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991.
Romi H Cohen I Landau D Alkrinawi S Yerushalmi B Hershkovitz R Newman-Heiman N Cutting GR Ofir R Sivan S Birk OS 《American journal of human genetics》2012,90(5):893-899
Meconium ileus, intestinal obstruction in the newborn, is caused in most cases by CFTR mutations modulated by yet-unidentified modifier genes. We now show that in two unrelated consanguineous Bedouin kindreds, an autosomal-recessive phenotype of meconium ileus that is not associated with cystic fibrosis (CF) is caused by different homozygous mutations in GUCY2C, leading to a dramatic reduction or fully abrogating the enzymatic activity of the encoded guanlyl cyclase 2C. GUCY2C is a transmembrane receptor whose extracellular domain is activated by either the endogenous ligands, guanylin and related peptide uroguanylin, or by an external ligand, Escherichia coli (E. coli) heat-stable enterotoxin STa. GUCY2C is expressed in the human intestine, and the encoded protein activates the CFTR protein through local generation of cGMP. Thus, GUCY2C is a likely candidate modifier of the meconium ileus phenotype in CF. Because GUCY2C heterozygous and homozygous mutant mice are resistant to E. coli STa enterotoxin-induced diarrhea, it is plausible that GUCY2C mutations in the desert-dwelling Bedouin kindred are of selective advantage. 相似文献
992.
993.
Goehring I Gerencser AA Schmidt S Brand MD Mulder H Nicholls DG 《The Journal of biological chemistry》2012,287(19):15706-15717
Oscillations in plasma membrane potential play a central role in glucose-induced insulin secretion from pancreatic β-cells and related insulinoma cell lines. We have employed a novel fluorescent plasma membrane potential (Δψ(p)) indicator in combination with indicators of cytoplasmic free Ca(2+) ([Ca(2+)](c)), mitochondrial membrane potential (Δψ(m)), matrix ATP concentration, and NAD(P)H fluorescence to investigate the role of mitochondria in the generation of plasma membrane potential oscillations in clonal INS-1 832/13 β-cells. Elevated glucose caused oscillations in plasma membrane potential and cytoplasmic free Ca(2+) concentration over the same concentration range required for insulin release, although considerable cell-to-cell heterogeneity was observed. Exogenous pyruvate was as effective as glucose in inducing oscillations, both in the presence and absence of 2.8 mM glucose. Increased glucose and pyruvate each produced a concentration-dependent mitochondrial hyperpolarization. The causal relationships between pairs of parameters (Δψ(p) and [Ca(2+)](c), Δψ(p) and NAD(P)H, matrix ATP and [Ca(2+)](c), and Δψ(m) and [Ca(2+)](c)) were investigated at single cell level. It is concluded that, in these β-cells, depolarizing oscillations in Δψ(p) are not initiated by mitochondrial bioenergetic changes. Instead, regardless of substrate, it appears that the mitochondria may simply be required to exceed a critical bioenergetic threshold to allow release of insulin. Once this threshold is exceeded, an autonomous Δψ(p) oscillatory mechanism is initiated. 相似文献
994.
The recent discovery of a model compounds of [NiFe] hydrogenase that catalyzes the heterolytic cleavage of the H2 molecule into a proton and a stable hydride in water solution under room conditions opened up the possibility to understand
the mechanism of H2 uptake by this peculiar class of enzymes. The simplest model compound belongs to the class of NiRu bimetallic cationic complexes
mimicking, in water solution and at room conditions, the hydrogenase active site. By using first-principles molecular dynamics
computer simulations, in the Car–Parrinello scheme, we investigated models including the water solvent and nitrate counterions.
Several simulations, starting from different initial configurations, provided information on the first step of the H2 cleavage: (1) the pathway of H2 approach towards the active site; (2) the role of the ruthenium-bonded water molecule in providing a base that extracts the
proton from the activated H2 molecule; (3) the minor role of Ni in activating the H2 molecule and its role in stabilizing the hydride produced. 相似文献
995.
SA Rad HS Zahiri KA Noghabi S Rajaei R Heidari L Mojallali 《World journal of microbiology & biotechnology》2012,28(1):313-321
In this study a comparison was made between type 1 and type 2 isopentenyl diphosphate isomerases (IDI) in improving lycopene
production in Escherichia coli. The corresponding genes of Bacillus licheniformis and the host (i
Bl
and i
Ec
, respectively) were expressed in lycopene producing E. coli strains by pTlyciBl and pTlyciEc plasmids, under the control of tac promoter. The results showed that the overexpression of i
Ec
improved the lycopene production from 33 ± 1 in E. coli Tlyc to 68 ± 3 mg/gDCW in E. coli TlyciEc. In contrast, the expression of i
Bl
increased the lycopene production more efficiently up to 80 ± 9 mg/gDCW in E. coli TlyciBl. The introduction of a heterologous mevalonate pathway to elevate the IPP abundance resulted in a lycopene production up
to 132 ± 5 mg/gDCW with i
Ec
in E. coli TlyciEc-mev and 181 ± 9 mg/gDCW with i
Bl
in E. coli TlyciBl-mev, that is, 4 and 5.6 times respectively. When fructose, mannose, arabinose, and acetate were each used as an auxiliary
substrate with glycerol, lycopene production was inhibited by different extents. Among auxiliary substrates tested, only citrate
was an improving one for lycopene production in all strains with a maximum of 198 ± 3 mg/gDCW in E. coli TlyciBl-mev. It may be concluded that the type 2 IDI performs better than the type 1 in metabolic engineering attempts for isoprenoid
production in E. coli. In addition, the metabolic engineering of citrate pathway seems a promising approach to have more isoprenoid accumulation
in E. coli. 相似文献
996.
Aiguadé J Balagué C Carranco I Caturla F Domínguez M Eastwood P Esteve C González J Lumeras W Orellana A Preciado S Roca R Vidal L Vidal B 《Bioorganic & medicinal chemistry letters》2012,22(10):3431-3436
A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy. 相似文献
997.
Davies DJ Crowe M Lucas N Quinn J Miller DD Pritchard S Grose D Bettini E Calcinaghi N Virginio C Abberley L Goldsmith P Michel AD Chessell IP Kew JN Miller ND Gunthorpe MJ 《Bioorganic & medicinal chemistry letters》2012,22(7):2620-2623
A series of novel benzimidazoles are discussed as NR2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists. High throughput screening (HTS) efforts identified a number of potent and selective NR2B antagonists such as 1. Exploration of the substituents around the core of this template identified a number of compounds with high potency for NR2B (pIC(50) >7) and good selectivity against the NR2A subunit (pIC(50) <4.3) as defined by FLIPR-Ca(2+) and radioligand binding studies. These agents offer potential for the development of therapeutics for a range of nervous system disorders including chronic pain, neurodegeneration, migraine and major depression. 相似文献
998.
Foundation (dominant or matrix) species play a key role in structuring plant communities, influencing processes from population to ecosystem scales. However, the effects of genotypic diversity of foundation species on these processes have not been thoroughly assessed in the context of assembling plant communities. We modified the classical filter model of community assembly to include genotypic diversity as part of the biotic filter. We hypothesized that the proportion of fit genotypes (i.e. competitively superior and dominant) affects niche space availability for subordinate species to establish with consequence for species diversity. To test this hypothesis, we used an individual‐based simulation model where a foundation species of varying genotypic diversity (number of genotypes and variability among genotypes) competes for space with subordinate species on a spatially heterogeneous lattice. Our model addresses a real and practical problem in restoration ecology: choosing the level of genetic diversity of re‐introduced foundation and subordinate species. Genotypic diversity of foundation species significantly affected equilibrium community diversity, measured as species richness, either positively or negatively, depending upon environmental heterogeneity. Increases in genotypic diversity gave the foundation species a wider niche breadth. Under conditions of high environmental heterogeneity, this wider niche breadth decreased niche space for other species, lowering species richness with increased genotypic diversity until the genotypes of the foundation species saturated the landscape. With a low level of environmental heterogeneity, increasing genotypic diversity caused the foundation species niche breadth to be overdispersed, resulting in a weak positive relationship with species richness. Under these conditions, some genotypes are maladapted to the environment lowering fitness of the foundation species. These effects of genotypic diversity were secondary to the larger effects of overall foundation species fitness and environmental heterogeneity. The novel aspect of incorporating genotype diversity in combination with environmental heterogeneity in community assembly models include predictions of either positive or negative relationships between species diversity and genotypic diversity depending on environmental heterogeneity, and the conditions under which these factors are potentially relevant. Mechanistically, differential niche availability is imposed by the foundation species. 相似文献
999.
Rennie EA Hansen SF Baidoo EE Hadi MZ Keasling JD Scheller HV 《Plant physiology》2012,159(4):1408-1417
Xylan is a major component of the plant cell wall and the most abundant noncellulosic component in the secondary cell walls that constitute the largest part of plant biomass. Dicot glucuronoxylan consists of a linear backbone of β(1,4)-linked xylose residues substituted with α(1,2)-linked glucuronic acid (GlcA). Although several genes have been implicated in xylan synthesis through mutant analyses, the biochemical mechanisms responsible for synthesizing xylan are largely unknown. Here, we show evidence for biochemical activity of GUX1 (for GlcA substitution of xylan 1), a member of Glycosyltransferase Family 8 in Arabidopsis (Arabidopsis thaliana) that is responsible for adding the glucuronosyl substitutions onto the xylan backbone. GUX1 has characteristics typical of Golgi-localized glycosyltransferases and a K(m) for UDP-GlcA of 165 μm. GUX1 strongly favors xylohexaose as an acceptor over shorter xylooligosaccharides, and with xylohexaose as an acceptor, GlcA is almost exclusively added to the fifth xylose residue from the nonreducing end. We also show that several related proteins, GUX2 to GUX5 and Plant Glycogenin-like Starch Initiation Protein6, are Golgi localized and that only two of these proteins, GUX2 and GUX4, have activity as xylan α-glucuronosyltransferases. 相似文献
1000.