribution from Ser181. In contrast, PAK6 and PAK7 display strong phorbol ester-independent binding to 14-3-3, with Ser113 critical for the interaction with PAK6. These data point to differential 14-3-3 regulation of PAKs in control of cell morphology. Database URL: https://ania-1433.lifesci.dundee.ac.uk/prediction/webserver/index.p

A Night of Quintets

Program listing performers and works performed

Oboe Studio Recital

Program listing performers and works performed

Alprazolam use and related harm among opioid substitution treatment clients - 12 months follow up after regulatory rescheduling

Background Alprazolam, has been associated with disproportionate harms compared to other benzodiazepines, especially among people in opioid substitution treatment (OST). We examine the effect of the rescheduling of alprazolam in Australia, from Schedule 4 to Schedule 8 in February 2014 amongst a high-risk population of clients in OST. Methods OST participants who reported recent (last month) alprazolam use were recruited from three Sydney clinics. Participants (n = 57) were interviewed immediately prior to rescheduling and again three months and 12 months after rescheduling. We examined self-reported patterns of drug use, drug availability, mental and physical health. A linear mixed models approach was used to analyse changes in alprazolam and other benzodiazepine use. Results Mean days of alprazolam use in the past 28 days decreased from 13.7 to 7.1 days, and mean weekly alprazolam dose decreased from 15.1 mg to 6.1 mg at 12 months follow-up (p = 0.001). Total weekly benzodiazepine use also reduced from a mean of 222 mg diazepam equivalent to 157 mg (p = 0.044). Other substance use did not change significantly. Reported mode of cost price of street alprazolam doubled from $5 to$10 over the 12-month period. Conclusion Alprazolam rescheduling resulted in an overall reduction in alprazolam and total benzodiazepine use, without substitution with other drugs, in the short term. Unintended harms were not observed. Rescheduling appears to have been effective in reducing alprazolam use in this high-risk population

Chromatin Modifiers SET-25 and SET-32 Are Required for Establishment but Not Long-Term Maintenance of Transgenerational Epigenetic Inheritance

Summary: Some epigenetic modifications are inherited from one generation to the next, providing a potential mechanism for the inheritance of environmentally acquired traits. Transgenerational inheritance of RNAi phenotypes in Caenorhabditis elegans provides an excellent model to study this phenomenon, and although studies have implicated both chromatin modifications and small RNA pathways in heritable silencing, their relative contributions remain unclear. Here, we demonstrate that the putative histone methyltransferases SET-25 and SET-32 are required for establishment of a transgenerational silencing signal but not for long-term maintenance of this signal between subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step process with distinct genetic requirements for establishment and maintenance of heritable silencing. Furthermore, small RNA sequencing reveals that the abundance of secondary siRNAs (thought to be the effector molecules of heritable silencing) does not correlate with silencing phenotypes. Together, our results suggest that the current mechanistic models of epigenetic inheritance are incomplete. : RNAi induces epigenetic silencing that is sometimes transgenerationally inherited. Woodhouse et al. show that the putative histone methyltransferases SET-25 and SET-32 are required to establish the epigenetic silencing signal. However, they are dispensable for the maintenance of silencing in subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step process. Keywords: transgenerational, epigenetics, small RNA, chromatin, inheritance, RNA

Chromatin Modifiers SET-25 and SET-32 Are Required for Establishment but Not Long-Term Maintenance of Transgenerational Epigenetic Inheritance

Summary: Some epigenetic modifications are inherited from one generation to the next, providing a potential mechanism for the inheritance of environmentally acquired traits. Transgenerational inheritance of RNAi phenotypes in Caenorhabditis elegans provides an excellent model to study this phenomenon, and although studies have implicated both chromatin modifications and small RNA pathways in heritable silencing, their relative contributions remain unclear. Here, we demonstrate that the putative histone methyltransferases SET-25 and SET-32 are required for establishment of a transgenerational silencing signal but not for long-term maintenance of this signal between subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step process with distinct genetic requirements for establishment and maintenance of heritable silencing. Furthermore, small RNA sequencing reveals that the abundance of secondary siRNAs (thought to be the effector molecules of heritable silencing) does not correlate with silencing phenotypes. Together, our results suggest that the current mechanistic models of epigenetic inheritance are incomplete. : RNAi induces epigenetic silencing that is sometimes transgenerationally inherited. Woodhouse et al. show that the putative histone methyltransferases SET-25 and SET-32 are required to establish the epigenetic silencing signal. However, they are dispensable for the maintenance of silencing in subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step process. Keywords: transgenerational, epigenetics, small RNA, chromatin, inheritance, RNA