Physical performance and Darwinian fitness in lizards

Strong evidence for a genetic basis of variation in physical performance has accumulated. Considering one of the basic tenets of evolutionary physiology--that physical performance and darwinian fitness are tightly linked--one may expect phenotypes with exceptional physiological capacities to be promoted by natural selection. Why then does physical performance remain considerably variable in human and other animal populations? Our analysis of locomotor performance in the common lizard (Lacerta vivipara) demonstrates that initial endurance (running time to exhaustion measured at birth) is indeed highly heritable, but natural selection in favour of this trait can be unexpectedly weak. A manipulation of dietary conditions unravels a proximate mechanism explaining this pattern. Fully fed individuals experience a marked reversal of performance within only one month after birth: juveniles with low endurance catch up, whereas individuals with high endurance lose their advantage. In contrast, dietary restriction allows highly endurant neonates to retain their locomotor superiority as they age. Thus, the expression of a genetic predisposition to high physical performance strongly depends on the environment experienced early in life.     

Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain

Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions. Their dynamic instability is controlled by numerous compounds and proteins, including colchicine and stathmin family proteins. The way in which microtubule instability is regulated at the molecular level has remained elusive, mainly because of the lack of appropriate structural data. Here, we present the structure, at 3.5 A resolution, of tubulin in complex with colchicine and with the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with two tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments shows changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, the tubulin-colchicine complex sheds light on the mechanism of colchicine's activity: we show that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.     

Tungsten isotope evidence that mantle plumes contain no contribution from the Earth's core

Osmium isotope ratios provide important constraints on the sources of ocean-island basalts, but two very different models have been put forward to explain such data. One model interprets (187)Os-enrichments in terms of a component of recycled oceanic crust within the source material. The other model infers that interaction of the mantle with the Earth's outer core produces the isotope anomalies and, as a result of coupled (186)Os-(187)Os anomalies, put time constraints on inner-core formation. Like osmium, tungsten is a siderophile ('iron-loving') element that preferentially partitioned into the Earth's core during core formation but is also 'incompatible' during mantle melting (it preferentially enters the melt phase), which makes it further depleted in the mantle. Tungsten should therefore be a sensitive tracer of core contributions in the source of mantle melts. Here we present high-precision tungsten isotope data from the same set of Hawaiian rocks used to establish the previously interpreted (186)Os-(187)Os anomalies and on selected South African rocks, which have also been proposed to contain a core contribution. None of the samples that we have analysed have a negative tungsten isotope value, as predicted from the core-contribution model. This rules out a simple core-mantle mixing scenario and suggests that the radiogenic osmium in ocean-island basalts can better be explained by the source of such basalts containing a component of recycled crust.     

Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced beta-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced beta-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K A(y) and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.     

The Vision Conference: Facilitating Creative Processes

This paper presents the principles behind the design and management of the Vision Conference: a one-day workshop in which a large group of participants meet to create ideas, projects, and visions for the future activities of a local community or an organization. A case study from a local community in Denmark is also presented to illustrate the organization, planning, and management of a Vision Conference. The paper focuses on the three central social processes of the conference: group work, problem solving, and facilitation. The paper ends with a discussion of creativity and creativity techniques suitable for Vision Conferences.     

Oncogenic protein tyrosine kinases

HER2 (human epidermal growth factor receptor-2; also known as erbB2) and its relatives HER1 (epidermal growth factor receptor; EGFR), HER3 and HER4 belong to the HER family of receptor tyrosine kinases. In normal cells, activation of this receptor tyrosine kinase family triggers a rich network of signaling pathways that control normal cell growth, differentiation, motility and adhesion in several cell lineages. The first tumor studied for an alteration of the HER2 oncogene is breast carcinoma, and so far the majority of studies have been performed on this oncotype. Although involvement of HER2 as a cause of human cell transformation needs to be further investigated, overexpression of the HER2 oncogene in human breast carcinomas has been associated with a more aggressive course of disease. It has been suggested that this association depends on HER2-driven proliferation, vessel formation and/or invasiveness; however, poor prognosis may not be directly related to the presence of the oncoprotein on the cell membrane but instead to the breast carcinoma subset identified by HER2 overexpression and characterized by a peculiar gene expression profile, as recently identified. HER2-positive tumors were recently shown to benefit from anthracyclin treatment and to be resistant to endocrine therapy. Despite the fact that many pathways interacting with HER2 are still not fully understood, this tyrosine kinase receptor is, to date, a promising molecule for targeted therapy.     

Identification of autonomous IAP LTR retrotransposons mobile in mammalian cells

Mammalian genomes contain two main classes of retrotransposons, the well-characterized long and short interspersed nuclear elements, which account for approximately 30% of the genome, and the long terminal repeat (LTR) retrotransposons, which resemble the proviral integrated form of retroviruses, except for the absence of an envelope gene in some cases. Genetic studies confirmed mobility of the latter class of elements in mice, with a high proportion of phenotypic mutations consequent to transposition of the intracisternal A particle (IAP) family of LTR retrotransposons. Using the mouse genome sequence and an efficient ex vivo retrotransposition assay, we identified functional, master IAP copies that encode all the enzymatic and structural proteins necessary for their autonomous transposition in heterologous cells. By introducing mutations, we found that the three genes gag, prt and pol are all required for retrotransposition and identified the IAP gene products by electron microscopy in the form of intracellular A-type particles in the transfected cells. These prototypic elements, devoid of an envelope gene, are the first LTR retrotransposons autonomous for transposition to be identified in mammals. Their high rates of retrotransposition indicate that they are potent insertional mutagens that could serve as safe (noninfectious) genetic tools in a large panel of cells.