Newly identified genetic risk variants for celiac disease related to the immune response

Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.     

Light echoes from ancient supernovae in the Large Magellanic Cloud

The light from historical supernovae could in principle still be visible as scattered-light echoes centuries after the explosion. The detection of light echoes could allow us to pinpoint the supernova event both in position and age and, most importantly, permit the acquisition of spectra to determine the 'type' of the supernova centuries after the direct light from the explosion first reached Earth. Although echoes have been discovered around some nearby extragalactic supernovae, targeted searches have not found any echoes in the regions of historical Galactic supernovae. Here we report three faint variable-surface-brightness complexes with high apparent proper motions pointing back to three of the six smallest (and probably youngest) previously catalogued supernova remnants in the Large Magellanic Cloud, which are believed to have been thermonuclear (type Ia) supernovae. Using the distance and apparent proper motions of these echo arcs, we estimate ages of 610 and 410 years for two of them.     

Evolution of a new enzyme for carbon disulphide conversion by an acidothermophilic archaeon

Extremophilic organisms require specialized enzymes for their exotic metabolisms. Acid-loving thermophilic Archaea that live in the mudpots of volcanic solfataras obtain their energy from reduced sulphur compounds such as hydrogen sulphide (H(2)S) and carbon disulphide (CS(2)). The oxidation of these compounds into sulphuric acid creates the extremely acidic environment that characterizes solfataras. The hyperthermophilic Acidianus strain A1-3, which was isolated from the fumarolic, ancient sauna building at the Solfatara volcano (Naples, Italy), was shown to rapidly convert CS(2) into H(2)S and carbon dioxide (CO(2)), but nothing has been known about the modes of action and the evolution of the enzyme(s) involved. Here we describe the structure, the proposed mechanism and evolution of a CS(2) hydrolase from Acidianus A1-3. The enzyme monomer displays a typical β-carbonic anhydrase fold and active site, yet CO(2) is not one of its substrates. Owing to large carboxy- and amino-terminal arms, an unusual hexadecameric catenane oligomer has evolved. This structure results in the blocking of the entrance to the active site that is found in canonical β-carbonic anhydrases and the formation of a single 15-?-long, highly hydrophobic tunnel that functions as a specificity filter. The tunnel determines the enzyme's substrate specificity for CS(2), which is hydrophobic. The transposon sequences that surround the gene encoding this CS(2) hydrolase point to horizontal gene transfer as a mechanism for its acquisition during evolution. Our results show how the ancient β-carbonic anhydrase, which is central to global carbon metabolism, was transformed by divergent evolution into a crucial enzyme in CS(2) metabolism.     

Symbiosis insights through metagenomic analysis of a microbial consortium

Symbioses between bacteria and eukaryotes are ubiquitous, yet our understanding of the interactions driving these associations is hampered by our inability to cultivate most host-associated microbes. Here we use a metagenomic approach to describe four co-occurring symbionts from the marine oligochaete Olavius algarvensis, a worm lacking a mouth, gut and nephridia. Shotgun sequencing and metabolic pathway reconstruction revealed that the symbionts are sulphur-oxidizing and sulphate-reducing bacteria, all of which are capable of carbon fixation, thus providing the host with multiple sources of nutrition. Molecular evidence for the uptake and recycling of worm waste products by the symbionts suggests how the worm could eliminate its excretory system, an adaptation unique among annelid worms. We propose a model that describes how the versatile metabolism within this symbiotic consortium provides the host with an optimal energy supply as it shuttles between the upper oxic and lower anoxic coastal sediments that it inhabits.     

Assembly dynamics of microtubules at molecular resolution

Microtubules are highly dynamic protein polymers that form a crucial part of the cytoskeleton in all eukaryotic cells. Although microtubules are known to self-assemble from tubulin dimers, information on the assembly dynamics of microtubules has been limited, both in vitro and in vivo, to measurements of average growth and shrinkage rates over several thousands of tubulin subunits. As a result there is a lack of information on the sequence of molecular events that leads to the growth and shrinkage of microtubule ends. Here we use optical tweezers to observe the assembly dynamics of individual microtubules at molecular resolution. We find that microtubules can increase their overall length almost instantaneously by amounts exceeding the size of individual dimers (8 nm). When the microtubule-associated protein XMAP215 (ref. 6) is added, this effect is markedly enhanced and fast increases in length of about 40-60 nm are observed. These observations suggest that small tubulin oligomers are able to add directly to growing microtubules and that XMAP215 speeds up microtubule growth by facilitating the addition of long oligomers. The achievement of molecular resolution on the microtubule assembly process opens the way to direct studies of the molecular mechanism by which the many recently discovered microtubule end-binding proteins regulate microtubule dynamics in living cells.