Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase.

Propionyl-coenzyme A carboxylase (PCC), a mitochondrial biotin-dependent enzyme, is essential for the catabolism of the amino acids Thr, Val, Ile and Met, cholesterol and fatty acids with an odd number of carbon atoms. Deficiencies in PCC activity in humans are linked to the disease propionic acidaemia, an autosomal recessive disorder that can be fatal in infants. The holoenzyme of PCC is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa. The alpha-subunit contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, whereas the beta-subunit supplies the carboxyltransferase (CT) activity. Here we report the crystal structure at 3.2-A resolution of a bacterial PCC alpha(6)beta(6) holoenzyme as well as cryo-electron microscopy (cryo-EM) reconstruction at 15-A resolution demonstrating a similar structure for human PCC. The structure defines the overall architecture of PCC and reveals unexpectedly that the alpha-subunits are arranged as monomers in the holoenzyme, decorating a central beta(6) hexamer. A hitherto unrecognized domain in the alpha-subunit, formed by residues between the BC and BCCP domains, is crucial for interactions with the beta-subunit. We have named it the BT domain. The structure reveals for the first time the relative positions of the BC and CT active sites in the holoenzyme. They are separated by approximately 55 A, indicating that the entire BCCP domain must translocate during catalysis. The BCCP domain is located in the active site of the beta-subunit in the current structure, providing insight for its involvement in the CT reaction. The structural information establishes a molecular basis for understanding the large collection of disease-causing mutations in PCC and is relevant for the holoenzymes of other biotin-dependent carboxylases, including 3-methylcrotonyl-CoA carboxylase (MCC) and eukaryotic acetyl-CoA carboxylase (ACC).

New results on ν μ → ν τ appearance with the OPERA experiment in the CNGS beam

The OPERA neutrino experiment is designed to perform the first observation of neutrino oscillations in direct appearance mode in the νμ→ντ channel, via the detection of the τ-leptons created in charged current ντ interactions. The detector, located in the underground Gran Sasso Laboratory, consists of an emulsion/lead target with an average mass of about 1.2 kt, complemented by electronic detectors. It is exposed to the CERN Neutrinos to Gran Sasso beam, with a baseline of 730 km and a mean energy of 17 GeV. The observation of the first ντ candidate event and the analysis of the 2008-2009 neutrino sample have been reported in previous publications. This work describes substantial improvements in the analysis and in the evaluation of the detection efficiencies and backgrounds using new simulation tools. The analysis is extended to a sub-sample of 2010 and 2011 data, resulting from an electronic detector-based pre-selection, in which an additional ντ candidate has been observed. The significance of the two events in terms of a νμ→ντ oscillation signal is of 2.40 σ.

Microstructural Parameters of Bone Evaluated Using HR-pQCT Correlate with the DXA-Derived Cortical Index and the Trabecular Bone Score in a Cohort of Randomly Selected Premenopausal Women.

BACKGROUND Areal bone mineral density is predictive for fracture risk. Microstructural bone parameters evaluated at the appendicular skeleton by high-resolution peripheral quantitative computed tomography (HR-pQCT) display differences between healthy patients and fracture patients. With the simple geometry of the cortex at the distal tibial diaphysis, a cortical index of the tibia combining material and mechanical properties correlated highly with bone strength ex vivo. The trabecular bone score derived from the scan of the lumbar spine by dual-energy X-ray absorptiometry (DXA) correlated ex vivo with the micro architectural parameters. It is unknown if these microstructural correlations could be made in healthy premenopausal women. METHODS Randomly selected women between 20-40 years of age were examined by DXA and HR-pQCT at the standard regions of interest and at customized sub regions to focus on cortical and trabecular parameters of strength separately. For cortical strength, at the distal tibia the volumetric cortical index was calculated directly from HR-pQCT and the areal cortical index was derived from the DXA scan using a Canny threshold-based tool. For trabecular strength, the trabecular bone score was calculated based on the DXA scan of the lumbar spine and was compared with the corresponding parameters derived from the HR-pQCT measurements at radius and tibia. RESULTS Seventy-two healthy women were included (average age 33.8 years, average BMI 23.2 kg/m(2)). The areal cortical index correlated highly with the volumetric cortical index at the distal tibia (R  =  0.798). The trabecular bone score correlated moderately with the microstructural parameters of the trabecular bone. CONCLUSION This study in randomly selected premenopausal women demonstrated that microstructural parameters of the bone evaluated by HR-pQCT correlated with the DXA derived parameters of skeletal regions containing predominantly cortical or cancellous bone. Whether these indexes are suitable for better predictions of the fracture risk deserves further investigation.

U7 snRNP-specific Lsm11 protein: dual binding contacts with the 100 kDa zinc finger processing factor (ZFP100) and a ZFP100-independent function in histone RNA 3' end processing

The 3' cleavage generating non-polyadenylated animal histone mRNAs depends on the base pairing between U7 snRNA and a conserved histone pre-mRNA downstream element. This interaction is enhanced by a 100 kDa zinc finger protein (ZFP100) that forms a bridge between an RNA hairpin element upstream of the processing site and the U7 small nuclear ribonucleoprotein (snRNP). The N-terminus of Lsm11, a U7-specific Sm-like protein, was shown to be crucial for histone RNA processing and to bind ZFP100. By further analysing these two functions of Lsm11, we find that Lsm11 and ZFP100 can undergo two interactions, i.e. between the Lsm11 N-terminus and the zinc finger repeats of ZFP100, and between the N-terminus of ZFP100 and the Sm domain of Lsm11, respectively. Both interactions are not specific for the two proteins in vitro, but the second interaction is sufficient for a specific recognition of the U7 snRNP by ZFP100 in cell extracts. Furthermore, clustered point mutations in three phylogenetically conserved regions of the Lsm11 N-terminus impair or abolish histone RNA processing. As these mutations have no effect on the two interactions with ZFP100, these protein regions must play other roles in histone RNA processing, e.g. by contacting the pre-mRNA or additional processing factors.

Atmospheric Soluble Dust Records from a Tibetan Ice Core: Possible Climate Proxies and Teleconnection With the Pacific Decadal Oscillation

In autumn 2005, a joint expedition between the University of Maine and the Institute of Tibetan Plateau Research recovered three ice cores from Guoqu Glacier (33 degrees 34'37.80 '' N, 91 degrees 10'35.3 '' E, 5720 m above sea level) on the northern side of Mt. Geladaindong, central Tibetan Plateau. Isotopes ( delta(18)O), major soluble ions (Na(+), K(+), Mg(2+), Ca(2+), Cl(-), NO(3)(-), SO(4)(2-)), and radionuclide (beta-activity) measurements from one of the cores revealed a 70-year record (1935-2005). Statistical analysis of major ion time series suggests that atmospheric soluble dust species dominate the chemical signature and that background dust levels conceal marine ion species deposition. The soluble dust time series have interspecies relations and common structure (empirical orthogonal function (EOF) 1), suggesting a similar soluble dust source or transport route. Annual and seasonal correlations between the EOF 1 time series and National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis climate variables (1948-2004) suggest that the Mt. Geladaindong ice core record provides a proxy for local and regional surface pressure. An approximately threefold decrease of soluble dust concentrations in the middle to late 1970s, accompanied by regional increases in pressure and temperature and decreases in wind velocity, coincides with the major 1976-1977 shift of the Pacific Decadal Oscillation (PDO) from a negative to a positive state. This is the first ice core evidence of a potential teleconnection between central Asian atmospheric soluble dust loading and the PDO. Analysis of temporally longer ice cores from Mt. Geladaindong may enhance understanding of the relationship between the PDO and central Asian atmospheric circulation and subsequent atmospheric soluble dust loading.

Air-Sea Interactions During the Passage of a Winter Storm Over the Gulf Stream: A Three-Dimensional Coupled Atmosphere-Ocean Model Study

A three-dimensional, regional coupled atmosphere-ocean model with full physics is developed to study air-sea interactions during winter storms off the U. S. east coast. Because of the scarcity of open ocean observations, models such as this offer valuable opportunities to investigate how oceanic forcing drives atmospheric circulation and vice versa. The study presented here considers conditions of strong atmospheric forcing (high wind speeds) and strong oceanic forcing (significant sea surface temperature (SST) gradients). A simulated atmospheric cyclone evolves in a manner consistent with Eta reanalysis, and the simulated air-sea heat and momentum exchanges strongly affect the circulations in both the atmosphere and the ocean. For the simulated cyclone of 19-20 January 1998, maximum ocean-to-atmosphere heat fluxes first appear over the Gulf Stream in the South Atlantic Bight, and this results in rapid deepening of the cyclone off the Carolina coast. As the cyclone moves eastward, the heat flux maximum shifts into the region near Cape Hatteras and later northeast of Hatteras, where it enhances the wind locally. The oceanic response to the atmospheric forcing is closely related to the wind direction. Southerly and southwesterly winds tend to strengthen surface currents in the Gulf Stream, whereas northeasterly winds weaken the surface currents in the Gulf Stream and generate southwestward flows on the shelf. The oceanic feedback to the atmosphere moderates the cyclone strength. Compared with a simulation in which the oceanic model always passes the initial SST to the atmospheric model, the coupled simulation in which the oceanic model passes the evolving SST to the atmospheric model produces higher ocean-to-atmosphere heat flux near Gulf Stream meander troughs. This is due to wind-driven lateral shifts of the stream, which in turn enhance the local northeasterly winds. Away from the Gulf Stream the coupled simulation produces surface winds that are 5 similar to 10% weaker. Differences in the surface ocean currents between these two experiments are significant on the shelf and in the open ocean.

Microsurgical and laser ablation analysis of interactions between the zones and layers of the tomato shoot apical meristern

Plants exhibit life-long organogenic and histogenic activity in a specialised organ, the shoot apical meristem. Leaves and flowers are formed within the ring-shaped peripheral zone, which surrounds the central zone, the site of the stem cells. We have undertaken a series of high-precision laser ablation and microsurgical tissue removal experiments to test the functions of different parts of the tomato meristem, and to reveal their interactions. Ablation of the central zone led to ectopic expression of the WUSCHEL gene at the periphery, followed by the establishment of a new meristem centre. After the ablation of the central zone, organ formation continued without a lag. Thus, the central zone does not participate in organogenesis, except as the ultimate source of founder cells. Microsurgical removal of the external L-1 layer induced periclinal cell divisions and terminal differentiation in the subtending layers. In addition, no organs were initiated in areas devoid of L-1, demonstrating an important role of the L-1 in organogenesis. L-1 ablation had only local effects, an observation that is difficult to reconcile with phyllotaxis theories that invoke physical tension operating within the meristem as a whole. Finally, regeneration of L-1 cells was never observed after ablation. This shows that while the zones of the meristem show a remarkable capacity to regenerate after interference, elimination of the L-1 layer is irreparable and causes terminal differentiation.

Influence of perylenediimide–pyrene supramolecular interactions on the stability of DNA-based hybrids: Importance of electrostatic complementarity

Aromatic pi–pi stacking interactions are ubiquitous in nature, medicinal chemistry and materials sciences. They play a crucial role in the stacking of nucleobases, thus stabilising the DNA double helix. The following paper describes a series of chimeric DNA–polycyclic aromatic hydrocarbon (PAH) hybrids. The PAH building blocks are electron-rich pyrene and electron-poor perylenediimide (PDI), and were incorporated into complementary DNA strands. The hybrids contain different numbers of pyrene–PDI interactions that were found to directly influence duplex stability. As the pyrene–PDI ratio approaches 1:1, the stability of the duplexes increases with an average value of 7.5 °C per pyrene–PDI supramolecular interaction indicating the importance of electrostatic complementarity for aromatic pi–pi stacking interactions.

Searches for heavy long-lived sleptons and R-Hadrons with the ATLAS detector in pp collisions at sqrts TeV

A search for long-lived particles is performed using a data sample of 4.7 fb(-1) from proton-proton collisions at a centre-of-mass energy. root s = 7 TeV collected by the ATLAS detector at the LHC. No excess is observed above the estimated background and lower limits, at 95% confidence level, are set on the mass of the long-lived particles in different scenarios, based on their possible interactions in the inner detector, the calorimeters and the muon spectrometer. Long-lived staus in gauge-mediated SUSY-breaking models are excluded up to a mass of 300 GeV for tan beta = 5-20. Directly produced long-lived sleptons are excluded up to a mass of 278 GeV. R-hadrons, composites of gluino (stop, sbottom) and light quarks, are excluded up to a mass of 985 GeV (683 GeV, 612 GeV) when using a generic interaction model. Additionally two sets of limits on R-hadrons are obtained that are less sensitive to the interaction model for R-hadrons. One set of limits is obtained using only the inner detector and calorimeter observables, and a second set of limits is obtained based on the inner detector alone.

Search for excited electrons and muons in sqrts=8 TeV proton-proton collisions with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for excited electrons and excited muons in the channel pp -> ll* -> ll gamma, assuming that excited leptons are produced via contact interactions. The analysis is based on 13 fb(-1) of pp collisions at a centre-of-mass energy of 8 TeV. No evidence for excited leptons is found, and a limit is set at the 95% credibility level on the cross section times branching ratio as a function of the excited-lepton mass m(l*). For m(l*) >= 0.8 TeV, the respective upper limits on sigma B(l(*) -> l gamma) are 0.75 and 0.90 fb for the e* and mu* searches. Limits on sigma B are converted into lower bounds on the compositeness scale 3. In the special case where Lambda = m(l*), excited-electron and excited-muon masses below 2.2 TeV are excluded.

Measurement of the cross-section for W boson production in association with b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

This paper reports a measurement of the W+b-jets (W+b+X and W+b (b) over bar +X) production cross-section in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC. These results are based on data corresponding to an integrated luminosity of 4.6 fb(-1), collected with the ATLAS detector. Cross-sections are presented as a function of jet multiplicity and of the transverse momentum of the leading b-jet for both the muon and electron decay modes of the W boson. The W+b-jets cross-section, corrected for all known detector effects, is quoted in a limited kinematic range. Combining the muon and electron channels, the fiducial cross-section for W+b-jets is measured to be 7.1 +/- 0.5 (stat) +/- 1.4 (syst) pb, consistent with the next-to-leading order QCD prediction, corrected for non-perturbative and double-parton interactions (DPI) contributions, of 4.70 +/- 0.09 (stat) (+0.60)(-0.49) (scale) +/- 0.06 (PDF) +/- 0.16 (non-pert) (+0.52)(-0.38) (DPI) pb.

Congenital Hepatic Fibrosis in the Franches-Montagnes Horse Is Associated with the Polycystic Kidney and Hepatic Disease 1 (PKHD1) Gene

Congenital hepatic fibrosis has been described as a lethal disease with monogenic autosomal recessive inheritance in the Swiss Franches-Montagnes horse breed. We performed a genome-wide association study with 5 cases and 12 controls and detected an association on chromosome 20. Subsequent homozygosity mapping defined a critical interval of 952 kb harboring 10 annotated genes and loci including the polycystic kidney and hepatic disease 1 (autosomal recessive) gene (PKHD1). PKHD1 represents an excellent functional candidate as variants in this gene were identified in human patients with autosomal recessive polycystic kidney and hepatic disease (ARPKD) as well as several mouse and rat mutants. Whereas most pathogenic PKHD1 variants lead to polycystic defects in kidney and liver, a small subset of the human ARPKD patients have only liver symptoms, similar to our horses with congenital hepatic fibrosis. The PKHD1 gene is one of the largest genes in the genome with multiple alternative transcripts that have not yet been fully characterized. We sequenced the genomes of an affected foal and 46 control horses to establish a comprehensive list of variants in the critical interval. We identified two missense variants in the PKHD1 gene which were strongly, but not perfectly associated with congenital hepatic fibrosis. We speculate that reduced penetrance and/or potential epistatic interactions with hypothetical modifier genes may explain the imperfect association of the detected PKHD1 variants. Our data thus indicate that horses with congenital hepatic fibrosis represent an interesting large animal model for the liver-restricted subtype of human ARPKD.

Backscattered energetic neutral atoms from the Moon in the Earth's plasma sheet observed by Chandarayaan-1/Sub-keV Atom Reflecting Analyzer instrument

We present the observations of energetic neutral atoms (ENAs) produced at the lunar surface in the Earth's magnetotail. When the Moon was located in the terrestrial plasma sheet, Chandrayaan-1 Energetic Neutrals Analyzer (CENA) detected hydrogen ENAs from the Moon. Analysis of the data from CENA together with the Solar Wind Monitor (SWIM) onboard Chandrayaan-1 reveals the characteristic energy of the observed ENA energy spectrum (the e-folding energy of the distribution function) ∼100 eV and the ENA backscattering ratio (defined as the ratio of upward ENA flux to downward proton flux) <∼0.1. These characteristics are similar to those of the backscattered ENAs in the solar wind, suggesting that CENA detected plasma sheet particles backscattered as ENAs from the lunar surface. The observed ENA backscattering ratio in the plasma sheet exhibits no significant difference in the Southern Hemisphere, where a large and strong magnetized region exists, compared with that in the Northern Hemisphere. This is contrary to the CENA observations in the solar wind, when the backscattering ratio drops by ∼50% in the Southern Hemisphere. Our analysis and test particle simulations suggest that magnetic shielding of the lunar surface in the plasma sheet is less effective than in the solar wind due to the broad velocity distributions of the plasma sheet protons.

Measurement of the production cross section of prompt J/ψ mesons in association with a W± boson in pp collisions at √8 = 7 TeV with the ATLAS detector

The process pp ! W±J/ provides a powerful probe of the production mechanism of charmonium in hadronic collisions, and is also sensitive to multiple parton interactions in the colliding protons. Using the 2011 ATLAS dataset of 4.5 fb−1 of p s =7TeV pp collisions at the LHC, the first observation is made of the production of W± +prompt J/ events in hadronic collisions, using W± → μѵμ and Jψ → μ+μ−. A yield of 27.4+7.5−6.5 W± + prompt J/ψ events is observed, with a statistical significance of 5.1ơ. The production rate as a ratio to the inclusive W± boson production rate is measured, and the double parton scattering contribution to the cross section is estimated.