Acoustic Survey of a 3/8-Scale Automotive Wind Tunnel

An acoustic survey that consists of insertion loss and flow noise measurements was conducted at key locations around the circuit of a 3/8-scale automotive acoustic wind tunnel. Descriptions of the test, the instrumentation, and the wind tunnel facility are included in the current report, along with data obtained in the test in the form of 1/3-octave-band insertion loss and narrowband flow noise spectral data

Catalytic Activity and Fluxional Behavior of Complexes Based on RuHCl(CO)(PPh₃)₃ and Xantphos-Type Ligands

With RuHCl(CO)(PPh3)3 as the starting material, the complexes RuHCl(CO)(PPh3)(L) were prepared for L = Xantphos and closely related ligands. Their catalytic activity in the direct amination of cyclohexanol showed large differences depending on the different backbone structures. In those complexes the Xantphos-type ligand backbones are slightly bent and display fluxionality, studied by VT-NMR. This was assigned to the "flipping" of the backbone via the bridging atoms in the xanthene backbone. Via line shape analysis of the peaks, the Gibbs free energy of activation of the flipping movement was found to be around 56 kJ/mol in all cases. However, the activation enthalpy and entropy differed considerably. Employing RuCl2(PPh3)3 as the precursor resulted in the trans-coordinated complexes RuCl2(PPh3)(L) for L = Xantphos, Sixantphos. Fluxionality was no longer observed, due to the fact that in these complexes the O atom in the backbone also coordinates to the Ru

Doxorubicin-Induced Cardiotoxicity in Collaborative Cross (CC) Mice Recapitulates Individual Cardiotoxicity in Humans.

Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Genetic determinants contributing to this variation are difficult to study using current mouse models. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 Collaborative Cross mouse strains given the same dose of doxorubicin. Mice from ten distinct strains were given 5 mg/kg of doxorubicin intravenously once weekly for 5 weeks (total 25 mg/kg). Mice were killed at acute or chronic timepoints. Body weight was assessed weekly, followed by terminal complete blood count, pathology and a panel of biomarkers. Linear models were fit to assess effects of treatment, sex, and sex-by-treatment interactions for each timepoint. Impaired growth and cardiac pathology occurred across all strains. Severity of these varied by strain and sex, with greater severity in males. Cardiac troponin I and myosin light chain 3 demonstrated strain- and sex-specific elevations in the acute phase with subsequent decline despite ongoing progression of cardiac disease. Acute phase cardiac troponin I levels predicted the ultimate severity of cardiac pathology poorly, whereas myosin light chain 3 levels predicted the extent of chronic cardiac injury in males. Strain- and sex-dependent renal toxicity was evident. Regenerative anemia manifested during the acute period. We confirm that variable susceptibility to doxorubicin-induced cardiotoxicity observed in humans can be modeled in a panel of CC strains. In addition, we identified a potential predictive biomarker in males. CC strains provide reproducible models to explore mechanisms contributing to individual susceptibility in humans

α-Synuclein Conformation Affects Its Tyrosine-Dependent Oxidative Aggregation †

Oxidative stress and aggregation of the protein α-synuclein are thought to be key factors in Parkinson’s disease. Previous work shows that cytochrome c plus H2O2 causes tyrosine-dependent in vitro peroxidative aggregation of proteins, including α-synuclein. Here, we examine the role of each of α-synuclein’s four tyrosine residues and how the protein’s conformation affects covalent oxidative aggregation. When α-synuclein adopts a collapsed conformation, tyrosine 39 is essential for wild-type-like covalent aggregation. This lone N-terminal tyrosine, however, is not required for wild type-like covalent aggregation in the presence of a denaturant or when α-synuclein is present in non-covalent fibrils. We also show that pre-formed oxidative aggregates are not incorporated into non-covalent fibrils. These data provide insight as to how dityrosine may be formed in Lewy bodies seen in Parkinson’s disease

α-Synuclein Conformation Affects Its Tyrosine-Dependent Oxidative Aggregation †

Oxidative stress and aggregation of the protein α-synuclein are thought to be key factors in Parkinson’s disease. Previous work shows that cytochrome c plus H2O2 causes tyrosine-dependent in vitro peroxidative aggregation of proteins, including α-synuclein. Here, we examine the role of each of α-synuclein’s four tyrosine residues and how the protein’s conformation affects covalent oxidative aggregation. When α-synuclein adopts a collapsed conformation, tyrosine 39 is essential for wild-type-like covalent aggregation. This lone N-terminal tyrosine, however, is not required for wild type-like covalent aggregation in the presence of a denaturant or when α-synuclein is present in non-covalent fibrils. We also show that pre-formed oxidative aggregates are not incorporated into non-covalent fibrils. These data provide insight as to how dityrosine may be formed in Lewy bodies seen in Parkinson’s disease

Millimetre observations of a sample of high-redshift obscured quasars

We present observations at 1.2 mm with MAMBO-II of a sample of z>~2 radio-intermediate obscured quasars, as well as CO observations of two sources with the Plateau de Bure Interferometer. Five out of 21 sources (24%) are detected at a significance of >=3sigma. Stacking all sources leads to a statistical detection of = 0.96+-0.11 mJy and stacking only the non-detections also yields a statistical detection, with = 0.51+-0.13 mJy. This corresponds to a typical far-infrared luminosity L_FIR~4x10^12 Lsol. If the far-infrared luminosity is powered entirely by star-formation, and not by AGN-heated dust, then the characteristic inferred star-formation rate is ~700 Msol yr-1. This far-infrared luminosity implies a dust mass of M_dust~3x10^8 Msol. We estimate that such large dust masses on kpc scales can plausibly cause the obscuration of the quasars. We present dust SEDs for our sample and derive a mean SED for our sample. This mean SED is not well fitted by clumpy torus models, unless additional extinction and far-infrared re-emission due to cool dust are included. There is a hint that the host galaxies of obscured quasars must have higher far-infrared luminosities and cool-dust masses and are therefore often found at an earlier evolutionary phase than those of unobscured quasars. For one source at z=2.767, we detect the CO(3-2) transition, with S_CO Delta nu=630+-50 mJy km s-1, corresponding to L_CO(3-2)= 3.2x10^7 Lsol, or L'_CO(3-2)=2.4x10^10 K km s-1 pc2. For another source at z=4.17, the lack of detection of the CO(4-3) line yields a limit of L'_CO(4-3)<1x10^10 K km s-1 pc2. Molecular gas masses, gas depletion timescales and gas-to-dust ratios are estimated (Abridged).Comment: Accepted by ApJ, 25 pages, 11 figures, 4 table

MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition

The first epithelial-to-mesenchymal transition (EMT) occurs in trophoblast stem (TS) cells during implantation. Inactivation of the serine/threonine kinase MAP3K4 in TS cells (TSKI4 cells) induces an intermediate state of EMT, where cells retain stemness, lose epithelial markers, and gain mesenchymal characteristics. Investigation of relationships among MAP3K4 activity, stemness, and EMT in TS cells may reveal key regulators of EMT. Here, we show that MAP3K4 activity controls EMT through the ubiquitination and degradation of HDAC6. Loss of MAP3K4 activity in TSKI4 cells results in elevated HDAC6 expression and the deacetylation of cytoplasmic and nuclear targets. In the nucleus, HDAC6 deacetylates the promoters of tight junction genes, promoting the dissolution of tight junctions. Importantly, HDAC6 knockdown in TSKI4 cells restores epithelial features, including cell-cell adhesion and barrier formation. These data define a role for HDAC6 in regulating gene expression during transitions between epithelial and mesenchymal phenotypes

Oil and the Macroeconomy in a Changing World: A Conference Summary

Analysis of oil-price movements is once again an important feature of economic policy discussions. To provide some background for this analysis, this paper summarizes a conference on the oil market held at the Federal Reserve Bank of Boston in June 2010. Four cross-cutting themes emerged from this symposium, which included scientific experts, market participants, business leaders, academics, and policymakers. First, the decline in real oil prices that followed the 1970s' oil shocks is unlikely to be repeated today, because there are fewer ways in which oil-importing countries can reduce oil demand or expand domestic supplies in response to higher prices. The second lesson of the conference, however, is that any prediction about oil markets is highly uncertain, a fact illustrated by the wide confidence intervals that result when futures-market data are used to quantify forecast uncertainty. Third, there is little consensus on whether new financial investment in commodity index funds has increased the volatility of oil prices. Finally, changes in oil prices still have large effects on the economy. Some research suggests that the rapid run-up in oil prices in 2007-08 may have significantly weakened the U.S. economy in the early stages of the Great Recession

19 F NMR Studies of α-Synuclein Conformation and Fibrillation

Fibrils of the intrinsically-disordered protein α-synuclein are hallmarks of Parkinson's disease. The fluorescent dye thioflavin T is often used to characterize fibrillation, but this assay may not provide quantitative information about structure and mechanism. To gain such information, we incorporated the 19F-labeled amino acid, 3-fluorotyrosine, into recombinant human α-synuclein at its endogenous tyrosine residues. Tyrosine 39 is in the positively-charged N-terminal region of this 140-residue protein. The other three, tyrosines, 125, 133, and 136, are near the C-terminus. 19F-nuclear magnetic resonance spectroscopy was used to study several properties of labeled α-synuclein, including its conformation; conformational changes induced by urea, spermine, and sodium dodecyl sulfate (SDS); its interaction with SDS micelles; and the kinetics of fibril formation. The results show that the tyrosines are in disordered regions but that there is some structure near position 39 that is disrupted by urea. SDS binding alters the conformation near position 39, but the C-terminal tyrosines are disordered under all conditions. The NMR data also indicate that SDS-micelle bound α-synuclein and the free protein exchange on the 10-ms time scale. Studies of fibrillation show the utility of 19F-labeled NMR. The data indicate that fibrillation is not accompanied by the formation of large quantities of low molecular-weight intermediates. Although dye-binding and 19F NMR data show that 1-mM SDS and 1-mM spermine accelerate aggregation compared to buffer alone, only the NMR data indicate that the species formed in SDS are smaller than those formed in buffer or buffer plus spermine. We conclude that 19F NMR spectroscopy is useful for obtaining residue-level, quantitative information about the structure, binding, and aggregation of α-synuclein