Comparison of conformational characteristics in structurally similar protein pairs.

Although it is known that three-dimensional structure is well conserved during the evolutionary development of proteins, there have been few studies that consider other parameters apart from divergence of the main-chain coordinates. In this study, we align the structures of 90 pairs of homologous proteins having sequence identities ranging from 5 to 100%. Their structures are compared as a function of sequence identity, including not only consideration of C alpha coordinates but also accessibility, Ooi numbers, secondary structure, and side-chain angles. We discuss how these properties change as the sequences become less similar. This will be of practical use in homology modeling, especially for modeling very distantly related or analogous proteins. We also consider how the average size and number of insertions and deletions vary as sequences diverge. This study presents further quantitative evidence that structure is remarkably well conserved in detail, as well as at the topological level, even when the sequences do not show similarity that is significant statistically.     

Taphonomies of Topography: From the Death of "Place" to Its Hyphenated Apotheosis

Non-Places: Introduction to an Anthropology of Supermodernity. Marc Augé. London: Verso, 1995. 122 pp.
Landscape and Power in Vienna. Robert Rotenberg. Baltimore: Johns Hopkins University Press, 1995. 385 pp.
Imagineering Atlanta: The Politics of Place in the City of Dreams. Charles Rutheiser. London: Verso, 1996. 322 pp.     

The Lin28/let-7 axis regulates glucose metabolism

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.     

Lessons from animal teaching

Many species are known to acquire valuable life skills and information from others, but until recently it was widely believed that animals did not actively facilitate learning in others. Teaching was regarded as a uniquely human faculty. However, recent studies suggest that teaching might be more common in animals than previously thought. Teaching is present in bees, ants, babblers, meerkats and other carnivores but is absent in chimpanzees, a bizarre taxonomic distribution that makes sense if teaching is treated as a form of altruism. Drawing on both mechanistic and functional arguments, we integrate teaching with the broader field of animal social learning, and show how this aids understanding of how and why teaching evolved, and the diversity of teaching mechanisms.     

Livestock production: recent trends, future prospects

The livestock sector globally is highly dynamic. In developing countries, it is evolving in response to rapidly increasing demand for livestock products. In developed countries, demand for livestock products is stagnating, while many production systems are increasing their efficiency and environmental sustainability. Historical changes in the demand for livestock products have been largely driven by human population growth, income growth and urbanization and the production response in different livestock systems has been associated with science and technology as well as increases in animal numbers. In the future, production will increasingly be affected by competition for natural resources, particularly land and water, competition between food and feed and by the need to operate in a carbon-constrained economy. Developments in breeding, nutrition and animal health will continue to contribute to increasing potential production and further efficiency and genetic gains. Livestock production is likely to be increasingly affected by carbon constraints and environmental and animal welfare legislation. Demand for livestock products in the future could be heavily moderated by socio-economic factors such as human health concerns and changing socio-cultural values. There is considerable uncertainty as to how these factors will play out in different regions of the world in the coming decades.     

Creation of genome-wide protein expression libraries using random activation of gene expression

Here we report the use of random activation of gene expression (RAGE) to create genome-wide protein expression libraries. RAGE libraries containing only 5 x 10(6) individual clones were found to express every gene tested, including genes that are normally silent in the parent cell line. Furthermore, endogenous genes were activated at similar frequencies and expressed at similar levels within RAGE libraries created from multiple human cell lines, demonstrating that RAGE libraries are inherently normalized. Pools of RAGE clones were used to isolate 19,547 human gene clusters, approximately 53% of which were novel when tested against public databases of expressed sequence tag (EST) and complementary DNA (cDNA). Isolation of individual clones confirmed that the activated endogenous genes can be expressed at high levels to produce biologically active proteins. The properties of RAGE libraries and RAGE expression clones are well suited for a number of biotechnological applications including gene discovery, protein characterization, drug development, and protein manufacturing.     

The Diving Response Mechanism and its Surprising Evolutionary Path in Seals andSea Lions

During the last half century or more, studies of diving physiologyand biochemistry made great progress in mechanistically explainingthe basic diving response of aquatic mammals and birds. Keycomponents of the diving response (apnea, bradycardia, peripheralvasoconstriction, redistribution of cardiac output) were foundin essentially all species analyzed and were generally takento be biological adaptations. By the mid 1970s, this approachto unravelling the diving response had run 'out of steam' andwas in conceptual stasis. The breakthrough which gave renewalto the field at this time was the development of microprocessorbased monitoring of diving animals in their natural environments,which led to a flurry of studies mostly confirming the basicoutlines of the diving response based upon laboratory studiesand firmly placing it into proper biological context, underliningits plasticity and species specificities. Now towards the endof the millenium, despite ever more detailed field monitoringof physiology, behaviour and ecology, mechanistic studies areagain approaching a point of diminishing returns. To avoid anotherconceptual stasis, what seems required are new initiatives whichwe anticipate may arise from two differing approaches. The firstis purely experimental, relying on magnetic resonance imaging(MRI) and spectroscopy (MRS) to expand the framework of theoriginal "diving response" concept. The second—evolutionarystudy of the diving response—is synthetic, linked to bothfield and laboratory studies. To date the evolution of the divingresponse has only been analyzed in pinnipeds and from thesestudies two kinds of patterns have emerged. (1) Some physiologicaland biochemical characters, required and used in diving animals,are highly conserved not only in pinnipeds but in all vertebrates;these traits are necessarily similar in all pinnipeds and includediving apnea, bradycardia, tissue specific hypoperfusion, andhypometabolism of hypoperfused tissues. (2) Another group offunctionally linked characters are more malleable and include(i) spleen mass, (ii) blood volume, and (iii) hemoglobin (Hb)pool size. Increases in any of these traits improve diving capacity.Assuming that conserved physiological function means conservedsequences in specific genes and their products (and that evolvingfunction requires changes in such sequences), it is possibleto rationalize both above trait categories in pinniped phytogeny.However, it is more difficult for molecular evolution theoryto explain how complex regulatory systems like those involvedin bradycardia and peripheral vasoconstriction remain the samethrough phylogenetic time than it is to explain physiologicalchange driven by positive natural selection.     

Partial characterisation of high-molecular weight glycoconjugates in the trail mucus of the freshwater pond snail Lymnaea stagnalis

We have studied the glycoconjugates in trail mucus of the pond snail Lymnaea stagnalis. The mucus was dissolved with 6 M guanidinium hydrochloride (GuHCl) and the major component was comprised of very high-M_r glycoconjugates that were eluted in the void volume of a Sepharose CL-4B gel-filtration column. This high-M_r material was pooled and thereafter subjected to density gradient centrifugation first in 4 M GuHCl/CsCl and subsequently 0.2 M GuHCl/CsCl to further remove non-glycosylated proteins and DNA. The harvested glycoconjugate pool chromatographed in the void volume of Sepharose CL-2B. However, reduction of disulfide bonds lowered the molecular size of approximately 80% of the void material yielding a major fragment and some minor smaller fragments in gel chromatography. The reduced glycoconjugates were digested with papain and yielded high molecular weight, proteinase-resistant glycopeptides. This fragmentation pattern is similar to that found for oligomeric gel-forming mucins in mammals and the amino acid composition (60% Ser/Thr) and sugar analysis of the glycopeptides is consistent with mucin-like molecules, there being no significant amounts of xylose or uronic acids. The residual 20% of the preparation, which apparently resisted reduction and protease digestion, had a similar amino acid composition to the bulk, but was somewhat different in sugar composition, containing some xylose and a significant amount of glucuronic acid. The two groups of molecules had very different morphologies in the electron microscope. Taken together, these data suggest that trail mucus is a complex mixture of at least two families of protein-glycoconjugate molecules based upon the gel-forming mucin and proteoglycan families, though we cannot rule out that polysaccharides may also be present.