A new interstellar molecule: tricarbon monoxide

The cold dark interstellar Taurus Molecular Cloud One (TMC-1) is a rich source of acetylenic and polyacetylenic molecular species. As well as linear closed-shell molecules (H(C triple bond C)nCN) and symmetric rotors (CH3C triple bond CH, CH3C triple bond CCN), several radicals (C triple bond CH, C triple bond CCN, (C triple bond C2H) have also been identified, many of which had not been studied previously in the laboratory. Whether the observed abundances can be understood in terms of purely gas-phase ion-molecule chemical schemes, which produce reasonable agreement for the simplest polyatomic species, is unclear; alternative models involving the particulate interstellar grains as catalysts or sources have also been suggested. We now report the detection in TMC-1 of a new molecule, tricarbon monoxide (C3O), whose pure rotational spectrum has only very recently been studied in the laboratory. As C3O is the first known interstellar carbon chain molecule to contain oxygen, its existence places an important new constraint on chemical schemes for cold interstellar clouds. In fact, the observed abundance of tricarbon monoxide fits quite well into our model of galactochemistry.     

CENP-B preserves genome integrity at replication forks paused by retrotransposon LTR

Centromere-binding protein B (CENP-B) is a widely conserved DNA binding factor associated with heterochromatin and centromeric satellite repeats. In fission yeast, CENP-B homologues have been shown to silence long terminal repeat (LTR) retrotransposons by recruiting histone deacetylases. However, CENP-B factors also have unexplained roles in DNA replication. Here we show that a molecular function of CENP-B is to promote replication-fork progression through the LTR. Mutants have increased genomic instability caused by replication-fork blockage that depends on the DNA binding factor switch-activating protein 1 (Sap1), which is directly recruited by the LTR. The loss of Sap1-dependent barrier activity allows the unhindered progression of the replication fork, but results in rearrangements deleterious to the retrotransposon. We conclude that retrotransposons influence replication polarity through recruitment of Sap1 and transposition near replication-fork blocks, whereas CENP-B counteracts this activity and promotes fork stability. Our results may account for the role of LTR in fragile sites, and for the association of CENP-B with pericentromeric heterochromatin and tandem satellite repeats.     

Fringe is a glycosyltransferase that modifies Notch

Notch receptors function in highly conserved intercellular signalling pathways that direct cell-fate decisions, proliferation and apoptosis in metazoans. Fringe proteins can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Here we establish the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. The post-translational modification of Notch by Fringe represents a striking example of modulation of a signalling event by differential receptor glycosylation and identifies a mechanism that is likely to be relevant to other signalling pathways.     

Inositol phosphates and cell signalling

Inositol 1,4,5-trisphosphate is a second messenger which regulates intracellular calcium both by mobilizing calcium from internal stores and, perhaps indirectly, by stimulating calcium entry. In these actions it may function with its phosphorylated metabolite, inositol 1,3,4,5-tetrakisphosphate. The subtlety of calcium regulation by inositol phosphates is emphasized by recent studies that have revealed oscillations in calcium concentration which are perhaps part of a frequency-encoded second-messenger system.     

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.     

Photoreceptor excitation and adaptation by inositol 1,4,5-trisphosphate

A central question concerning vision is the identity of the biochemical pathway that underlies phototransduction. The large size of the ventral photoreceptors of Limulus polyphemus renders them a favourite preparation for investigating this problem. The fact that a single photon opens approximately 1,000 ionic channels in these photoreceptors suggests the need for an internal transmitter. We have investigated whether inositol 1,4,5-trisphosphate (InsP3) functions as such an internal transmitter, given that InsP3 may act as an intracellular messenger in other cellular processes. Here we report that in Limulus, intracellular pressure injection of InsP3 both excites and adapts ventral photoreceptors in a manner similar to light.     

Disruption of extended defects in solid oxide fuel cell anodes for methane oxidation

Point defects largely govern the electrochemical properties of oxides: at low defect concentrations, conductivity increases with concentration; however, at higher concentrations, defect-defect interactions start to dominate. Thus, in searching for electrochemically active materials for fuel cell anodes, high defect concentration is generally avoided. Here we describe an oxide anode formed from lanthanum-substituted strontium titanate (La-SrTiO3) in which we control the oxygen stoichiometry in order to break down the extended defect intergrowth regions and create phases with considerable disordered oxygen defects. We substitute Ti in these phases with Ga and Mn to induce redox activity and allow more flexible coordination. The material demonstrates impressive fuel cell performance using wet hydrogen at 950 degrees C. It is also important for fuel cell technology to achieve efficient electrode operation with different hydrocarbon fuels, although such fuels are more demanding than pure hydrogen. The best anode materials to date--Ni-YSZ (yttria-stabilized zirconia) cermets--suffer some disadvantages related to low tolerance to sulphur, carbon build-up when using hydrocarbon fuels (though device modifications and lower temperature operation can avoid this) and volume instability on redox cycling. Our anode material is very active for methane oxidation at high temperatures, with open circuit voltages in excess of 1.2 V. The materials design concept that we use here could lead to devices that enable more-efficient energy extraction from fossil fuels and carbon-neutral fuels.     

Stepwise phosphorylation of myo-inositol leading to myo-inositol hexakisphosphate in Dictyostelium

Although myo-inositol hexakisphosphate (InsP6; phytate) is the most abundant inositol phosphate in nature and probably has a wide variety of functions, neither the route of its synthesis from myo-inositol nor its metabolic relationships with other inositol-containing compounds (such as the second messenger inositol 1,4,5-trisphosphate, Ins(1,4,5)P3) are known. Here we report that the pathway by which InsP6 is synthesized in the cellular slime mould Dictyostelium, and in cell-free preparations derived from them, is catalysed by a series of soluble ATP-dependent kinases independently of the metabolism of both phosphatidylinositol and Ins(1,4,5)P3. The intermediates between myo-inositol and InsP6 are Ins3P, Ins(3,6)P2, Ins(3,4,6)P3, Ins(1,3,4,6)P4 and Ins(1,3,4,5,6)P5. The 3- and 5-phosphates of InsP6 take part in futile cycles in which Ins(1,2,4,5,6)P5 and Ins(1,2,3,4,6)P5 are rapidly formed by dephosphorylation of InsP6, only to be rephosphorylated to yield their precursor.