The RBBP6/ZBTB38/MCM10 axis regulates DNA replication and common fragile site stability.

Faithful DNA replication is essential for the maintenance of genome integrity. Incomplete genome replication leads to DNA breaks and chromosomal rearrangements, which are causal factors in cancer and other human diseases. Despite their importance, the molecular mechanisms that control human genome stability are incompletely understood. Here, we report a pathway that is required for human genome replication and stability. This pathway has three components: an E3 ubiquitin ligase, a transcriptional repressor, and a replication protein. The E3 ubiquitin ligase RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38. This repressor negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Cells lacking RBBP6 experience reduced replication fork progression and increased damage at common fragile sites due to ZBTB38 accumulation and MCM10 downregulation. Our results uncover a pathway that ensures genome-wide DNA replication and chromosomal stability.

5-HT2A: its role in frontally mediated executive function and related psychopathology.

Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.

A brain-behaviour initiative for South Africa: the time is right.

BACKGROUND: Many have advocated for science and health research in developing world settings. However, there has been less focus on the value of basic and clinical neuroscience research in this context. The current paper focuses on the relevance of a brain-behaviour research initiative in South Africa. METHODS: Workshops sponsored by the University of Cape Town Research Office and by the National Research Foundation have recently focused on the state of South African basic and clinical neuroscience, and on how to strengthen research in these areas. The context of the discussion included national science and health priorities, as well as local research opportunities. RESULTS: Neuropsychiatric disorders account for the second largest proportion of the burden of disease in South Africa, but receive relatively little research funding. There is a critical need for research, and there are unique research opportunities, in areas such as trauma and resilience, impulsive behaviour (eg violence, sexual risk taking, and substance abuse), and neuroAIDS. Basic, clinical, and systems research can all make important contributions. CONCLUSION: There is a need to apprise policy-makers in developing world countries such as South Africa of the need for increased expenditure on basic and clinical neuroscience research. Local and international collaboration may be useful in increasing research capacity in South Africa, and ultimately in improving mental health services.