The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design

The worldwide spread of H5N1 avian influenza has raised concerns that this virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the neuraminidase enzyme of the virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A viruses form two genetically distinct groups: group-1 contains the N1 neuraminidase of the H5N1 avian virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs.     

Characterization of a carbohydrate transporter from symbiotic glomeromycotan fungi

The symbiotic relationships between mycorrhizal fungi and plants have an enormous impact on terrestrial ecosystems. Most common are the arbuscular mycorrhizas, formed by fungi belonging to the phylum Glomeromycota. Arbuscular mycorrhizal fungi facilitate the uptake of soil nutrients by plants and in exchange obtain carbohydrates, thus representing a large sink for atmospheric plant-fixed CO(2). However, how carbohydrates are transported through the symbiotic interface is still unknown. Here we report the characterization of the first known glomeromycotan monosaccharide transporter, GpMST1, by exploiting the unique symbiosis of a glomeromycotan fungus (Geosiphon pyriformis) with cyanobacteria. The GpMST1 gene has a very low GC content and contains six introns with unusual boundaries. GpMST1 possesses twelve predicted transmembrane domains and functions as a proton co-transporter with highest affinity for glucose, then mannose, galactose and fructose. It belongs to an as yet uncharacterized phylogenetic monosaccharide transporter clade. This initial characterization of a new transporter family involved in fungal symbiosis will lead to a better understanding of carbon flows in terrestrial environments.     

Rank clocks

Many objects and events, such as cities, firms and internet hubs, scale with size in the upper tails of their distributions. Despite intense interest in using power laws to characterize such distributions, most analyses have been concerned with observations at a single instant of time, with little analysis of objects or events that change in size through time (notwithstanding some significant exceptions). It is now clear that the evident macro-stability in such distributions at different times can mask a volatile and often turbulent micro-dynamics, in which objects can change their position or rank-order rapidly while their aggregate distribution appears quite stable. Here I introduce a graphical representation termed the 'rank clock' to examine such dynamics for three distributions: the size of cities in the US from ad 1790, the UK from ad 1901 and the world from 430 bc. Our results destroy any notion that rank-size scaling is universal: at the micro-level, these clocks show cities and civilizations rising and falling in size at many times and on many scales. The conventional model explaining such scaling on the basis of growth by proportionate effect cannot replicate these micro-dynamics, suggesting that such models and explanations are considerably less general than has hitherto been assumed.     

Corneal avascularity is due to soluble VEGF receptor-1

Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.     

AN EXTENSION OF TOPSIS FOR FUZZY MCDM BASED ON VAGUE SET THEORY

1.Introduction The multicriteria decision-making problem(Kickert1978)is a kind of problem that all the alternatives in the choice set can be evaluated according to a number of criteria.A MCDM problem can be concisely expressed in matrix format as C1C2C n11112122122212nnm m m mnA x x xMA x x xA x x x=W={w1,w2,,wn}where A1,A2,,Am are possible alternatives among which decision-makers have to choose,C1,C2,,C n are the criteria with which alternative performance are measured,xi j is the rati…     

VIEWING URBAN DISRUPTIONS FROM A DECISION INFORMATICS PERSPECTIVE

1. Introduction Urban infrastructures are the focus of terrorist acts because, quite simply, they produce the most visible impact, if not casualties. From the September 11, 2001 (i.e., “9/11”) attack on New York City’s World Trade Center to the more recent March 11, 2004, attack on Madrid’s commuter trains, it is obvious that urban centers are indeed vulnerable to such hideous acts. A systemic or holistic approach to securing the infrastructure systems that underpin an urban center isr…     

MODELING COMMERCIAL PROCESSES AND CUSTOMER BEHAVIORS TO ESTIMATE THE DIFFUSION RATE OF NEW PRODUCTS

1. Introduction In his famous seminal book (Rogers 1962), Rogers introduced and popularized a generic framework for analyzing and describing how the mechanism of diffusion of innovations works inside a given population. In this general approach, “innovation” can of course be understood in a large way: it may indeed referto various contexts such as the learning of a new practice, the use of a new tool, the launch of a new product, etc. The strength of Rogers' point of view comes from the fac…