Insulin degrading enzyme is a cellular receptor mediating varicella-zoster virus infection and cell-to-cell spread

Varicella-zoster virus (VZV) causes chickenpox and shingles. While varicella is likely spread as cell-free virus to susceptible hosts, the virus is transmitted by cell-to-cell spread in the body and in vitro. Since VZV glycoprotein E (gE) is essential for virus infection, we postulated that gE binds to a cellular receptor. We found that insulin-degrading enzyme (IDE) interacts with gE through its extracellular domain. Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus. These studies indicate that IDE is a cellular receptor for both cell-free and cell-associated VZV.     

Direct evidence that receptor site-4 of sodium channel gating modifiers is not dipped in the phospholipid bilayer of neuronal membranes

In a recent note to Nature, R. MacKinnon has raised the possibility that potassium channel gating modifiers are able to partition in the phospholipid bilayer of neuronal membranes and that by increasing their partial concentration adjacent to their receptor, they affect channel function with apparent high affinity (Lee and MacKinnon (2004) Nature 430, 232-235). This suggestion was adopted by Smith et al. (Smith, J. J., Alphy, S., Seibert, A. L., and Blumenthal, K. M. (2005) J. Biol. Chem. 280, 11127-11133), who analyzed the partitioning of sodium channel modifiers in liposomes. They found that certain modifiers were able to partition in these artificial membranes, and on this basis, they have extrapolated that scorpion beta-toxins interact with their channel receptor in a similar mechanism as that proposed by MacKinnon. Since this hypothesis has actually raised a new conception, we examined it in binding assays using a number of pharmacologically distinct scorpion beta-toxins and insect and mammalian neuronal membrane preparations, as well as by analyzing the rate by which the toxin effect on gating of Drosophila DmNa(v)1 and rat brain rNa(v)1.2a develops. We show that in general, scorpion beta-toxins do not partition in neuronal membranes and that in the case in which a depressant beta-toxin partitions in insect neuronal membranes, this partitioning is unrelated to its interaction with the receptor site and the effect on the gating properties of the sodium channel. These results negate the hypothesis that the high affinity of beta-toxins for sodium channels is gained by their ability to partition in the phospholipid bilayer and clearly indicate that the receptor site for scorpion beta-toxins is accessible to the extracellular solvent.     

Eliminating non-renewable CO2 emissions from sewage treatment: an anaerobic migrating bed reactor pilot plant study

The aim of this work was to demonstrate at pilot scale a high level of energy recovery from sewage utilising a primary Anaerobic Migrating Bed Reactor (AMBR) operating at ambient temperature to convert COD to methane. The focus is the reduction in non-renewable CO(2) emissions resulting from reduced energy requirements for sewage treatment. A pilot AMBR was operated on screened sewage over the period June 2003 to September 2004. The study was divided into two experimental phases. In Phase 1 the process operated at a feed rate of 10 L/h (HRT 50 h), SRT 63 days, average temperature 28 degrees C and mixing time fraction 0.05. In Phase 2 the operating parameters were 20 L/h, 26 days, 16 degrees C and 0.025. Methane production was 66% of total sewage COD in Phase 1 and 23% in Phase 2. Gas mixing of the reactor provided micro-aeration which suppressed sulphide production. Intermittent gas mixing at a useful power input of 6 W/m(3) provided satisfactory process performance in both phases. Energy consumption for mixing was about 1.5% of the energy conversion to methane in both operating phases. Comparative analysis with previously published data confirmed that methane supersaturation resulted in significant losses of methane in the effluent of anaerobic treatment systems. No cases have been reported where methane was considered to be supersaturated in the effluent. We have shown that methane supersaturation is likely to be significant and that methane losses in the effluent are likely to have been greater than previously predicted. Dissolved methane concentrations were measured at up to 2.2 times the saturation concentration relative to the mixing gas composition. However, this study has also demonstrated that despite methane supersaturation occurring, micro-aeration can result in significantly lower losses of methane in the effluent (<11% in this study), and has demonstrated that anaerobic sewage treatment can genuinely provide energy recovery. The goal of demonstrating a high level of energy recovery in an ambient anaerobic bioreactor was achieved. An AMBR operating at ambient temperature can achieve up to 70% conversion of sewage COD to methane, depending on SRT and temperature.     

Differential growth identified in salamander larvae half‐sib cohorts: Survival strategy?

In this study we describe the growth of several different larval cohorts (i.e. half-siblings of the same mother born on the same day) of a rare, xeric-adapted salamander Salamandra s. infraimmaculata Martens, 1885, under constant density and food conditions from birth to metamorphosis. The larvae spend the critical first phase of their lives in water, mostly in temporary ponds. Age and weight at metamorphosis were highly affected by varying food conditions. We have identified six different growth modes that these larvae use, both fast growing and slow growing. Each larval cohort was found to use 2-4 different such growth modes regardless of their initial weight. Fast growing modes (I-III) will enable larvae to survive dry years, and metamorphose bigger. Slow growing modes (IV-VI), used by 8% of the larval population, will enable survival only in rainy years. These last growth modes effect differential temporal dispersal in wet years by delaying the emergence of postmetamorphs onto land. Distribution of growth modes in the larval population is affected by food but not by density conditions. Late-born, fast-growing larvae will have an advantage in dry years being able to metamorphose and disperse, whereas the slow-growing larvae will survive only in wet years.     

A polymorphism in New Zealand inbred mouse strains that inactivates phosphatidylcholine transfer protein

New Zealand obese (NZO/HlLt) male mice develop polygenic diabetes and altered phosphatidylcholine metabolism. The gene encoding phosphatidylcholine transfer protein (PC-TP) is sited within the support interval for Nidd3, a recessive NZO-derived locus on Chromosome 11 identified by prior segregation analysis between NZO/HlLt and NON/Lt. Sequence analysis revealed that the NZO-derived PC-TP contained a non-synonymous point mutation that resulted in an Arg120His substitution, which was shared by the related NZB/BlNJ and NZW/LacJ mouse strains. Consistent with the structure-based predictions, functional studies demonstrated that Arg120His PC-TP was inactive, suggesting that this mutation contributes to the deficiencies in phosphatidylcholine metabolism observed in NZO mice.     

WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data

Background  

Analysis of High Throughput (HTP) Data such as microarray and proteomics data has provided a powerful methodology to study patterns of gene regulation at genome scale. A major unresolved problem in the post-genomic era is to assemble the large amounts of data generated into a meaningful biological context. We have developed a comprehensive software tool, WholePathwayScope (WPS), for deriving biological insights from analysis of HTP data.     

The twentieth century struggle to decipher insulin signalling

Following the discovery of insulin, it took the rest of the twentieth century to understand how this hormone regulates intracellular metabolism. What are the main discoveries that led to our current understanding of this process? And how is this new knowledge being exploited in an attempt to develop improved drugs to treat the epidemic of type-2 diabetes?     

A graph-search framework for associating gene identifiers with documents

Background  

One step in the model organism database curation process is to find, for each article, the identifier of every gene discussed in the article. We consider a relaxation of this problem suitable for semi-automated systems, in which each article is associated with a ranked list of possible gene identifiers, and experimentally compare methods for solving this geneId ranking problem. In addition to baseline approaches based on combining named entity recognition (NER) systems with a "soft dictionary" of gene synonyms, we evaluate a graph-based method which combines the outputs of multiple NER systems, as well as other sources of information, and a learning method for reranking the output of the graph-based method.