The structure of melts in binary metal oxide‐silica systems may be described in terms of monomers, dimers, chains, sheets, and three‐dimensional network structures. For the bulk compositions between orthosilicate and tectosilicate, three well‐defined ranges may be distinguished. For bulk nonbridging oxygen per silicon (NBO/Si) of about 2 or less, monomers, dimers, and chains coexist. In the range between metasilicate and disilicate there is usually a combination of monomers, chains, and sheets. Sheets are, however, uncommon or absent in systems where the field strength of the metal cation exceeds that of Mg2+. In those cases, monomers, chains, and three‐dimensional network units coexist. In the bulk compositional range of NBO/Si ≳1, sheets, chains, and three‐dimensional network structures coexist. In all systems the cations of high field strength show a preference for the most depolymerized structural units. Aluminum and probably ferric iron are tetrahedrally coordinated when charge balanced by a monovalent or divalent cation. Aluminate complexes thus formed show a preference for the most polymerized structural units in the melt. The degree of preference increases with decreasing field strength of the charge‐balancing cation. Ferrite complexes may form separate (MFe)4+‐O or (M0.5Fe)4+‐O clusters in the melts. Titanium and phosphorus are always tetrahedrally coordinated. These cations do not substitute significantly for Si4+ in tetrahedral coordination, but form separate clusters. The anionic structural model described above is consistent with viscosity and expansivity data for melts on binary metal oxide‐silica joins. The phase equilibrium data, such as the position of liquidus boundaries between mineral phases of different degress of polymerization on binary metal oxide‐silica joins, may be explained with the melt structure model. The observed expansion of immiscible liquid volumes on MO‐SiO2 joins with increasing field strength of the M cation is in accord with the enhanced stability of three‐dimensional network units in the melts as a function of increased field strength of the metal cation. Most volatile‐free natural magmatic liquids will contain chain, sheet, and three‐dimensional structural units. The proportion of sheet units in magmas with the same ratio of nonbridging oxygens to tetrahedral cations will decrease with increasing M2+/M+. The proportion of three‐dimensional structural units increases at the expense of chain and sheet units as the magma becomes more acidic. On the basis of the observed relationships between melt structure and physical properties the decreased compressibility and viscosity of basic magma compared with acidic magma may be explained. Application of this structural model to natural magma also explains why the pressure dependence of the viscosity of basic magmas is smaller than that of andesitic magmas.

Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. Frequently, the chemotactic activity of cytokines depends on a modified N-terminus of the polypeptide. Among those, the N-terminus of monocyte chemoattractant protein 1 (CCL2 and MCP-1) is modified to a pyroglutamate (pE-) residue protecting against degradation in vivo. Here, we show that the N-terminal pE-formation depends on glutaminyl cyclase activity. The pE-residue increases stability against N-terminal degradation by aminopeptidases and improves receptor activation and signal transduction in vitro. Genetic ablation of the glutaminyl cyclase iso-enzymes QC (QPCT) or isoQC (QPCTL) revealed a major role of isoQC for pE1-CCL2 formation and monocyte infiltration. Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration. The pharmacologic efficacy of QC/isoQC-inhibition was assessed in accelerated atherosclerosis in ApoE3*Leiden mice, showing attenuated atherosclerotic pathology following chronic oral treatment. Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers. The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

Mg,Fe)(Si,Al)O 3 perovskite samples with varying Fe and Al concentration were synthesised at high pressure and temperature at varying conditions of oxygen fugacity using a multianvil press, and were characterised using ex situ X-ray diraction, electron microprobe, MoÈ ssbauer spectroscopy and analytical transmission electron microscopy. The Fe 3+ /SFe ratio was determined from MoÈ ssbauer spectra recorded at 293 and 80 K, and shows a nearly linear dependence of Fe 3+ / SFe with Al composition of (Mg,Fe)(Si,Al)O 3 perovskite. The Fe 3+ /SFe values were obtained for selected samples of (Mg,Fe)(Si,Al)O 3 perovskite using electron energy-loss near-edge structure (ELNES) spectroscopy, and are in excellent agreement with MoÈ ssbauer data, demonstrating that Fe 3+ /SFe can be determined with a spatial resolution on the order of nm. Oxygen concentrations were determined by combining bulk chemical data with Fe 3+ /SFe data determined by MoÈ ssbauer spectroscopy, and show a signi®cant concentration of oxygen vacancies in (Mg,Fe)(Si,Al)O 3 perovskite.

The sequence of phase transitions reported in the Conclusions section of this article contained an error: the labels ``x~0.40'' and ``RT'' were exchanged. The corrected sequence of transitions is given below:The Royal Society of Chemistry apologises for this error and any consequent inconvenience to authors and readers.

Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system.

A single Landau free energy expansion is used to describe phase transitions in perovskites, from a cubic parent structure to tetragonal and orthorhombic structures with space groups related to the M 3 and R 25 points of the Pm3 -m reciprocal lattice. This expansion permits relationships between symmetry-adapted forms of the spontaneous strain and individual order parameter components to be predicted. Data from the literature for (Ca,Sr)TiO 3 perovskites are analyzed in the light of these predictions. Shear strains for I4/mcm, Pnma, and Cmcm structures tend to conform to the predicted pattern. The Pm3 -m ↔ I4/mcm transition has nearly tricritical character as a function of temperature in CaTiO 3 and more nearly second-order character as a function of composition at the Sr-rich end of the solid solution. Coupling with the volume strain appears to be both temperature and composition dependent, which may be a general feature of phase transitions in perovskites. Renormalization of fourth-order terms by changing the volume coupling coefficients could be responsible for the unusual order parameter evolution shown by CaTiO 3 and for changes in thermodynamic character of the phase transitions as a function of composition. The pattern of strain variations also correlates closely with patterns of variations in heat capacity from the literature, suggesting revisions to the subsolidus phase diagram for the (Ca,Sr)TiO 3 solid solution above room temperature.

Recent kinetic and structural studies on various thiamin-dependent enzymes, including the bacterial E1 component of the pyruvate dehydrogenase complex (PDHc), suggested an active center communication between the cofactors in these multimeric enzymes. This regulatory mode has been inferred from the dissymmetry of active sites in proteolytic patterns and X-ray structures and from a complex macroscopic kinetic behavior not being consistent with independently working active sites. Here, direct microscopic kinetic evidence for this hypothesis is presented for the alpha2beta2-type E1 component of the human pyruvate dehydrogenase complex. Only one of the two thiamin molecules bound to the two active sites is in a chemically activated state exhibiting an apparent C2 ionization rate constant of approximately 50 s(-1) at pH 7.6 and 30 degrees C, whereas the thiamin in the "inactive site" ionizes with a rate that is at least 3 orders of magnitude smaller. The chemical nonequivalence is also exhibited in the ability to bind the substrate analogue methyl acetylphosphonate and in the catalytic turnover of the substrate pyruvate in the E1-only reaction. In the activated active site, pyruvate is rapidly bound and decarboxylated with apparent forward rate constants of covalent pyruvate binding of 2 s(-1) and decarboxylation of the formed 2-lactyl-thiamin intermediate of 5 s(-1). In the dormant site, these steps are as slow as 0.03 s(-1). Under the conditions that were used, only the heterotetramer can be detected by analytical ultracentrifugation, thus ruling out the possibility that multiple oligomeric species with different reactivities cause the observed kinetic effects. The results are consistent with the recently suggested model of an active site synchronization in PDHc-E1 via a proton wire that keeps the two active sites in an alternating activation state [Frank, R. A., et al. (2004) Science 306, 872]. Kinetic studies on the related thiamin enzymes transketolase, pyruvate oxidase, and bacterial pyruvate decarboxylase are not consistent with a chemical and/or functional nonequivalence of the active sites as observed in the E1 component of hsPDHc. We hypothesize that the alternating sites reaction in PDHc-E1 aids in the synchronized acyl transfer to the E2 component in the highly organized multienzyme complex.

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