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61.
Michot C Le Goff C Goldenberg A Abhyankar A Klein C Kinning E Guerrot AM Flahaut P Duncombe A Baujat G Lyonnet S Thalassinos C Nitschke P Casanova JL Le Merrer M Munnich A Cormier-Daire V 《American journal of human genetics》2012,90(4):740-745
Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368∗]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368∗] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis. 相似文献
62.
Yin W Carballo-Jane E McLaren DG Mendoza VH Gagen K Geoghagen NS McNamara LA Gorski JN Eiermann GJ Petrov A Wolff M Tong X Wilsie LC Akiyama TE Chen J Thankappan A Xue J Ping X Andrews G Wickham LA Gai CL Trinh T Kulick AA Donnelly MJ Voronin GO Rosa R Cumiskey AM Bekkari K Mitnaul LJ Puig O Chen F Raubertas R Wong PH Hansen BC Koblan KS Roddy TP Hubbard BK Strack AM 《Journal of lipid research》2012,53(1):51-65
In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study. 相似文献
63.
Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage 总被引:1,自引:0,他引:1
Joseph A. Wamstad Jeffrey M. Alexander Rebecca M. TrutyAvanti Shrikumar Fugen LiKirsten E. Eilertson Huiming DingJohn N. Wylie Alexander R. PicoJohn A. Capra Genevieve Erwin Steven J. KattmanGordon M. Keller Deepak Srivastava Stuart S. LevineKatherine S. Pollard Alisha K. HollowayLaurie A. Boyer Benoit G. Bruneau 《Cell》2012,151(1):206-220
64.
Chaofeng Lin Eloise I. Larsen Genevieve R. Larsen Malcolm E. Cox James J. Smith 《Hydrobiologia》2012,696(1):63-76
Bacterially mediated iron redox cycling exerts a strong influence on groundwater geochemistry, but few studies have investigated iron biogeochemical processes in coastal alluvial aquifers from a microbiological viewpoint. The shallow alluvial aquifer located adjacent to Poona estuary on the subtropical Southeast Queensland coast represents a redox-stratified system where iron biogeochemical cycling potentially affects water quality. Using a 300 m transect of monitoring wells perpendicular to the estuary, we examined groundwater physico-chemical conditions and the occurrence of cultivable bacterial populations involved in iron (and manganese, sulfur) redox reactions in this aquifer. Results showed slightly acidic and near-neutral pH, suboxic conditions and an abundance of dissolved iron consisting primarily of iron(II) in the majority of wells. The highest level of dissolved iron(III) was found in a well proximal to the estuary most likely a result of iron curtain effects due to tidal intrusion. A number of cultivable, (an)aerobic bacterial populations capable of diverse carbon, iron, or sulfur metabolism coexisted in groundwater redox transition zones. Our findings indicated aerobic, heterotrophic respiration and bacterially mediated iron/sulfur redox reactions were integral to carbon cycling in the aquifer. High abundances of dissolved iron and cultivable iron and sulfur bacterial populations in estuary-adjacent aquifers have implications for iron transport to marine waters. This study demonstrated bacterially mediated iron redox cycling and associated biogeochemical processes in subtropical coastal groundwaters using culture-based methods. 相似文献
65.
Leyi Gong Yun-Chou Tan Genevieve Boice Sarah Abbot Kristen McCaleb Pravin Iyer Fengrong Zuo Joseph Dal Porto Brian Wong Sue Jin Alice Chang Patricia Tran Gary Hsieh Linghao Niu Ada Shao Deborah Reuter Christine M. Lukacs R. Ursula Kammlott Andreas Kuglstatter David Goldstein 《Bioorganic & medicinal chemistry letters》2012,22(24):7381-7387
A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC50 of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model. 相似文献
66.
Is diversification history of maize influencing selection of soil bacteria by roots? 总被引:1,自引:0,他引:1
Bouffaud ML Kyselková M Gouesnard B Grundmann G Muller D Moënne-Loccoz Y 《Molecular ecology》2012,21(1):195-206
A wide range of plant lines has been propagated by farmers during crop selection and dissemination, but consequences of this crop diversification on plant-microbe interactions have been neglected. Our hypothesis was that crop evolutionary history shaped the way the resulting lines interact with soil bacteria in their rhizospheres. Here, the significance of maize diversification as a factor influencing selection of soil bacteria by seedling roots was assessed by comparing rhizobacterial community composition of inbred lines representing the five main genetic groups of maize, cultivated in a same European soil. Rhizobacterial community composition of 21-day-old seedlings was analysed using a 16S rRNA taxonomic microarray targeting 19 bacterial phyla. Rhizobacterial community composition of inbred lines depended on the maize genetic group. Differences were largely due to the prevalence of certain Betaproteobacteria and especially Burkholderia, as confirmed by quantitative PCR and cloning/sequencing. However, these differences in bacterial root colonization did not correlate with plant microsatellite genetic distances between maize genetic groups or individual lines. Therefore, the genetic structure of maize that arose during crop diversification (resulting in five main groups), but not the extent of maize diversification itself (as determined by maize genetic distances), was a significant factor shaping rhizobacterial community composition of seedlings. 相似文献
67.
Mosquitoes transmit numerous arboviruses including dengue and chikungunya virus (CHIKV). In recent years, mosquito species Aedes albopictus has expanded in the Indian Ocean region and was the principal vector of chikungunya outbreaks in La Reunion and neighbouring islands in 2005 and 2006. Vector‐associated bacteria have recently been found to interact with transmitted pathogens. For instance, Wolbachia modulates the replication of viruses or parasites. However, there has been no systematic evaluation of the diversity of the entire bacterial populations within mosquito individuals particularly in relation to virus invasion. Here, we investigated the effect of CHIKV infection on the whole bacterial community of Ae. albopictus. Taxonomic microarrays and quantitative PCR showed that members of Alpha‐ and Gammaproteobacteria phyla, as well as Bacteroidetes, responded to CHIKV infection. The abundance of bacteria from the Enterobacteriaceae family increased with CHIKV infection, whereas the abundance of known insect endosymbionts like Wolbachia and Blattabacterium decreased. Our results clearly link the pathogen propagation with changes in the dynamics of the bacterial community, suggesting that cooperation or competition occurs within the host, which may in turn affect the mosquito traits like vector competence. 相似文献
68.
Songok EM Luo M Liang B Mclaren P Kaefer N Apidi W Boucher G Kimani J Wachihi C Sekaly R Fowke K Ball BT Plummer FA 《PloS one》2012,7(1):e30048
To identify novel biomarkers for HIV-1 resistance, including pathways that may be critical in anti-HIV-1 vaccine design, we carried out a gene expression analysis on blood samples obtained from HIV-1 highly exposed seronegatives (HESN) from a commercial sex worker cohort in Nairobi and compared their profiles to HIV-1 negative controls. Whole blood samples were collected from 43 HIV-1 resistant sex workers and a similar number of controls. Total RNA was extracted and hybridized to the Affymetrix HUG 133 Plus 2.0 micro arrays (Affymetrix, Santa Clara CA). Output data was analysed through ArrayAssist software (Agilent, San Jose CA). More than 2,274 probe sets were differentially expressed in the HESN as compared to the control group (fold change ≥1.3; p value ≤0.0001, FDR <0.05). Unsupervised hierarchical clustering of the differentially expressed genes readily distinguished HESNs from controls. Pathway analysis through the KEGG signaling database revealed a majority of the impacted pathways (13 of 15, 87%) had genes that were significantly down regulated. The most down expressed pathways were glycolysis/gluconeogenesis, pentose phosphate, phosphatidyl inositol, natural killer cell cytotoxicity and T-cell receptor signaling. Ribosomal protein synthesis and tight junction genes were up regulated. We infer that the hallmark of HIV-1 resistance is down regulation of genes in key signaling pathways that HIV-1 depends on for infection. 相似文献
69.
70.
Mehdi Ghorbal Christine Scheidig-Benatar Salma Bouizem Christophe Thomas Genevieve Paisley Claire Faltermeier Melanie Liu Artur Scherf Jose-Juan Lopez-Rubio Deshmukh N. Gopaul 《PloS one》2012,7(10)