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Sandrine Vuillaumier-Barrot Céline Bouchet-Séraphin Malika Chelbi Louise Devisme Samuel Quentin Steven Gazal Annie Laquerrière Catherine Fallet-Bianco Philippe Loget Sylvie Odent Dominique Carles Anne Bazin Jacqueline Aziza Alix Clemenson Fabien Guimiot Maryse Bonnière Sophie Monnot Christine Bole-Feysot Jean-Pierre Bernard Laurence Loeuillet Marie Gonzales Koryna Socha Bernard Grandchamp Tania Attié-Bitach Férechté Encha-Razavi Nathalie Seta 《American journal of human genetics》2012,91(6):1135-1143
Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a “cobblestone” brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies. 相似文献
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Pedro de Atauri Míriam Tarrado-Castellarnau Josep Tarrag-Celada Carles Foguet Effrosyni Karakitsou Josep Joan Centelles Marta Cascante 《PLoS computational biology》2021,17(7)
Metabolic adaptations to complex perturbations, like the response to pharmacological treatments in multifactorial diseases such as cancer, can be described through measurements of part of the fluxes and concentrations at the systemic level and individual transporter and enzyme activities at the molecular level. In the framework of Metabolic Control Analysis (MCA), ensembles of linear constraints can be built integrating these measurements at both systemic and molecular levels, which are expressed as relative differences or changes produced in the metabolic adaptation. Here, combining MCA with Linear Programming, an efficient computational strategy is developed to infer additional non-measured changes at the molecular level that are required to satisfy these constraints. An application of this strategy is illustrated by using a set of fluxes, concentrations, and differentially expressed genes that characterize the response to cyclin-dependent kinases 4 and 6 inhibition in colon cancer cells. Decreases and increases in transporter and enzyme individual activities required to reprogram the measured changes in fluxes and concentrations are compared with down-regulated and up-regulated metabolic genes to unveil those that are key molecular drivers of the metabolic response. 相似文献
15.
Michael Garton Carles Corbi-Verge Yuan Hu Satra Nim Nadya Tarasova Brad Sherborne Philip M. Kim 《Proteins》2019,87(3):236-244
Peptide-based therapeutics are an alternative to small molecule drugs as they offer superior specificity, lower toxicity, and easy synthesis. Here we present an approach that leverages the dramatic performance increase afforded by the recent arrival of GPU accelerated thermodynamic integration (TI). GPU TI facilitates very fast, highly accurate binding affinity optimization of peptides against therapeutic targets. We benchmarked TI predictions using published peptide binding optimization studies. Prediction of mutations involving charged side-chains was found to be less accurate than for non-charged, and use of a more complex 3-step TI protocol was found to boost accuracy in these cases. Using the 3-step protocol for non-charged side-chains either had no effect or was detrimental. We use the benchmarked pipeline to optimize a peptide binding to our recently discovered cancer target: EME1. TI calculations predict beneficial mutations using both canonical and non-canonical amino acids. We validate these predictions using fluorescence polarization and confirm that binding affinity is increased. We further demonstrate that this increase translates to a significant reduction in pancreatic cancer cell viability. 相似文献
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Chartier-Harlin MC Dachsel JC Vilariño-Güell C Lincoln SJ Leprêtre F Hulihan MM Kachergus J Milnerwood AJ Tapia L Song MS Le Rhun E Mutez E Larvor L Duflot A Vanbesien-Mailliot C Kreisler A Ross OA Nishioka K Soto-Ortolaza AI Cobb SA Melrose HL Behrouz B Keeling BH Bacon JA Hentati E Williams L Yanagiya A Sonenberg N Lockhart PJ Zubair AC Uitti RJ Aasly JO Krygowska-Wajs A Opala G Wszolek ZK Frigerio R Maraganore DM Gosal D Lynch T Hutchinson M Bentivoglio AR Valente EM Nichols WC Pankratz N 《American journal of human genetics》2011,(3):140-406
Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease. 相似文献
17.
Casamayor EO Ferrera I Cristina X Borrego CM Gasol JM 《Environmental microbiology》2007,9(8):1969-1985
We show the potential of flow cytometry as a fast tool for population identification and enumeration of photosynthetic sulfur bacteria. Purple (PSB) and green sulfur bacteria (GSB) oxidize hydrogen sulfide to elemental sulfur that can act as storage compound to be further oxidized to sulfate generating the reducing power required for growth. Both groups have different elemental sulfur allocation strategies: whereas PSB store elemental sulfur as intracellular inclusions, GSB allocate sulfur globules externally. We used well-characterized laboratory strains and complex natural photosynthetic populations developing in a sharply stratified meromictic lake to show that PSB and GSB could be detected, differentiated and enumerated in unstained samples using a blue laser-based flow cytometer. Variations in cell-specific pigment content and the dynamics of sulfur accumulation, both intra- and extracellularly, were also detected in flow cytometric plots as sulfur accumulation changed the light scatter characteristics of the cells. These data were used to show the potential for studies on the metabolic status and the rate of activity at the single-cell level. Flow cytometric identification and enumeration resulted in faster and more precise analyses than previous approaches, and may open the door to more complex ecophysiological experiments with photosynthetic sulfur bacteria in mixed cultures and natural environments. 相似文献
18.
Pérez D Crespo M Solé L Prat M Carcasona C Calama E Otal R Gavaldá A Gómez-Angelats M Miralpeix M Puig C 《Bioorganic & medicinal chemistry letters》2011,21(5):1545-1548
The synthesis of diverse functionalized ureas in a semi-parallel fashion is described, as well as their β1/β2-adrenergic activities and the corresponding structure-activity relationship (SAR). We have focused on lipophilicity and duration of action, and we have discovered a strong correlation in this series of molecules. A quantitative structure-activity relationship (QSAR) analysis will be presented that quantifies this relationship. 相似文献
19.
Lisa Fauteux Matthew T. Cottrell David L. Kirchman Carles M. Borrego Maria Carolina Garcia-Chaves Paul A. del Giorgio 《PloS one》2015,10(4)
There is now evidence that aerobic anoxygenic phototrophic (AAP) bacteria are widespread across aquatic systems, yet the factors that determine their abundance and activity are still not well understood, particularly in freshwaters. Here we describe the patterns in AAP abundance, cell size and pigment content across wide environmental gradients in 43 temperate and boreal lakes of Québec. AAP bacterial abundance varied from 1.51 to 5.49 x 105 cells mL-1, representing <1 to 37% of total bacterial abundance. AAP bacteria were present year-round, including the ice-cover period, but their abundance relative to total bacterial abundance was significantly lower in winter than in summer (2.6% and 7.7%, respectively). AAP bacterial cells were on average two-fold larger than the average bacterial cell size, thus AAP cells made a greater relative contribution to biomass than to abundance. Bacteriochlorophyll a (BChla) concentration varied widely across lakes, and was not related to AAP bacterial abundance, suggesting a large intrinsic variability in the cellular pigment content. Absolute and relative AAP bacterial abundance increased with dissolved organic carbon (DOC), whereas cell-specific BChla content was negatively related to chlorophyll a (Chla). As a result, both the contribution of AAP bacteria to total prokaryotic abundance, and the cell-specific BChla pigment content were positively correlated with the DOC:Chla ratio, both peaking in highly colored, low-chlorophyll lakes. Our results suggest that photoheterotrophy might represent a significant ecological advantage in highly colored, low-chlorophyll lakes, where DOC pool is chemically and structurally more complex. 相似文献
20.
Stphanie Sherpa Maya Guguen Julien Renaud Michael G. B. Blum Thierry Gaude Frdric Laporte Mustafa Akiner Bulent Alten Carles Aranda Hlne Barre‐Cardi Romeo Bellini Mikel Bengoa Paulis Xiao‐Guang Chen Roger Eritja Eleonora Flacio Cipriano Foxi Intan H. Ishak Katja Kalan Shinji Kasai Fabrizio Montarsi Igor Pajovi Duan Petri Rosa Termine Nataa Turi Gonzalo M. Vazquez‐Prokopec Enkelejda Velo Goran Vignjevi Xiaohong Zhou Laurence Desprs 《Ecology and evolution》2019,9(22):12658-12675
Invasive species can encounter environments different from their source populations, which may trigger rapid adaptive changes after introduction (niche shift hypothesis). To test this hypothesis, we investigated whether postintroduction evolution is correlated with contrasting environmental conditions between the European invasive and source ranges in the Asian tiger mosquito Aedes albopictus. The comparison of environmental niches occupied in European and source population ranges revealed more than 96% overlap between invasive and source niches, supporting niche conservatism. However, we found evidence for postintroduction genetic evolution by reanalyzing a published ddRADseq genomic dataset from 90 European invasive populations using genotype–environment association (GEA) methods and generalized dissimilarity modeling (GDM). Three loci, among which a putative heat‐shock protein, exhibited significant allelic turnover along the gradient of winter precipitation that could be associated with ongoing range expansion. Wing morphometric traits weakly correlated with environmental gradients within Europe, but wing size differed between invasive and source populations located in different climatic areas. Niche similarities between source and invasive ranges might have facilitated the establishment of populations. Nonetheless, we found evidence for environmental‐induced adaptive changes after introduction. The ability to rapidly evolve observed in invasive populations (genetic shift) together with a large proportion of unfilled potential suitable areas (80%) pave the way to further spread of Ae. albopictus in Europe. 相似文献