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991.
Holleboom AG Karlsson H Lin RS Beres TM Sierts JA Herman DS Stroes ES Aerts JM Kastelein JJ Motazacker MM Dallinga-Thie GM Levels JH Zwinderman AH Seidman JG Seidman CE Ljunggren S Lefeber DJ Morava E Wevers RA Fritz TA Tabak LA Lindahl M Hovingh GK Kuivenhoven JA 《Cell metabolism》2011,14(6):811-818
Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene. 相似文献
992.
993.
Diana Walluscheck Kathrin Reissig Khuloud Bajbouj Oliver Ullrich Roland Hartig Hala Gali‐Muhtasib Antje Diestel Albert Roessner Regine Schneider‐Stock 《Journal of cellular and molecular medicine》2011,15(7):1528-1541
Besides the well‐understood DNA damage response via establishment of G2 checkpoint arrest, novel studies focus on the recovery from arrest by checkpoint override to monitor cell cycle re‐entry. The aim of this study was to investigate the role of Chk1 in the recovery from G2 checkpoint arrest in HCT116 (human colorectal cancer) wt, p53–/– and p21–/– cell lines following H2O2 treatment. Firstly, DNA damage caused G2 checkpoint activation via Chk1. Secondly, overriding G2 checkpoint led to (i) mitotic slippage, cell cycle re‐entry in G1 and subsequent G1 arrest associated with senescence or (ii) premature mitotic entry in the absence of p53/p21WAF1 causing mitotic catastrophe. We revealed subtle differences in the initial Chk1‐involved G2 arrest with respect to p53/p21WAF1: absence of either protein led to late G2 arrest instead of the classic G2 arrest during checkpoint initiation, and this impacted the release back into the cell cycle. Thus, G2 arrest correlated with downstream senescence, but late G2 arrest led to mitotic catastrophe, although both cell cycle re‐entries were linked to upstream Chk1 signalling. Chk1 knockdown deciphered that Chk1 defines long‐term DNA damage responses causing cell cycle re‐entry. We propose that recovery from oxidative DNA damage‐induced G2 arrest requires Chk1. It works as cutting edge and navigates cells to senescence or mitotic catastrophe. The decision, however, seems to depend on p53/p21WAF1. The general relevance of Chk1 as an important determinant of recovery from G2 checkpoint arrest was verified in HT29 colorectal cancer cells. 相似文献
994.
Sadasivan VD Narpala SR Budil DE Sacco A Carrier RL 《Journal of molecular modeling》2011,17(11):2953-2963
Intestinal mucus, a viscous secretion that lines the mucosa, is believed to be a barrier to absorption of many therapeutic
compounds and carriers, and is known to play an important physiological role in controlling pathogen invasion. Nevertheless,
there is as yet no clear understanding of the barrier properties of mucus, such as the nature of the molecular interactions
between drug molecules and mucus components as well as those that govern gel formation. Secretory mucins, large and complex
glycoprotein molecules, are the principal determinants of the viscoelastic properties of intestinal mucus. Despite the important
role that mucins play in controlling transport and in diseases such as cystic fibrosis, their structures remain poorly characterized.
The major intestinal secretory mucin gene, MUC2, has been identified and fully sequenced. The present study was undertaken
to determine a detailed structure of the cysteine-rich region within the C-terminal end of human intestinal mucin (MUC2) via
homology modeling, and explore possible configurations of a dimer of this cysteine-rich region, which may play an important
role in governing mucus gel formation. Based on sequence–structure alignments and three-dimensional modeling, a cystine knot
tertiary structure homologous to that of human chorionic gonadotropin (HCG) is predicted at the C-terminus of MUC2. Dimers
of this C-terminal cystine knot (CTCK) were modeled using sequence alignment based on HCG and TGF-beta, followed by molecular
dynamics and simulated annealing. Results support the formation of a cystine knot dimer with a structure analogous to that
of HCG.
相似文献
995.
Changes in species composition of European acid grasslands observed along a gradient of nitrogen deposition 总被引:1,自引:0,他引:1
Carly Stevens Cecilia Duprè Cassandre Gaudnik Edu Dorland Nancy Dise David Gowing Albert Bleeker Didier Alard Roland Bobbink David Fowler Vigdis Vandvik Emmanuel Corcket J. Owen Mountford Per Arild Aarrestad Serge Muller Martin Diekmann 《植被学杂志》2011,22(2):207-215
Question: Which environmental variables affect floristic species composition of acid grasslands in the Atlantic biogeographic region of Europe along a gradient of atmospheric N deposition? Location: Transect across the Atlantic biogeographic region of Europe including Ireland, Great Britain, Isle of Man, France, Belgium, The Netherlands, Germany, Norway, Denmark and Sweden. Materials and Methods: In 153 acid grasslands we assessed plant and bryophyte species composition, soil chemistry (pH, base cations, metals, nitrate and ammonium concentrations, total C and N, and Olsen plant available phosphorus), climatic variables, N deposition and S deposition. Ordination and variation partitioning were used to determine the relative importance of different drivers on the species composition of the studied grasslands. Results: Climate, soil and deposition variables explained 24% of the total variation in species composition. Variance partitioning showed that soil variables explained the most variation in the data set and that climate and geographic variables accounted for slightly less variation. Deposition variables (N and S deposition) explained 9.8% of the variation in the ordination. Species positively associated with N deposition included Holcus mollis and Leontodon hispidus. Species negatively associated with N deposition included Agrostis curtisii, Leontodon autumnalis, Campanula rotundifolia and Hylocomium splendens. Conclusion: Although secondary to climate gradients and soil biogeochemistry, and not as strong as for species richness, the impact of N and S deposition on species composition can be detected in acid grasslands, influencing community composition both directly and indirectly, presumably through soil‐mediated effects. 相似文献
996.
Pop N Igel P Brennauer A Cabrele C Bernhardt GN Seifert R Buschauer A 《Journal of receptor and signal transduction research》2011,31(4):271-285
The four functionally expressed human neuropeptide Y receptor subtypes (hY(1)R, hY(2)R, hY(4)R, hY(5)R) belong to class A of the G-protein-coupled receptors (GPCRs) and interact with pertussis toxin-sensitive G(i/o)-proteins. The number of small molecules described as ligands for hY(1)R and hY(5)R exceeds by far those for hY(2)R. Potent non-peptidergic ligands for the hY(4)R are not available so far. Here, we report on the functional reconstitution of the hY(2)R and the hY(4)R in Sf9 insect cells using the baculovirus system. Sf9 cells were genetically engineered by infection with up to four different baculoviruses, combining the receptors with G-proteins of the G(i/o) family and regulators of G-protein signaling (RGS) proteins to improve signal-to-noise ratio. In steady-state GTPase assays, using pNPY (Y(2)) and hPP (Y(4)), the GPCRs coupled to various G(i)/G(o)-proteins and both, RGS4 and GAIP, enhanced the signals. Co-expression systems hY(2)R + G?(i2) and hY(4)R + G?(i2)/G?(o) + RGS4, combined with G?(1)?(2), yielded best signal-to-noise ratios. hY(2)R function was validated using both agonistic peptides (NPY, PYY, NPY(13?36)) and selective non-peptidergic antagonists (BIIE0246 and derivatives), whereas the hY(4)R model was characterized with peptidergic agonists (PP, NPY, GW1229, and BW1911U90). Tunicamycin inhibited receptor N-glycosylation diminished NPY signals at hY(2)R and abolished hY(4)R function. Investigations with monovalent salts showed sensitivity of hY(4)R toward Na(+), revealing moderate constitutive activity. After validation, an acylguanidine (UR-PI284) was identified as a weak non-peptide Y(4)R antagonist. In summary, the established steady-state GTPase assays provide sensitive test systems for the characterization of Y(2) and Y(4) receptor ligands. 相似文献
997.
Cry2Aa, one of the major insecticidal proteins produced by Bacillus thuringiensis subsp. kurstaki HD1, is known to be active against both lepidopteran and dipteran larvae. In order to determine whether Cry2Aa could enhance or synergize the mosquitocidal activity of B. thuringiensis subsp. israelensis, we constructed a plasmid vector that harbored the cry2Aa operon and transformed crystalliferous and acrystalliferous strains of this bacterium. The wild-type B. thuringiensis subsp. israelensis, a recombinant B. thuringiensis subsp. israelensis producing Cry2A along with its native major mosquitocidal proteins, and a recombinant B. thuringiensis subsp. israelensis producing Cry2Aa alone were tested against three major mosquito species — Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus. Our results demonstrated that Cry2Aa does not synergize or enhance the mosquitocidal activity of B. thuringiensis subsp. israelensis against these important vectors of disease. 相似文献
998.
Zuccolo A Bowers JE Estill JC Xiong Z Luo M Sebastian A Goicoechea JL Collura K Yu Y Jiao Y Duarte J Tang H Ayyampalayam S Rounsley S Kudrna D Paterson AH Pires JC Chanderbali A Soltis DE Chamala S Barbazuk B Soltis PS Albert VA Ma H Mandoli D Banks J Carlson JE Tomkins J dePamphilis CW Wing RA Leebens-Mack J 《Genome biology》2011,12(5):R48-14
Background
Recent phylogenetic analyses have identified Amborella trichopoda, an understory tree species endemic to the forests of New Caledonia, as sister to a clade including all other known flowering plant species. The Amborella genome is a unique reference for understanding the evolution of angiosperm genomes because it can serve as an outgroup to root comparative analyses. A physical map, BAC end sequences and sample shotgun sequences provide a first view of the 870 Mbp Amborella genome.Results
Analysis of Amborella BAC ends sequenced from each contig suggests that the density of long terminal repeat retrotransposons is negatively correlated with that of protein coding genes. Syntenic, presumably ancestral, gene blocks were identified in comparisons of the Amborella BAC contigs and the sequenced Arabidopsis thaliana, Populus trichocarpa, Vitis vinifera and Oryza sativa genomes. Parsimony mapping of the loss of synteny corroborates previous analyses suggesting that the rate of structural change has been more rapid on lineages leading to Arabidopsis and Oryza compared with lineages leading to Populus and Vitis. The gamma paleohexiploidy event identified in the Arabidopsis, Populus and Vitis genomes is shown to have occurred after the divergence of all other known angiosperms from the lineage leading to Amborella.Conclusions
When placed in the context of a physical map, BAC end sequences representing just 5.4% of the Amborella genome have facilitated reconstruction of gene blocks that existed in the last common ancestor of all flowering plants. The Amborella genome is an invaluable reference for inferences concerning the ancestral angiosperm and subsequent genome evolution. 相似文献999.
Fairfield H Gilbert GJ Barter M Corrigan RR Curtain M Ding Y D'Ascenzo M Gerhardt DJ He C Huang W Richmond T Rowe L Probst FJ Bergstrom DE Murray SA Bult C Richardson J Kile BT Gut I Hager J Sigurdsson S Mauceli E Di Palma F Lindblad-Toh K Cunningham ML Cox TC Justice MJ Spector MS Lowe SW Albert T Donahue LR Jeddeloh J Shendure J Reinholdt LG 《Genome biology》2011,12(9):R86-12
We report the development and optimization of reagents for in-solution, hybridization-based capture of the mouse exome. By validating this approach in a multiple inbred strains and in novel mutant strains, we show that whole exome sequencing is a robust approach for discovery of putative mutations, irrespective of strain background. We found strong candidate mutations for the majority of mutant exomes sequenced, including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis. 相似文献
1000.
Jordan DB Wagschal K Fan Z Yuan L Braker JD Heng C 《Journal of industrial microbiology & biotechnology》2011,38(11):1821-1835
β-d-Xylosidase/α-l-arabinofuranosidase from Selenomonas ruminantium is the most active enzyme reported for catalyzing hydrolysis of 1,4-β-d-xylooligosaccharides to d-xylose. One property that could use improvement is its relatively high affinities for d-glucose and d-xylose (K
i ~ 10 mM), which would impede its performance as a catalyst in the saccharification of lignocellulosic biomass for the production
of biofuels and other value-added products. Previously, we discovered that the W145G variant expresses K
i
d-glucose and K
i
d-xylose twofold and threefold those of the wild-type enzyme. However, in comparison to the wild type, the variant expresses 11% lower
k
cat
d-xylobiose and much lower stabilities to temperature and pH. Here, we performed saturation mutagenesis of W145 and discovered that the
variants express K
i values that are 1.5–2.7-fold (d-glucose) and 1.9–4.6-fold (d-xylose) those of wild-type enzyme. W145F, W145L, and W145Y express good stability and, respectively, 11, 6, and 1% higher
k
cat
d-xylobiose than that of the wild type. At 0.1 M d-xylobiose and 0.1 M d-xylose, kinetic parameters indicate that W145F, W145L, and W145Y catalytic activities are respectively 46, 71, and 48% greater
than that of the wild-type enzyme. 相似文献