Changing patterns of infectious disease

Despite a century of often successful prevention and control efforts, infectious diseases remain an important global problem in public health, causing over 13 million deaths each year. Changes in society, technology and the microorganisms themselves are contributing to the emergence of new diseases, the re-emergence of diseases once controlled, and to the development of antimicrobial resistance. Two areas of special concern in the twenty-first century are food-borne disease and antimicrobial resistance. The effective control of infectious diseases in the new millennium will require effective public health infrastructures that will rapidly recognize and respond to them and will prevent emerging problems.     

Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain

In fetal alcohol syndrome (FAS), cerebellar hypoplasia is associated with impaired insulin-stimulated survival signaling. This study characterizes ethanol dose-effects on cerebellar development, expression of genes required for insulin and insulin-like growth factor (IGF) signaling, and the upstream mechanisms and downstream consequences of impaired signaling in relation to acetylcholine (ACh) homeostasis. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0%, 2%, 4.5%, 6.5%, or 9.25% ethanol from gestation day 6. Ethanol caused dose-dependent increases in severity of cerebellar hypoplasia, neuronal loss, proliferation of astrocytes and microglia, and DNA damage. Ethanol also reduced insulin, IGF-I, and IGF-II receptor binding, insulin and IGF-I receptor tyrosine kinase activities, ATP, membrane cholesterol, and choline acetyltransferase (ChAT) expression. In vitro studies linked membrane cholesterol depletion to impaired insulin receptor binding and insulin-stimulated ChAT. In conclusion, cerebellar hypoplasia in FAS is mediated by insulin/IGF resistance with attendant impairments in energy production and ACh homeostasis. Received 4 May 2006; received after revision 13 June 2006; accepted 20 June 2006     

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10??). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.     

A cryptic protease couples deubiquitination and degradation by the proteasome

The 26S proteasome is responsible for most intracellular proteolysis in eukaryotes. Efficient substrate recognition relies on conjugation of substrates with multiple ubiquitin molecules and recognition of the polyubiquitin moiety by the 19S regulatory complex--a multisubunit assembly that is bound to either end of the cylindrical 20S proteasome core. Only unfolded proteins can pass through narrow axial channels into the central proteolytic chamber of the 20S core, so the attached polyubiquitin chain must be released to allow full translocation of the substrate polypeptide. Whereas unfolding is rate-limiting for the degradation of some substrates and appears to involve chaperone-like activities associated with the proteasome, the importance and mechanism of degradation-associated deubiquitination has remained unclear. Here we report that the POH1 (also known as Rpn11 in yeast) subunit of the 19S complex is responsible for substrate deubiquitination during proteasomal degradation. The inability to remove ubiquitin can be rate-limiting for degradation in vitro and is lethal to yeast. Unlike all other known deubiquitinating enzymes (DUBs) that are cysteine proteases, POH1 appears to be a Zn(2+)-dependent protease.     

Kant on science and normativity

The aim of this paper is to explore Kant’s account of normativity through the prism of the distinction between the natural and the human sciences. Although the pragmatic orientation of the human sciences is often defined in contrast with the theoretical orientation of the natural sciences, I show that they are in fact regulated by one and the same norm, namely reason’s demand for autonomy.     

Variability and memory of protein levels in human cells

Protein expression is a stochastic process that leads to phenotypic variation among cells. The cell-cell distribution of protein levels in microorganisms has been well characterized but little is known about such variability in human cells. Here, we studied the variability of protein levels in human cells, as well as the temporal dynamics of this variability, and addressed whether cells with higher than average protein levels eventually have lower than average levels, and if so, over what timescale does this mixing occur. We measured fluctuations over time in the levels of 20 endogenous proteins in living human cells, tagged by the gene for yellow fluorescent protein at their chromosomal loci. We found variability with a standard deviation that ranged, for different proteins, from about 15% to 30% of the mean. Mixing between high and low levels occurred for all proteins, but the mixing time was longer than two cell generations (more than 40 h) for many proteins. We also tagged pairs of proteins with two colours, and found that the levels of proteins in the same biological pathway were far more correlated than those of proteins in different pathways. The persistent memory for protein levels that we found might underlie individuality in cell behaviour and could set a timescale needed for signals to affect fully every member of a cell population.     

Half-metallic graphene nanoribbons

Electrical current can be completely spin polarized in a class of materials known as half-metals, as a result of the coexistence of metallic nature for electrons with one spin orientation and insulating nature for electrons with the other. Such asymmetric electronic states for the different spins have been predicted for some ferromagnetic metals--for example, the Heusler compounds--and were first observed in a manganese perovskite. In view of the potential for use of this property in realizing spin-based electronics, substantial efforts have been made to search for half-metallic materials. However, organic materials have hardly been investigated in this context even though carbon-based nanostructures hold significant promise for future electronic devices. Here we predict half-metallicity in nanometre-scale graphene ribbons by using first-principles calculations. We show that this phenomenon is realizable if in-plane homogeneous electric fields are applied across the zigzag-shaped edges of the graphene nanoribbons, and that their magnetic properties can be controlled by the external electric fields. The results are not only of scientific interest in the interplay between electric fields and electronic spin degree of freedom in solids but may also open a new path to explore spintronics at the nanometre scale, based on graphene.