Robert W. Tucker

Signal transduction for proliferation and differentiation in keratinocytes.

In mouse and human epidermis, the Ca2+ environment of the basal cell layer is substantially below serum Ca2+, while that of the granular cell layer is unusually high. Reduction of extracellular Ca2+ concentration (Cao) in the medium of keratinocyte cultures maintains a basal cell phenotype while serum Ca2+ concentrations induce terminal differentiation. Measurements of intracellular Ca2+ (Cai) by the use of Fura 2 and digital imaging technology reveal that Cai increases 10-20-fold in response to an increase in Cao and remains elevated. Concomitant with the rise in Cai is an increase in the metabolism of phosphatidylinositol (PI) to yield inositol phosphates and diacylglycerol. PI metabolism is also stimulated by calcium ionophores suggesting that a rise in Cai is directly responsible. The consequent increase in diacylglycerol and Cai would activate protein kinase C, an event known to trigger epidermal differentiation. Specific Cao and Cai determine the expression of individual markers of keratinocyte differentiation in vitro. These findings may account for the importance of the Ca2+ gradient for maintaining regulated growth and differentiation of the epidermis in vivo.

Revisions in need of revising: What went wrong in the Iraq war

Though critics have made a number of telling points against the Bush admin-istrations conduct of the Iraq war, the most serious problems facing Iraq and its American occupiers – criminal anarchy and lawlessness, a raging insurgency and a society divided into rival and antagonistic groups – were virtually inevitable consequences that flowed from the act of war itself. Military and civilian planners were culpable in failing to plan for certain tasks, but the most serious problems had no good solution. Even so, there are lessons to be learned. These include the danger that the imperatives of ‘force protection’ may sacrifice the broader political mission of US forces and the need for scepticism over the capacity of outsiders to develop the skill and expertise required to reconstruct decapitated states.

Role of Microtubules and Centrioles in Growth Regulation of Mammalian Cells

Recent studies have shown that hormonal growth factors can change the cytoskeleton (Tucker et al., 1979a; Tucker, 1980) and that changes in the cytoskeleton can affect the efficiency with which exogenous growth factors induce DNA synthesis (Teng et al., 1977; Vasiliev et al., 1971; Friedkin et al., 1979; Otto et al., 1979; Crossin and Carney, 1981a; Tucker, 1980; Baker, 1976b). The role of microtubules and centrioles in these interactions between growth factors and the cell has not yet been defined. However, one hypothesis, the surface modulation theory (Yahara and Edelman, 1979), which explains how microtubules might affect the role of growth factors, has been widely accepted. This theory assumes that growth factor receptors are connected to cytoplasmic microtubules and actin filaments, and that unhooking receptors from the cytoskeleton results in increased receptor motility and enhanced clustering or capping of receptors. This change of receptor position in the plasma membrane in turn either decreases or increases stimulation of DNA synthesis (McClain and Edelman, 1980; McClain et al., 1977). While this hypothesis is attractive because it explains many diverse pieces of data in the literature, there is no definitive evidence that microtubules in fact directly affect the mobility of surface receptors. Moreover, recent studies (DeMey et al., 1978; Osborn and Weber, 1977; Tucker et al., 1978; Eichhorn and Peterkofsky, 1979) have not supported previous evidence (Brinkley et al., 1975; Fuller and Brinkley, 1976; Edelman and Yahara, 1976; Rubin and Warren, 1979; Zimmer et al., 1980; Fonte and Porter, 1974) for different distributions of microtubules in cells (neoplastic and nonneoplastic) that respond differently to growth factors.

The nuclear future

Nuclear weapons have been a central element of American foreign and military policy since the Cold War began. Indeed, much of the warp and woof of the Soviet-American rivalry has been translated into domestic debate about our nuclear arsenal, its form, its relationship to other elements of policy, and the uses to which it should be put. If the rivalry, which was the essence of the Cold War, is now to undergo a radical decline in importance, may we expect that those weapons which so distinguished that rivalry will recede from our concerns in parallel? Will the end of the Cold War mean the denuclearization of American policy?

Measurement of Free Intracellular Calcium (Cai) in Fibroblasts

Measurement of intracellular calcium has long been a goal in many areas of biology. Calcium has been heralded as an intracellular messenger because of its unique structure and binding properties (Kretsingeret al., 1980), which allow Ca2+ ion to bind and activate specific regulatory molecules, such as calmodulin (Cheung, 1980). Ca2+ -activated processes have been implicated in signal transduction in metabolism, neural transmission, excitation-con traction coupling, and mitosis, and, more recently, in the stimulation of early mitogenic events in cells as diverse as fibroblasts (Boyntonet al., 1980; Chafouleaset al., 1982; Morriset al., 1984; McNeilet al., 1985; Tuckeret al., 1986) and lymphocytes (Heskethet al., l983;Gelfandet al., 1986).

The Cultured Murine Epidermal Keratinocyte and Studies of Differentiation

A gradient of free Ca2+ exists in mouse and human epidermis in which the Ca2+ environment of the basal cell layer is substantially below serum Ca2+ while that of the granular cell layer is unusually high. Reduction of extracellular Ca2+ concentration (Cao) in the medium of keratinocyte cultures maintains a basal cell phenotype in the substrate attached population while Ca2+ concentrations in the range found in serum induce terminal differentiation. Measurements of intracellular Ca2+ (Cai) by the use of the Ca2+ sensitive fluorescent dye Fura 2 and digital imaging technology reveal that Cai under basal cell culture conditions is about 25–40 nM and increases 10–20 fold in response to an increase in Cao Concomitant with the rise in Cai is a rapid increase in the metabolism of phosphatidylinositol (PI) to yield inositol phosphates and diacylglycerol. PI metabolism is also stimulated by calcium ionophores suggesting that a rise in Cai is directly responsible for stimulating PI metabolism. Phorbol esters, which activate cellular protein kinase C, also induce epidermal differentiation in vivo and in vitro even when Cao is low. Since stimulating PI metabolism by the addition of bacterial phospholipase C to culture medium mimics the action of phorbol esters, a trigger for epidermal differentiation in vivo and in vitro is likely to be the activation of PI turnover. The consequent increase in diacylgfycerol and Cai would activate protein kinase C and trigger the differentiation program. The importance of the proper Cao and Cai is emphasized since the expression of specific markers of keratinocyte differentiation in vitro is linked to specific Cao, and marker expression is sequentially regulated.

Some Considerations on the Soviet-American Relationship in the 1990s

In considering current speculation on the prospects for the Soviet-American relationship in the coming decade, it may be useful to recall past speculation on this relationship. The record is not one to inspire a great deal of confidence in present efforts to foresee the future. At the close of the 1940s the best known projection of the Soviet-American relationship was, of course, the National Security Council document NSC-68. That now-famous document, written in the shadow of the Chinese Communist victory and the Soviet Union’s development of the atomic bomb, forecast a year of maximum danger that would be reached in 1954. The 1950s ended with what was seen as an ominous disparity in missile development and an almost equally ominous disparity in rates of economic growth, prompting widespread fears that the terms of the balance of power were shifting sharply to our disadvantage. A decade later the domestic trauma of Vietnam led many to conclude that the 1970s would find a general American withdrawal in the world, and certainly in the developing world. When the 1970s drew to a close the Soviet-American relationship was seen to have entered a period even more dangerous perhaps than the period marking the early years of the Cold War. In Europe and in the Persian Gulf the United States was considered to face a decade of peril during which it would have to mount its best efforts in order to reverse a balance of military power, strategic and conventional, that now favored the Soviet Union.

Studies of Intracellular Free Calcium in Human Lymphocytes Using Fura 2 and Digital Image Analysis

different types of lymphocytes4 have emphasized the importance of spatial and temporal localization of Cai changes within single living cells. We have measured the fluorescence of intracellular fura Z5 by digital image analysis in order to quantitate variations of Cai within single human peripheral lymphocytes stimulated by the mitogen PHA-L6 nucleus and cytosol) P and differences in the activation potency of mitogens in