Weapons of mass destruction: virulence factors of the global killer enterotoxigenic Escherichia coli

Enterotoxigenic Escherichia coli (ETEC) is the most common cause of food and water-borne E. coli-mediated human diarrhoea worldwide. The incidence in developing countries is estimated at 650 million cases per year, resulting in 800 000 deaths, primarily in children under the age of five. ETEC is also the most common cause of diarrhoea among travellers, including the military, from industrialized nations to less developed countries. In addition, ETEC is a major pathogen of animals, being responsible for scours in cattle and neonatal and postweaning diarrhoea in pigs and resulting in significant financial losses. Studies on the pathogenesis of ETEC infections have concentrated on the plasmid-encoded heat-stable and heat-labile enterotoxins and on the plasmid-encoded antigenically variable colonization factors. Relatively little work has been carried out on chromosomally encoded virulence factors. Here, we review the known virulence factors of ETEC and highlight the future for combating this major disease.     

Structural evidence for a proton transfer pathway coupled with haem reduction of cytochrome c″ from Methylophilus methylotrophus

The crystal structures of the oxidized and reduced forms of cytochrome c″ from Methylophilus methylotrophus were solved from X-ray synchrotron data to atomic resolution. The overall fold of the molecule in the two redox states is very similar and is comparable to that of the oxygen-binding protein from the purple phototrophic bacterium Rhodobacter sphaeroides. However, significant modifications occur near the haem group, in particular the detachment from axial binding of His95 observed upon reduction as well as the adoption of different conformations of some protonatable residues that form a possible proton path from the haem pocket to the protein surface. These changes are associated with the previously well characterized redox-Bohr behaviour of this protein. Furthermore they provide a model for one of the presently proposed mechanisms of proton translocation in the much more complex protein cytochrome c oxidase.     

Gastrointestinal nematode infection is associated with variation in innate immune responsiveness

Ex vivo monocyte cytokine responses (IL-1beta, TNF-alpha, IL-12p70, IL-10, TGF-beta) to bacterial TLR2 and TLR4 ligands were quantified in 47 gastrointestinal (GI) nematode-exposed children in Pemba Island, Tanzania. Worminess (estimated by faecal egg counts (FEC)) had a positive relationship with pro-inflammatory TNF-alpha and IL-1beta responsiveness to the TLR ligands. In particular, there was a strong significant relationship with TNF-alpha response to TLR4 ligand (LPS). There were no significant associations between regulatory responses (IL-10, TGF-beta) and worminess. These results are consistent with the possibility that GI nematodes modulate innate responses and may indicate a potential mechanism for interactions between GI nematodiasis and important bystander pathogens.     

Modelling multivariate outcomes in hierarchical data, with application to cluster randomised trials

In the cluster randomised study design, the data collected have a hierarchical structure and often include multivariate outcomes. We present a flexible modelling strategy that permits several normally distributed outcomes to be analysed simultaneously, in which intervention effects as well as individual-level and cluster-level between-outcome correlations are estimated. This is implemented in a Bayesian framework which has several advantages over a classical approach, for example in providing credible intervals for functions of model parameters and in allowing informative priors for the intracluster correlation coefficients. In order to declare such informative prior distributions, and fit models in which the between-outcome covariance matrices are constrained, priors on parameters within the covariance matrices are required. Careful specification is necessary however, in order to maintain non-negative definiteness and symmetry between the different outcomes. We propose a novel solution in the case of three multivariate outcomes, and present a modified existing approach and novel alternative for four or more outcomes. The methods are applied to an example of a cluster randomised trial in the prevention of coronary heart disease. The modelling strategy presented would also be useful in other situations involving hierarchical multivariate outcomes.     

Distribution and function of potassium channels in the electrosensory lateral line lobe of weakly electric apteronotid fish

Potassium channels are one of the fundamental requirements for the generation of action potentials in the nervous system, and their characteristics shape the output of neurons in response to synaptic input. We review here the distribution and function of a high-threshold potassium channel (Kv3.3) in the electrosensory lateral line lobe of the weakly electric fish Apteronotus leptorhynchus, with particular focus on the pyramidal cells in this brain structure. These cells contain both high-threshold Kv3.3 channels, as well as low-threshold potassium channels of unknown molecular identity. Kv3.3 potassium channels regulate burst discharge in pyramidal cells and enable sustained high frequency firing through their ability to reduce an accumulation of low-threshold potassium current.W. H. Mehaffey and F. R. Fernandez contributed equally to this work.     

An index of osmotic adjustment that allows comparison of its magnitude across species and experiments

It is difficult to compare the magnitude of osmotic adjustment (OA) between species and experiments. Currently, comparisons are made by determining the magnitude of OA (MPa) at predetermined values of leaf water content, e.g. a relative water content (RWC) of 70%. The relationship between the natural logarithms of leaf water content (RWC, dependent variable) and leaf osmotic potential (π, independent variable) has a slope of 1.0 for the concentration effect. For tissues that adjust osmotically, the slope will be less than 1.0 and the osmotic index will be 1.0 – slope. The index applies to all the patterns of ln(RWC) vs ln(π) observed in experiments and is independent of the amount of drying achieved. An index of 1.0 is full capacity for OA, and a value of 0.0 is no OA. Three examples of the application of the index are given for data published on sorghum, wheat and grape vines.