ALBERT

Beschreibung: To evaluate compaction and interstitial melt expulsion during cumulate formation, a 20 m cumulate section including the UG2 and UG3 chromitites from a 264 m drill core through the Upper Critical Zone of the Bushveld Complex (South Africa) has been studied. The cumulates in the studied section are as follows: 3 m plagioclase pyroxenite to pyroxenite, pegmatoid footwall pyroxenite at the lower contact to UG2, 0·7 m UG2 chromitite, 6·8 m pyroxenite, 0·24 m UG3 chromitite, 2·0 m plagioclase-rich pyroxenite changing locally to norite, the two 5 cm leader stringers UG3a and UG3b, and 7 m total of olivine pyroxenites grading into plagioclase pyroxenites. All pyroxenites are dominated by orthopyroxene (opx) and the cumulate sequence is topped by mottled anorthosite grading into norite. Stratigraphic concentrations of major and trace elements of 52 bulk-rock samples were determined. Bulk-rock Mg-numbers are 0·79–0·81 throughout the silicate cumulate units, and 0·40–0·46 in the chromitite layers. The stratigraphic distribution of six incompatible trace elements (K, Rb, Ba, Cs, Zr and Th) has been used to determine the amount of trapped liquid ( F TL ) or paleo-porosity in the cumulate rocks. Final porosities (volume fractions), based on averages from the six trace elements, are 0·06–0·33 in the pyroxenites. In chromitite layers, trapped melt fractions of 0·12–0·36 are calculated from incompatible trace element concentrations, but bulk SiO 2 concentrations and X-ray tomography yield 0·04–0·17 higher porosities. Hence, the bulk silicate fraction in the chromitites may not necessarily correspond to the trapped liquid fraction, as poikilitic opx was crystallizing while the silicate melt still equilibrated. Using a previously derived experiment-based model for compaction time scales, gravitationally driven chemical compaction in the UG2–UG3–pyroxenite section is calculated to occur within 1–10 years. This time frame corresponds to the times necessary to cool a 20 m layer by 10–50°C, the temperature interval argued to encompass the liquidus and almost complete solidification. Compaction within a decade can in fact easily develop the paleo-porosities indirectly observed today and is probably stopped by crystallization of the interstitial liquid. Contrary to previous assertions, melt expulsion from the cumulate pile does not hinder compaction; calculated permeabilities would allow for the migration of an order of magnitude higher amount of melt than has to be expelled from the 20 m pile of cumulate. The pegmatoid zones in the chromitite footwalls enriched in incompatible trace elements are consistent with a collection of interstitial melts expelling from the underlying compacting pyroxenites. Their entrapment below the chromitite layers suggests that these act as permeability barriers. This is in part due to their finer grain size compared with the pyroxenites, but is mainly due to the crystallization of large poikilitic opx during compaction.

Beschreibung: Coinductive definitions, such as that of an infinite stream, may often be described by elegant logic programs, but ones for which SLD-refutation is of no value as SLD-derivations fall into infinite loops. Such definitions give rise to questions of lazy corecursive derivations and parallelism, as execution of such logic programs can have both recursive and corecursive features at once. Observational and coalgebraic semantics have been used to study them abstractly. The programming developments have often occurred separately and have usually been implementation-led. Here, we give a coherent semantics-led account of the issues, starting with abstract category theoretic semantics, developing coalgebra to characterize naturally arising trees and proceeding towards implementation of a new dialect, CoALP, of logic programming, characterised by guarded lazy corecursion and parallelism.

Beschreibung: : Intrinsically disordered proteins (IDPs) play central roles in many biological processes. Consequently, an accurate description of the disordered state is an important step towards a comprehensive understanding of a number of important biological functions. In this work we describe a new web server, Mollack, for the automated construction of unfolded ensembles that uses both experimental and molecular simulation data to construct models for the unfolded state. An important aspect of the method is that it calculates a quantitative estimate of the uncertainty in the constructed ensemble, thereby providing an objective measure of the quality of the final model. Overall, Mollack facilitates structure-function studies of disordered proteins. Availability and Implementation: http://cmstultz-mollack.mit.edu Contact: cmstultz@mit.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Beschreibung: Candida albicans is a dimorphic yeast commonly found on human mucosal membranes that switches from yeast to hyphal morphology in response to environmental factors. The change to hyphal growth requires histone H3 modifications by the yeast-specific histone acetyltransferase Rtt109. In addition to its role in morphogenesis, Rtt109-dependent acetylation of histone H3 lysine residues 9 and 56 has regulatory functions during DNA replication and repair. Boric acid (BA) is a broad-spectrum agent that specifically inhibits C. albicans hyphal growth, locking the fungus in its harmless commensal yeast state. The present study characterizes the effect of BA on C. albicans histone acetylation in respect to specificity, time-course and significance. We demonstrate that sublethal concentrations of BA reduce H3K9/H3K56 acetylation, both on a basal level and in response to genotoxic stress. Acetylation at other selected histone sites were not affected by BA. qRT-PCR expression analysis of the DNA repair gene Rad51 indicated no elevated level of genotoxic stress during BA exposure. A forward-mutation analysis demonstrated the BA does not increase spontaneous or induced mutations . The findings suggest that DNA repair remains effective even when histone H3 acetylation decreases and dispels the notion that BA treatment impairs genome integrity in yeast.

Beschreibung: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P -value = 1.58 x 10 –25 ). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ~14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P -value = 7.89 x 10 –09 ) and rs13294895 (OR = 1.09 [1.06–1.12]; P -value = 2.97 x 10 –11 ). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P -value = 2.77 x 10 –05 ). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

Beschreibung: Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to 〈1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case–control data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI , an allosteric binder of GABA receptors, GABARAPL1 , the GABA receptor-associated protein, and SLC6A11 , a postsynaptic GABA transporter. We also identified CNVs in COBL , deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER , a neuron-specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors ( GRID1 , GRIK2 and GRIK4 ), synaptic regulators ( NRXN3 , SLC6A8 and SYN3 ), transcription factor (ZNF804A) and RNA-binding protein FMR1 . Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms.

Beschreibung: Shiga toxin (Stx) 2e of Stx-producing Escherichia coli (STEC) represents the major virulence factor responsible for the pig edema disease which is characterized by hemorrhagic lesions, neurological disorders and often fatal outcomes. Stx2e-producing strains from the intestine of slaughtered pigs ( n  = 3), feces of piglets with postweaning diarrhea or edema disease ( n  = 12) and feces of humans with asymptomatic infections or mild diarrhea ( n  = 13) were comparatively analyzed for the binding specificities of Stx2e to glycosphingolipids (GSLs) of the globo-series. Besides equivalent binding towards globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), we could demonstrate specific interaction of Stx2e preparations from human and porcine STEC isolates with Forssman GSL. Notably, Forssman GSL was recognized neither by structurally closely related Stx2 nor by Stx1 derived from human STEC isolates conferring Stx2e a unique recognition feature. Noteworthy, 7 (54%) of the 13 human and 8 (53%) of the 15 pig Stx2e samples exhibited cytotoxic action towards human brain microvascular endothelial cells. Our findings provide a basis for further exploring the functional role of the promiscuous receptor repertoire of Stx2e and the exact nature of the mechanisms that underlie different pathological outcomes of Stx2e-producing STEC in humans and pigs.

Beschreibung: The deep crustal magmatic history of arc volcanoes is obscured by diversity in mantle inputs, modest isotopic contrast between magma and wall-rock, and overprinting processes in the middle and upper crust. To identify and quantify processes in the deep arc crust, we investigated the evolution of the mafic composite North Sister Volcano, the oldest and most mafic of the Three Sisters Volcanic Field of the central Oregon Cascade arc. Here, intra-arc extension limits the degree of magma interaction with the mid- to upper crust and the range in primitive magmas delivered from the mantle is known. North Sister Volcano has produced low-K basaltic andesitic magmas (0·5–0·8 wt % K 2 O) for ~400 kyr during four central-vent eruptive stages and along the late, 11 km long Matthieu Lakes Fissure. Although restricted in bulk composition (53–55 wt % SiO 2 ), North Sister basaltic andesites from different stages cluster into elemental and isotopic groups. Over time, North Sister basaltic andesites generally have decreasing compatible elements, such as Ni (from 112 to 40 ppm), and increasing Al 2 O 3 and TiO 2 . Concurrently, incompatible elements remain the same or decrease (e.g. from 302 to 247 ppm Ba). Isotopic variations at North Sister are small, but systematically progress toward more mantle-like ratios with time; 87 Sr/ 86 Sr decreases (from 0·70369 to 0·70356), and 144 Nd/ 143 Nd increases (from 0·51285 to 0·51292). We present a multi-stage petrological model for the evolution of North Sister magmas to account for: (1) the generation of low-K basaltic andesite; (2) geochemical variations within the eruptive stages; (3) evolution of the magma system over time to more mantle-like compositions. The earliest and most isotopically ‘crust-like’ (highest 87 Sr/ 86 Sr and lowest 143 Nd/ 144 Nd) North Sister magma is consistent with two-component mixing of regionally typical mantle-derived, low-K tholeiites with partial melts of the crust. Crustal melts must be high in SiO 2 and Al 2 O 3 , and most probably result from low-degree melting of plagioclase–clinopyroxene amphibole-bearing gabbro at high pressure. Variations in highly compatible elements within compositional groups (e.g. 60 ppm Ni within a single group) reflect fractionation of plagioclase, olivine, and clinopyroxene and recharge by more primitive basaltic andesite that overprint longer-term variations between groups. To understand the evolution of the North Sister basaltic andesite magmas through time, we use an energy-constrained model that balances assimilation of refractory gabbroic wall-rocks and abundant recharge by mantle-derived low-K tholeiites. These complementary processes allow Sr and Nd isotopic ratios to become more like those of the regional basalts while maintaining high Ni concentrations. Low-K basaltic andesites like those of North Sister Volcano are found along the Oregon Cascade arc and they imply that low-K tholeiitic magmas interact with a refractory mafic underplate along its length. Dominantly basaltic andesite volcanoes are common in arcs and provide insight into the extensive, albeit compositionally cryptic mafic underplating and intraplating that affects arc crust.

Beschreibung: Phase assemblages, melting relations and melt compositions of a dry carbonated pelite (DG2) and a carbonated pelite with 1·1 wt % H 2 O (AM) have been experimentally investigated at 5·5–23·5 GPa and 1070–1550°C. The subsolidus mineralogies to 16 GPa contain garnet, clinopyroxene, coesite or stishovite, kyanite or corundum, phengite or potassium feldspar (≤8 GPa with and without H 2 O, respectively), and then K-hollandite, a Ti phase and ferroan dolomite/Mg-calcite or aragonite + ferroan magnesite at higher pressures. The breakdown of clinopyroxene at 〉16 GPa causes Na-rich Ca-carbonate containing up to 11 wt % Na 2 O to replace aragonite and leads to the formation of an Na-rich CO 2 fluid. Further pressure increase leads to typical Transition Zone minerals such as the CAS phase and one or two perovskites, which completely substitute garnet at the highest investigated pressure (23·5 GPa). Melting at 5·5–23·5 GPa yields alkali-rich magnesio-dolomitic (DG2) to ferro-dolomitic (AM) carbonate melts at temperatures 200–350°C below the mantle geotherm, lower than for any other studied natural composition. Melting reactions are controlled by carbonates and alkali-hosting phases: to 16 GPa clinopyroxene remains residual, Na is compatible and the magnesio- to ferro-dolomitic carbonate melts have extremely high K 2 O/Na 2 O ratios. K 2 O/Na 2 O weight ratios decrease from 26–41 at 8 GPa to 1·2 at 16 GPa when K-hollandite expands its stability field with increasing pressure. At 〉16 GPa, Na is repartitioned between several phases, and again becomes incompatible as at 〈3 GPa, leading to Na-rich carbonate melts with K 2 O/Na 2 O ratios 1. This leaves the pressure interval of c . 4–15 GPa for ultrapotassic metasomatism. Comparison of the solidus with typical subducting slab-surface temperatures yields two distinct depths of probable carbonated pelite melting: at 6–9 GPa where the solidus has a negative Clapeyron slope between the intersection of the silicate and carbonate melting reactions at ~5 GPa, and the phengite or potassium feldspar stability limit at ~9 GPa. The second opportunity is related to possible slab deflection along the 660 km discontinuity, leading to thermal relaxation and partial melting of the fertile carbonated pelites, thus recycling sedimentary CO 2 , alkalis and other lithophile and strongly incompatible elements back into the mantle.

Beschreibung: Carbonatite and silicate rocks occurring within a single magmatic complex may originate through liquid immiscibility. We thus experimentally determined carbonatite/silicate melt partition coefficients ( D carbonate melt/silicate melt , hereafter D ) for 45 elements to understand their systematics as a function of melt composition and to provide a tool for identifying the possible conjugate nature of silicate and carbonatite magmas. Static and, when necessary, centrifuging piston cylinder experiments were performed at 1–3 GPa, 1150–1260°C such that two well-separated melts resulted. Bulk compositions had Na K, Na ~ K, and Na K; for the latter we also varied bulk H 2 O (0–4 wt %) and SiO 2 contents. Oxygen fugacities were between iron–wüstite and slightly below hematite–magnetite and were not found to exert significant control on partitioning. Under dry conditions alkali and alkaline earth elements partition into the carbonatite melt, as did Mo and P ( D Mo 〉8, D P = 1·6–3·3). High field strength elements (HFSE) prefer the silicate melt, most strongly Hf ( D Hf = 0·04). The REE have partition coefficients around unity with D La/Lu = 1·6–2·3. Transition metals have D 〈 1 except for Cu and V ( D Cu ~ 1·3, D V = 0·95–2). The small variability of the partition coefficients in all dry experiments can be explained by a comparable width of the miscibility gap, which appears to be flat-topped in our dry bulk compositions. For all carbonatite and silicate melts, Nb/Ta and Zr/Hf fractionate by factors of 1·3–3·0, in most cases much more strongly than in silicate–oxide systems. With the exception of the alkalis, partition coefficients for the H 2 O-bearing systems are similar to those for the anhydrous ones, but are shifted in favour of the carbonatite melt by up to an order of magnitude. An increase of bulk silica and thus SiO 2 in the silicate melt (from 35 to 69 wt %) has a similar effect. Two types of trace element partitioning with changing melt composition can be observed. The magnitude of the partition coefficients increases for the alkalis and alkaline earths with the width of the miscibility gap, whereas partition coefficients for the REE shift by almost two orders of magnitude from partitioning into the silicate melt ( D La = 0·47) to strongly partitioning into the carbonatite melt ( D La = 38), whereas D La / D Lu varies by only a factor of three. The partitioning behavior can be rationalized as a function of ionic potential ( Z / r ). Alkali and alkaline earth elements follow a trend, the slope of which depends on the K/Na ratio and H 2 O content. Contrasting the sodic and potassic systems, alkalis have a positive correlation in D vs Z / r space in the potassic case and Cs to K partition into the silicate melt in the presence of H 2 O. For the divalent third row transition metals on the one hand and for the tri- and tetravalent REE and HFSE on the other, two trends of negative correlation of D vs Z / r can be defined. Nevertheless, the highest ionic strength network-modifying cations (V, Nb, Ta, Ti and Mo) do not follow any trend; understanding their behavior would require knowledge of their bonding environment in the carbonatite melt. Strong partitioning of REE into the carbonatite melt ( D REE = 5·8–38·0) occurs only in H 2 O-rich compositions for which carbonatites unmix from evolved alkaline melts with the conjugate silicate melt being siliceous. We thus speculate that upon hydrous carbonatite crystallization, the consequent saturation in fluids may lead to hydrothermal systems concentrating REE in secondary deposits.