Pertussis toxin-sensitive G proteins regulate lymphoid lineage specification in multipotent hematopoietic progenitors.

Lymphoid and myeloid lineage segregation is a major developmental step during early hematopoiesis from hematopoietic stem cells. It is not clear, however, whether multipotent progenitors (MPPs) adopt a lymphoid or myeloid fate through stochastic mechanisms, or whether this process can be regulated by extracellular stimuli. In this study, we show that lymphoid lineage specification occurs in MPPs before lymphoid lineage priming, during which MPPs migrate from the proximal to the distal region relative to the endosteum of the bone marrow. Lymphoid-specified MPPs have low myeloid differentiation potential in vivo, but potently differentiate into myeloid cells in vitro. When treated with pertussis toxin, an inhibitor of G protein-coupled receptor signaling, lymphoid-specified MPPs regain in vivo myeloid potential, and their localization is dispersed in the bone marrow. These results clearly demonstrate that specific microenvironments that favorably support lymphoid or myeloid lineage development exist at structurally distinct regions in the bone marrow.

Receptor signaling in immune cell development and function.

Immune cell development and function must be tightly regulated through cell surface receptors to ensure proper responses to pathogen and tolerance to self. In T cells, the signal from the T-cell receptor is essential for T-cell maturation, homeostasis, and activation. In mast cells, the high-affinity receptor for IgE transduces signal that promotes mast cell survival and induces mast cell activation. In dendritic cells and macrophages, the toll-like receptors recognize microbial pathogens and play critical roles for both innate and adaptive immunity against pathogens. Our research explores how signaling from these receptors is transduced and regulated to better understand these immune cells. Our recent studies have revealed diacylglycerol kinases and TSC1/2-mTOR as critical signaling molecules/regulators in T cells, mast cells, dendritic cells, and macrophages.

Drug driving and the management of risk: the perspectives and practices of a sample of problem drug users.

This paper reports on a qualitative study of the attitudes and risk management strategies of a sample of problem drug users in relation to driving while under the influence of drugs. Interviews were conducted with 26 individuals (21 men and 5 women) all of whom had been addicted to heroin and had admitted to driving while under the influence of illegal drugs. The drug users reported four main strategies for managing the risks associated with drug driving: attempting to limit their drug intake to their tolerance level; delaying driving after taking a drug until they felt safe; stopping driving if they felt unsafe while behind the wheel; and avoiding driving altogether under the influence of certain drugs. However, the interviewees' accounts of their drug driving behaviour suggest that these strategies are not only far from reliable, they may also act to encourage drug driving by creating a false sense of security. The reassurance they provide may also undermine any educational messages targeting drug driving. There was little in the problem users' accounts to suggest that media campaigns or a more effective method of detection would have much influence upon their behaviour. The paper concludes that the most realistic approach to the problem may be to incorporate drug driving interventions within drug treatment programmes.