ALBERT

Description: A discontinuous grid finite-difference (FD) method with non-uniform time step Runge–Kutta scheme on curvilinear collocated-grid is developed for seismic wave simulation. We introduce two transition zones: a spatial transition zone and a temporal transition zone, to exchange wavefield across the spatial and temporal discontinuous interfaces. A Gaussian filter is applied to suppress artificial numerical noise caused by down-sampling the wavefield from the finer grid to the coarser grid. We adapt the non-uniform time step Runge–Kutta scheme to a discontinuous grid FD method for further increasing the computational efficiency without losing the accuracy of time marching through the whole simulation region. When the topography is included in the modelling, we carry out the discontinuous grid method on a curvilinear collocated-grid to obtain a sufficiently accurate free-surface boundary condition implementation. Numerical tests show that the proposed method can sufficiently accurately simulate the seismic wave propagation on such grids and significantly reduce the computational resources consumption with respect to regular grids.

Description: We investigate the evolution of the mass–metallicity ( M – Z ) relation with a large sample of 53 444 star-forming galaxies (SFGs) at 0.04 〈  z  〈 0.12, selected from the catalogue of Max-Planck-Institute for Astrophysics–John Hopkins University (MPA–JHU) emission-line measurements for the Sloan Digital Sky Survey Data Release 7. Regarding the sample of SFGs, we correct the observational bias and raise the aperture covering fractions to check the reliability of the metallicity evolution. (i) We show that the redshift evolution of the log (Hα) and log([O  iii ]) luminosities is displayed in our sample. (ii) We find the metallicity evolution of ~0.15 dex at log ( M * /M ) ~ 9.3 in SFGs at 0.04 〈  z  〈 0.12. (iii) After applying the luminosity thresholds of log ( L Hα ) 〉 41.0 and $\log (L_{\rm [O\,\scriptscriptstyle {III}]}) 〉 39.7$ , we find that the metallicity evolution is shown well, and that the evolution of the star formation rate (SFR) is still shown well under the latter luminosity threshold, but the evolution is not observed under the former. (iv) The evolution of the M – Z relation seems to disappear at about log ( M * /M ) 〉 10.0 after applying the luminosity threshold of log ( L Hα ) 〉 41.0 or $\log (L_{\rm [O\,\scriptscriptstyle {III}]}) 〉 39.7$ . (v) We find α = 0.09 and α = 0.07 in the equation, μ = log M * – αlog (SFR), for log ( L Hα ) 〉 41.0 and $\log (L_{\rm [O\,\scriptscriptstyle {III}]}) 〉 39.7$ samples, respectively, and these imply that the evolution of the M – Z relation might have a weaker dependence on the SFR in our sample.

Description: Single-nucleotide polymorphisms, either inherited or due to spontaneous DNA damage, are associated with numerous diseases. Developing tools for site-specific nucleotide modification may one day provide a way to alter disease polymorphisms. Here, we describe the in vitro selection and characterization of a new deoxyribozyme called F-8, which catalyzes nucleotide excision specifically at thymidine. Cleavage by F-8 generates 3'- and 5'-phosphate ends recognized by DNA modifying enzymes, which repair the targeted deoxyribonucleotide while maintaining the integrity of the rest of the sequence. These results illustrate the potential of DNAzymes as tools for DNA manipulation.

Description: We investigated biomass and composition of heterotrophic microbes in the Costa Rica Dome during June–July 2010 as part of a broader study of plankton trophic dynamics. Because picophytoplankton (〈2 μm) are known to dominate in this unique upwelling region, we hypothesized tight biomass relationships between size-determined predator–prey pairs (i.e. picoplankton–nano-grazers, nanoplankton–micro-grazers) within the microbial community. Integrated biomass of heterotrophic bacteria ranged from 180 to 487 mg C m –2 and was significantly correlated with total autotrophic carbon. Heterotrophic protist (H-protist) biomass ranged more narrowly from 488 to 545 mg C m –2 , and was comprised of 60% dinoflagellates, 30% other flagellates and 11% ciliates. Nano-sized (〈20 μm) protists accounted for the majority (57%) of grazer biomass and were positively correlated with picoplankton, partially supporting our hypothesis, but nanoplankton and micro-grazers (〉20 μm) were not significantly correlated. The relative constancy of H-protist biomass among locations despite clear changes in integrated autotrophic biomass, Chl a , and primary production suggests that mesozooplankton may exert a tight top-down control on micro-grazers. Biomass-specific consumption rates of phytoplankton by protistan grazers suggest an instantaneous growth rate of 0.52 day –1 for H-protists, similar to the growth rate of phytoplankton and consistent with a trophically balanced ecosystem dominated by pico-nanoplankton interactions.

Description: Individual saposin A (A–/–) and saposin B (B–/–)-deficient mice show unique phenotypes caused by insufficient degradation of myelin-related glycosphingolipids (GSLs): galactosylceramide and galactosylsphingosine and sulfatide, respectively. To gain insight into the interrelated functions of saposins A and B, combined saposin AB-deficient mice (AB–/–) were created by knock-in point mutations into the saposins A and B domains on the prosaposin locus. Saposin A and B proteins were undetectable in AB–/– mice, whereas prosaposin, saposin C and saposin D were expressed near wild-type (WT) levels. AB–/– mice developed neuromotor deterioration at 〉61 days and exhibited abnormal locomotor activity and enhanced tremor. AB–/– mice (~96 days) lived longer than A–/– mice (~85 days), but shorter than B–/– mice (~644 days). Storage materials were observed in Schwann cells and neuronal processes by electron microscopy. Accumulation of p62 and increased levels of LC3-II were detected in the brainstem suggesting altered autophagy. GSL analyses by (liquid chromatography) LC/MS identified substantial increases in lactosylceramide in AB–/– mouse livers. Sulfatide accumulated, but galactosylceramide remained at WT levels, in the AB–/– mouse brains and kidneys. Brain galactosylsphingosine in AB–/– mice was ~68% of that in A–/– mice. These findings indicate that combined saposins A and B deficiencies attenuated GalCer-β-galactosylceramidase and GM1-β-galactosidase functions in the degradation of lactosylceramide preferentially in the liver. Blocking sulfatide degradation from the saposin B deficiency diminished galactosylceramide accumulation in the brain and kidney and galctosylsphingosine in the brain. These analyses of AB–/– mice continue to delineate the tissue differential interactions of saposins in GSL metabolism.

Description: The Luonan Basin, located in the transitional zone between temperate and subtropical China, is an important locality for human evolution during the early to middle Pleistocene. The loess deposits in the Luonan Basin contain numerous in situ lithic artefacts; the deposits also constitute suitable material for dating the artefacts and are potentially useful for reconstructing the climatic fluctuations which is important for studying the adaptation and occupation of the area by early humans. We carried out a combined rock magnetic and geochemical investigation of a loess sequence from the Liuwan Palaeolithic site in the Luonan Basin. The results indicate a mixture of magnetic minerals, including magnetite/maghemite and hematite/goethite. Magnetic susceptibility was used as a palaeoclimate proxy on the Chinese Loess Plateau; however, its application to the Luonan Basin may be problematic because the provenance of the loess parent material, as well as the depositional environment, differs from that of the Chinese Loess Plateau. We found that rock magnetic parameters related to the grain size of magnetic minerals, such as SIRM/ and ARM /SIRM, are better palaeoclimatic indicators than magnetic susceptibility. Overall, the magnetic results, together with the results of bulk grain-size and chemical index of alteration, indicate that the interglacial environment of early humans in Luonan Basin was warmer and more humid than the coeval environment of the Chinese Loess Plateau.

Description: Silencing the mutant huntingtin gene ( muHTT ) is a direct and simple therapeutic strategy for the treatment of Huntington disease (HD) in principle. However, targeting the HD mutation presents challenges because it is an expansion of a common genetic element (a CAG tract) that is found throughout the genome. Moreover, the HTT protein is important for neuronal health throughout life, and silencing strategies that also reduce the wild-type HTT allele may not be well tolerated during the long-term treatment of HD. Several HTT silencing strategies are in development that target genetic sites in HTT that are outside of the CAG expansion, including HD mutation-linked single-nucleotide polymorphisms and the HTT promoter. Preclinical testing of these genetic therapies has required the development of a new mouse model of HD that carries these human-specific genetic targets. To generate a fully humanized mouse model of HD, we have cross-bred BACHD and YAC18 on the Hdh –/– background. The resulting line, Hu97/18, is the first murine model of HD that fully genetically recapitulates human HD having two human HTT genes, no mouse Hdh genes and heterozygosity of the HD mutation. We find that Hu97/18 mice display many of the behavioral changes associated with HD including motor, psychiatric and cognitive deficits, as well as canonical neuropathological abnormalities. This mouse line will be useful for gaining additional insights into the disease mechanisms of HD as well as for testing genetic therapies targeting human HTT.

Description: Elevated expression and activity of N -acetylglucosaminyltransferase V (Mgat5) in hepatocellular carcinoma (HCC) is a common early event involved in tumor invasion during hepatocarcinogenesis. A better understanding of the functional role and the molecular mechanism for Mgat5-targeted protein and downstream signaling pathway behind hepatoma invasion and metastasis is urgently needed. Here, we show that Mgat5 overexpression promoted anchorage-independent growth and inhibited anoikis in hepatoma cells. This effect was reversed by glycosyltransferase inactive mutant Mgat5 L188R transfection, α-mannosidase II inhibitor swainsonine treatment and N -acetyl glucosamine (GlcNAc) phosphotransferase (GPT) inhibitor tunicamycin administration. Mgat5 overexpression increased p21-activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase inactivation with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor P21-activated kinase inhibitor III (IPA3) treatment reversed anoikis resistance in Mgat5-overexpressed hepatoma cells. Furthermore, Mgat5 overexpression upregulated β-1-6-GlcNAc branched N-glycosylation and following phosphorylation of epidermal growth factor receptor (EGFR) in hepatoma cells. EGFR tyrosine kinase inhibitors AG1478 and Iressa treatment declined anchorage-independent growth and anoikis resistance, which could be rescued by constitutive active mutant PAK1 T423E coexpression in Mgat5-overexpressed hepatoma cells. Conversely, knockdown of Mgat5 reduced EGFR/PAK1-dependent anoikis resistance, which could be reversed by PAK1 T423E. These results identified Mgat5-mediated β-1-6-GlcNAc branched N-glycosylation and following activation of EGFR as a potential novel upstream molecular event for PAK1-induced anoikis resistance in hepatoma cells, implicating that molecular targeted therapeutics against Mgat5/EGFR/PAK1 might open a new avenue for personalized medicine in advanced-stage HCC patients.

Description: 〈span class="paragraphSection"〉〈div class="boxTitle"〉Abstract〈/div〉The perfectly matched layer (PML) is an efficient absorbing technique for numerical wave simulation. The complex frequency-shifted PML (CFS-PML) introduces two additional parameters in the stretching function to make the absorption frequency dependent. This can help to suppress converted evanescent waves from near grazing incident waves, but does not efficiently absorb low-frequency waves below the cut-off frequency. To absorb both the evanescent wave and the low-frequency wave, the double-pole CFS-PML having two poles in the coordinate stretching function was developed in computational electromagnetism. Several studies have investigated the performance of the double-pole CFS-PML for seismic wave simulations in the case of a narrowband seismic wavelet and did not find significant difference comparing to the CFS-PML. Another difficulty to apply the double-pole CFS-PML for real problems is that a practical strategy to set optimal parameter values has not been established. In this work, we study the performance of the double-pole CFS-PML for broad-band seismic wave simulation. We find that when the maximum to minimum frequency ratio is larger than 16, the CFS-PML will either fail to suppress the converted evanescent waves for grazing incident waves, or produce visible low-frequency reflection, depending on the value of α. In contrast, the double-pole CFS-PML can simultaneously suppress the converted evanescent waves and avoid low-frequency reflections with proper parameter values. We analyse the different roles of the double-pole CFS-PML parameters and propose optimal selections of these parameters. Numerical tests show that the double-pole CFS-PML with the optimal parameters can generate satisfactory results for broad-band seismic wave simulations.〈/span〉