ALBERT

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: We report the detection of eight vibronic bands of C 3 , seven of which have been hitherto unobserved in astrophysical objects, in the translucent cloud towards HD 169454. Four of these bands are also found towards two additional objects: HD 73882 and HD 154368. Very high signal-to-noise ratio (~1000 and higher) and high resolving power ( R  = 80 000) UVES-VLT spectra (Paranal, Chile) allow for detecting novel spectral features of C 3 , even revealing weak perturbed features in the strongest bands. The work presented here provides the most complete spectroscopic survey of the so far largest carbon chain detected in translucent interstellar clouds. High-quality laboratory spectra of C 3 are measured using cavity ring-down absorption spectroscopy in a supersonically expanding hydrocarbon plasma, to support the analysis of the identified bands towards HD 169454. A column density of N (C 3 ) = (6.6 ± 0.2) 10 12  cm –2 is inferred and the excitation of the molecule exhibits two temperature components; T exc  = 22 ± 1 K for the low- J states and T exc  = 187 ± 25 K for the high- J tail. The rotational excitation of C 3 is reasonably well explained by models involving a mechanism including inelastic collisions, formation and destruction of the molecule, and radiative pumping in the far-infrared. These models yield gas kinetic temperatures comparable to those found for T exc . The assignment of spectral features in the UV-blue range 3793–4054 Å may be of relevance for future studies aiming at unravelling spectra to identify interstellar molecules associated with the diffuse interstellar bands (DIBs).

Beschreibung: Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study ( n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 x 10 –10 ) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 x 10 –6 ) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 x 10 –5 ) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk ( P = 2.1 x 10 –3 ). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

Beschreibung: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7- K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 x 10 –6 ], AKAP9- M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 x 10 –6 ) and NEK10- L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 x 10 –17 ). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7- K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 x 10 –8 ); for AKAP9- M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 x 10 –10 ). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Beschreibung: Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8 ), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 x 10 –5 . Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS ( P = 3 x 10 –6 ), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 x 10 –9 . Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

Beschreibung: The origin of pyroxenites and their relation to melt migration in the mantle have been investigated in two pyroxenite-rich zones in the Beni Bousera massif. Based on combined field, microtextural, mineralogical and geochemical observations, the pyroxenites were separated into four types. Type-I Cr-diopside websterites contain bright green diopside and have primitive bulk Ni, Cr and Mg-number. Their trace element systematics are characterized by slight light rare earth element (LREE) enrichment compared with the middle (MREE) and heavy (H)REE, and negative high field strength element (HFSE) anomalies in bulk-rock and mineral compositions suggesting that they result from melting of metasomatized mantle. Trace element concentrations of melts calculated to be in equilibrium with Type-I cpx have a subduction-like signature and show a close similarity to certain lavas erupted in the Alboran Basin. Calculated mineral equilibration temperatures of ~1200 to 1350°C are close to the basalt liquidus and higher than for other pyroxenite types in Beni Bousera, which generally yield 〈1100°C. Type-II spinel websterites are also primitive, but contain augitic clinopyroxene; their whole-rock compositions are characterized by high Ti, Ni, and Mg-number, intermediate Cr and trace element patterns with LREE depletion over the MREE and HREE. Type-III garnet pyroxenites, which include the famous diamond-pseudomorph-bearing garnet pyroxenites, are more evolved than Types-I and -II and have low and variable Mg-number correlating with an Fe-enrichment trend. High bulk-rock and garnet HREE to LREE ratios result from high-pressure fractionation of garnet and augitic cpx at calculated pressures of 〉45 to 20–30 kbar. Type-III pyroxenites display strong variations of LREE and HFSE depletion and strong bulk Nb/Ta fractionation. Calculated melts in equilibrium with augitic cpx are variably enriched in incompatible trace elements similar to intraplate basalts. Type-IV pyroxenites are composed of green diopside, opx, garnet and plagioclase and/or spinel. Whole-rocks have high Na 2 O, CaO and Al 2 O 3 concentrations and high Mg-number, are HREE depleted, and have positive Eu and Sr anomalies. Garnets are characterized by low HREE/MREE and positive Eu anomalies. The absence of bulk-rock HREE enrichment indicates a metamorphic origin for this garnet, which is corroborated by the presence of Al-rich metamorphic spinels. Relict magmatic plagioclase indicates a shallower (〈10 kbar) crustal origin for these pyroxenites. Their metamorphic assemblage yields temperatures and pressures of 800–980°C and 14 kbar, indicating a pressure increase during the metamorphic overprint. The whole-rock geochemistry of Type-IV pyroxenites is comparable with that of rocks from the lower crustal section of the Kohistan (northern Pakistan) paleo-arc, indicating a possible origin of these rocks as cumulates in the deeper arc crust and subsequent delamination into the underlying mantle.

Beschreibung: The study of symbiotic systems is of considerable importance in our understanding of binary system stellar evolution in systems where mass-loss or transfer takes place. Elemental abundances are of special significance since they can be used to track mass exchange. However, there are few symbiotic giants for which the abundances are fairly well determined. Here, we present for the first time a detailed analysis of the chemical composition for the giants in the RW Hya and SY Mus systems. The analysis is based on high-resolution ( R  ~ 50 000), high signal-to-noise (S/N), near-IR spectra. Spectrum synthesis employing standard local thermal equilibrium (LTE) analysis and atmosphere models was used to obtain photospheric abundances of CNO and elements around the iron peak (Sc, Ti, Fe, and Ni). Our analysis reveals a significantly sub-solar metallicity, [Fe/H] ~ –0.75, for the RW Hya giant confirming its membership in the Galactic halo population and a near-solar metallicity for the SY Mus giant. The very low 12 C/ 13 C isotopic ratios, ~6–10, derived for both objects indicate that the giants have experienced the first dredge-up.