Pluripotent cells of embryonic origin proliferate at unusually rapid rates and have a characteristic cell cycle structure with truncated gap phases. To define the molecular basis for this we have characterized the cell cycle control of murine embryonic stem cells and early primitive ectoderm-like cells. These cells display precocious Cdk2, cyclin A and cyclin E kinase activities that are conspicuously cell cycle independent. Suppression of Cdk2 activity significantly decreased cycling times of pluripotent cells, indicating it to be rate-limiting for rapid cell division, although this had no impact on cell cycle structure and the establishment of extended gap phases. Cdc2-cyclin B was the only Cdk activity that was identified to be cell cycle regulated in pluripotent cells. Cell cycle regulation of cyclin B levels and Y 15 regulation of Cdc2 contribute to the temporal changes in Cdc2-cyclin B activity. E2F target genes are constitutively active throughout the cell cycle, reflecting the low activity of pocket proteins such as p107 and pRb and constitutive activity of pRb-kinases. These results show that rapid cell division cycles in primitive cells of embryonic origin are driven by extreme levels of Cdk activity that lack normal cell cycle periodicity.

Although the onset of most mental disorders usually occurs during the first three decades of life, effective treatment is typically not initiated until a number of years later. Although there is increasing evidence to suggest that intervention during the early stages of a disorder may help reduce the severity and/or the persistence of the initial or primary disorder and prevent secondary disorders, additional research is needed into appropriate treatment for early stage cases as well as the long-term effects of early intervention, and to appropriate service design for those in the early stages of a mental illness. This will mean not only the strengthening and re-engineering of existing systems but also, crucially, the construction of new streams of care for young people in transition to adulthood.

Personalized medicine is rapidly becoming a reality in today's physical medicine. However, as yet this is largely an aspirational goal in psychiatry, despite significant advances in our understanding of the biochemical, genetic and neurobiological processes underlying major mental disorders. Preventive medicine relies on the availability of predictive tools; in psychiatry we still largely lack these. Furthermore, our current diagnostic systems, with their focus on well-established, largely chronic illness, do not support a pre-emptive, let alone a preventive, approach, since it is during the early stages of a disorder that interventions have the potential to offer the greatest benefit. Here, we present a clinical staging model for severe mental disorders and discuss examples of biological markers that have already undergone some systematic evaluation and that could be integrated into such a framework. The advantage of this model is that it explicitly considers the evolution of psychopathology during the development of a mental illness and emphasizes that progression of illness is by no means inevitable, but can be altered by providing appropriate interventions that target individual modifiable risk and protective factors. The specific goals of therapeutic intervention are therefore broadened to include the prevention of illness onset or progression, and to minimize the risk of harm associated with more complex treatment regimens. The staging model also facilitates the integration of new data on the biological, social and environmental factors that influence mental illness into our clinical and diagnostic infrastructure, which will provide a major step forward in the development of a truly pre-emptive psychiatry.

Forkhead transcription factors have redundant roles in the control of CLB2 cluster genes during the G2-M period of the cell cycle, in collaboration with Mcm1p.

Highlights • A clinical staging model mapping the development, progression, and extension of mental illness over time, may prove to be heuristically and practically useful in clinical practice and basic research. • Clinical staging will aid clinicians to select treatments that are particularly relevant to the earlier stages of illness, when such interventions are likely to be more effective and less harmful than those delivered later in the course of illness. • Clinical staging will allow more precise mapping of the relations between known biological markers and psychosocial risk factors and stage of illness, enabling better integration and representation of knowledge.

No abstract

Cyclin A/cdk2 is active during S and G2 phases of the cell cycle, but its regulation and function during G2 phase is poorly understood. In this study we have examined the regulation of cyclin A/cdk2 activity during normal G2 phase progression and in genotoxin-induced G2 arrest. We show that cyclin A/cdk2 is activated in early G2 phase by a cdc25 activity. In the G2 phase checkpoint arrest initiated in response to various forms of DNA damage, the cdc25-dependent activation of both cyclin A/cdk2 and cyclin B1/cdc2 is blocked. Ectopic expression of cdc25B, but not cdc25C, in G2 phase arrested cells e ciently activated both cyclin A/cdk2 and cyclin B1/cdc2. Finally, we demonstrate that the block in cyclin A/cdk2 activation in the G2 checkpoint arrest is independent of ATM/ATR. We speculate that the ATM/ ATR-independent block in G2 phase cyclin A/cdk2 activation may act as a further layer of checkpoint control, and that blocking G2 phase cyclin A/cdk2 activation contributes to the G2 phase checkpoint arrest. Oncogene (2001) 20, 921 ± 932.

It is in the interest of those in the advanced phases of a disorder that clinicians acknowledge the limitations of treatment and actively attempt to plan treatment utilizing alternate models. It is essential to be clear that such approaches do not equate to the abandonment of care, but rather to the reconceptualizing of feasible and personalized treatment goals, a rebalancing of the risks and benefits of intervention, the management of illness behaviour, and the approaches that allow the patient to live gainfully within their limitations.