Redox regulation of the mitogen-activated protein kinase pathway during lymphocyte activation

AbstractWe have previously demonstrated an obligatory requirement for intracellular reactive oxygen species generation during T lymphocyte activation, and have proposed that intracellular reactive oxygen species may act as signalling agents in the regulation of certain cellular processes, for example, during cell cycle entry. To test this hypothesis, we have been interested to determine which, if any, cell cycle entry events are affected by oxidative signalling. In earlier studies, we have identified the transcription factors NF-κB and AP-1 as molecular targets for oxidative signalling processes during cell cycle entry, and have shown that oxidative signalling is involved in the regulation of early changes in gene expression during the G0 to G1 phase transition. To extend these initial observations, we have examined the effect of antioxidant treatment on the activity of the mitogen-activated protein kinases erk1 and erk2, as members of a signal transduction pathway known to directly regulate transcription factor function. Using as a probe cysteamine, an aminothiol compound with both antioxidant and antiproliferative activity, we have identified erk2, a key element of the MAP kinase pathway, as being responsive to oxidative signalling during lymphocyte activation. These observations provide further evidence to suggest a role for intracellular oxidant generation as a regulatory mechanism during cell cycle entry, and establish a link between oxidative signalling and other aspects of the intracellular signalling network that is activated in response to mitogenic stimulation

Tip1/CLIP-170 Protein Is Required for Correct Chromosome Poleward Movement in Fission Yeast

The plus-end microtubule binding proteins (+TIPs) play an important role in the regulation of microtubule stability and cell polarity during interphase. In S. pombe, the CLIP-170 like protein Tip1, together with the kinesin Tea2, moves along the microtubules towards their plus ends. Tip1 also requires the EB1 homolog Mal3 to localize to the microtubule tips. Given the requirement for Tip1 for microtubule stability, we have investigated its role during spindle morphogenesis and chromosome movement. Loss of Tip1 affects metaphase plate formation and leads to the activation of the spindle assembly checkpoint. In the absence of Tip1 we also observed the appearance of lagging chromosomes, which do not influence the normal rate of spindle elongation. Our results suggest that S. pombe Tip1/CLIP170 is directly or indirectly required for correct chromosome poleward movement independently of Mal3/EB1

The fission yeast spindle orientation checkpoint: a model that generates tension?

International audienceIn all eukaryotes, the alignment of the mitotic spindle with the axis of cell polarity is essential for accurate chromosome segregation as well as for the establishment of cell fate, and thus morphogenesis, during development. Studies in invertebrates, higher eukaryotes and yeast suggest that astral microtubules interact with the cell cortex to position the spindle. These microtubules are thought to impose pushing or pulling forces on the spindle poles to affect the rotation or movement of the spindle. In the fission yeast model, where cell division is symmetrical, spindle rotation is dependent on the interaction of astral microtubules with the cortical actin cytoskeleton. In these cells, a bub1-dependent mitotic checkpoint, the spindle orientation checkpoint (SOC), is activated when the spindles fail to align with the cell polarity axis. In this paper we review the mechanism that orientates the spindle during mitosis in fission yeast, and discuss the consequences of misorientation on metaphase progression

Improving mental health in young people.

The gap between unmet need and access to care for mental ill-health is wider for adolescents and young people aged 12-25 years than any other age group worldwide. This age group is the peak time of onset for many mental disorders including mood, substance abuse and psychotic disorders. Effective interventions in primary or specialist care are likely to be most cost-effective at this age. Yet in most countries there are few opportunities for young people and their families to gain access to treatment and care for mental ill-health and preventive interventions. This is especially important for young people exposed to trauma and adversity. Few countries give sufficient attention to safeguarding and improving the mental health of young people and few have developed policies and programs to support this. Policy and practice changes suitable for each country have two essential starting points: improved understanding of youth mental health within communities; and involving young people and their families in decisions that affect them. Using information technology to assist care is another desirable feature of modern service development suitable for any environment. New directions and models of care to respond to better awareness and help-seeking and new approaches to health promotion are being developed in several countries, and psychiatrists have a central role in supporting these developments

Clinical staging: A heuristic and practical strategy for new research and better health and social outcomes for psychotic and related mood disorders

Most mental illnesses emerge during adolescence and early adulthood, with considerable associated distress and functional decline appearing during this critical developmental phase. Our current diagnostic system lacks therapeutic validity, particularly for the early stages of mental disorders when symptoms are still emerging and intensifying and have not yet stabilized sufficiently to fit the existing syndromal criteria. While this is, in part, due to the difficulty of distinguishing transient developmental or normative changes from the early symptoms of persistent and disabling mental illness, these factors have contributed to a growing movement for the reform of our current diagnostic system to more adequately inform the choice of therapeutic strategy, particularly in the early stages of a mental illness. The clinical staging model, which defines not only the extent of progression of a disorder at a particular point in time but also where a person lies currently along the continuum of the course of an illness, is particularly useful as it differentiates early, milder clinical phenomena from those that accompany illness progression and chronicity. This will not only enable clinicians to select treatments relevant to earlier stages of an illness, where such interventions are likely to be more effective and less harmful than treatments delivered later in the course of illness, but also allow a more efficient integration of our rapidly expanding knowledge of the biological, social, and psychological vulnerability factors involved in the development of mental illness into a useful diagnostic framework. </jats:p

Toward a twenty-first century approach to youth mental health care.

Mental health difficulties are easily the key health issue faced by adolescents and young adults in the developed world today. Epidemiological studies have shown that the incidence and prevalence of the mental disorders, as well as their contribution to the overall burden of disease, is highest in those in the 15 to 24 year age group, and yet young people in this age range are the least likely to access services for mental health problems. This issue is particularly problematic given that untreated, or poorly treated, mental disorders are associated with ongoing disability, including impaired social functioning, poor educational achievement, unemployment, substance abuse, and violence that all too often leads to a cycle of dysfunction and disadvantage that is difficult to break. Young people tend to be reluctant to discuss emotional concerns with a general practitioner if indeed they have a regular doctor, and the traditional mental health services, which cater to the needs of children or older adults, are highly alienating to young people. A new approach to mental health services for young people is clearly needed-one that considers young people's unique developmental issues, their help-seeking needs and behaviors, and the complex and evolving patterns of symptoms and morbidity common in this age group. This article describes Australian innovation in the provision of youth mental health services, which has been informed by an evidence-based approach and dedicated advocacy, that seeks to contribute to this much needed reform process. [ABSTRACT FROM AUTHOR

Sister Kinetochore Recapture in Fission Yeast Occurs by Two Distinct Mechanisms, Both Requiring Dam1 and Klp2

In eukaryotic cells, proper formation of the spindle is necessary for successful cell division. We have studied chromosome recapture in the fission yeast Schizosaccharomyces pombe. We show by live cell analysis that lost kinetochores interact laterally with intranuclear microtubules (INMs) and that both microtubule depolymerization (end-on pulling) and minus-end–directed movement (microtubule sliding) contribute to chromosome retrieval to the spindle pole body (SPB). We find that the minus-end–directed motor Klp2 colocalizes with the kinetochore during its transport to the SPB and contributes to the effectiveness of retrieval by affecting both end-on pulling and lateral sliding. Furthermore, we provide in vivo evidence that Dam1, a component of the DASH complex, also colocalizes with the kinetochore during its transport and is essential for its retrieval by either of these mechanisms. Finally, we find that the position of the unattached kinetochore correlates with the size and orientation of the INMs, suggesting that chromosome recapture may not be a random process