A role for the Rb family of proteins in controlling telomere length

The molecular mechanisms of cellular mortality have recently begun to be unraveled. In particular, it has been discovered that cells that lack telomerase are subject to telomere attrition with each round of replication, eventually leading to loss of telomere capping function at chromosome ends. Critically short telomeres and telomeres lacking telomere-binding proteins lose their functionality and are metabolized as DNA breaks, thus generating chromosomal fusions. Telomerase activity is sufficient to rescue short telomeres and confers an unlimited proliferative capacity. In addition, the tumor-suppressor pathway Cdkn2a/Rb1 has also been implicated as a barrier to immortalization. Here, we report a connection between the members of the retinoblastoma family of proteins, Rb1 (retinoblastoma 1), Rbl1 (retinoblastoma-like 1) and Rbl2 (retinoblastoma-like 2), and the mechanisms that regulate telomere length. In particular, mouse embryonic fibroblasts doubly deficient in Rbl1 and Rbl2 or triply deficient in Rbl1, Rbl2 and Rb1 have markedly elongated telomeres compared with those of wildtype or Rb1-deficient cells. This deregulation of telomere length is not associated with increased telomerase activity. Notably, the abnormally elongated telomeres in doubly or triply deficient cells retain their end-capping function, as shown by the normal frequency of chromosomal fusions. These findings demonstrate a connection between the Rb1 family and the control of telomere length in mammalian cells.     

Top ten biotechnologies for improving health in developing countries

Most research into genomics and other related biotechnologies is concerned with the priorities of industrialized nations, and yet a limited number of projects have shown that these technologies could help improve health in developing countries. To encourage the successful application of biotechnology to global health, we carried out a study in which we asked an international group of eminent scientists with expertise in global health issues to identify the top ten biotechnologies for improving health in developing countries. The results offer concrete guidance to those in a position to influence the direction of research and development, and challenge common assumptions about the relevance and affordability of biotechnology for developing countries.     

Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4

Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Intracellular signalling mechanisms mediated by TIRs are similar, with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.     

Pure science and the problem of progress

How should we understand scientific progress? Kuhn famously discussed science as its own internally driven venture, structured by paradigms. He also famously had a problem describing progress in science, as problem-solving ability failed to provide a clear rubric across paradigm change—paradigm changes tossed out problems as well as solving them. I argue here that much of Kuhn’s inability to articulate a clear view of scientific progress stems from his focus on pure science and a neglect of applied science. I trace the history of the distinction between pure and applied science, showing how the distinction came about, the rhetorical uses to which the distinction has been put, and how pure science came to be both more valued by scientists and philosophers. I argue that the distinction between pure and applied science does not stand up to philosophical scrutiny, and that once we relinquish it, we can provide Kuhn with a clear sense of scientific progress. It is not one, though, that will ultimately prove acceptable. For that, societal evaluations of scientific work are needed.     

Beaver herbivory of willow under two flow regimes: a comparative study on the Green and Yampa rivers

The effect of flow regulation on plant-herbivore ecology has received very little attention, despite the fact that flow regulation can alter both plant and animal abundance and environmental factors that mediate interactions between them. To determine how regulated flows have impacted beaver ( Castor Canadensis ) and sandbar willow ( Salix exigua ) ecology, we first quantified the abundance and mapped the spatial distribution of sandbar willow on alluvial sections of the flow-regulated Green River and free-flowing Yampa River in northwestern Colorado. We then established 16 and 15 plots (1 m x 2.7 m) in patches of willow on the Green and Yampa Rivers, respectively, to determine whether rates of beaver herbivory of willow differed between rivers (Green versus Yampa River), seasons (fall-winter versus spring-summer), and years (spring 1998-spring 1999 versus spring 1999-spring 2000). Areal extent of willow was similar on each river, but Green River willow patches were smaller and more numerous. Beavers cut more stems during fall and winter than spring and summer and cut over 6 times more stems (percentage basis) on the Green River than on the Yampa River. We attribute the between-river difference in herbivory to higher availability of willow, greater beaver density, and lower availability of young Fremont cottonwood ( Populus deltoids subsp. wislizenii ; an alternative food source) on the Green River. Flow regulation increased willow availability to beaver by promoting the formation of island patches that are continuously adjacent to water and feature a perimeter with a relatively high proportion of willow interfacing with water.