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31.
Violeta Muñoz-Fuentes Pilar Cacheiro Terrence F. Meehan Juan Antonio Aguilar-Pimentel Steve D. M. Brown Ann M. Flenniken Paul Flicek Antonella Galli Hamed Haseli Mashhadi Martin Hrabě de Angelis Jong Kyoung Kim K. C. Kent Lloyd Colin McKerlie Hugh Morgan Stephen A. Murray Lauryl M. J. Nutter Patrick T. Reilly John R. Seavitt Je Kyung Seong Michelle Simon Hannah Wardle-Jones Ann-Marie Mallon Damian Smedley Helen E. Parkinson the IMPC consortium 《Conservation Genetics》2018,19(4):995-1005
The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species. This type of analyses could be used to select optimal breeders in endangered species to maintain or increase fitness and avoid variants associated to impaired-health phenotypes or loss-of-function mutations in genes of critical importance. We also show, using selected examples from various mammal species, how IMPC data can aid in the identification of candidate genes for studying a condition of interest, deliver information about the mechanisms involved, or support predictions for the function of genes that may play a role in adaptation. With genotyping costs decreasing and the continued improvements of bioinformatics tools, the analyses we demonstrate can be routinely applied. 相似文献
32.
Oluwasola Lawal Hugo Knobel Hans Weda Tamara M. E. Nijsen Royston Goodacre Stephen J. Fowler the BreathDx consortium 《Metabolomics : Official journal of the Metabolomic Society》2018,14(5):66
Introduction
Infections such as ventilator-associated pneumonia (VAP) can be caused by one or more pathogens. Current methods for identifying these pathogenic microbes often require invasive sampling, and can be time consuming, due to the requirement for prolonged cultural enrichment along with selective and differential plating steps. This results in delays in diagnosis which in such critically ill patients can have potentially life-threatening consequences. Therefore, a non-invasive and timely diagnostic method is required. Detection of microbial volatile organic compounds (VOCs) in exhaled breath is proposed as an alternative method for identifying these pathogens and may distinguish between mono- and poly-microbial infections.Objectives
To investigate volatile metabolites that discriminate between bacterial mono- and co-cultures.Methods
VAP-associated pathogens Enterobacter cloacae and Pseudomonas aeruginosa were cultured individually and together in artificial sputum medium for 24 h and their headspace was analysed for potential discriminatory VOCs by thermal desorption gas chromatography–mass spectrometry.Results
Of the 70 VOCs putatively identified, 23 were found to significantly increase during bacterial culture (i.e. likely to be released during metabolism) and 13 decreased (i.e. likely consumed during metabolism). The other VOCs showed no transformation (similar concentrations observed as in the medium). Bacteria-specific VOCs including 2-methyl-1-propanol, 2-phenylethanol, and 3-methyl-1-butanol were observed in the headspace of axenic cultures of E. cloacae, and methyl 2-ethylhexanoate in the headspace of P. aeruginosa cultures which is novel to this investigation. Previously reported VOCs 1-undecene and pyrrole were also detected. The metabolites 2-methylbutyl acetate and methyl 2-methylbutyrate, which are reported to exhibit antimicrobial activity, were elevated in co-culture only.Conclusion
The observed VOCs were able to differentiate axenic and co-cultures. Validation of these markers in exhaled breath specimens could prove useful for timely pathogen identification and infection type diagnosis.33.
Craig C. Teerlink Daniel Leongamornlert Tokhir Dadaev Alun Thomas James Farnham Robert A. Stephenson Shaun Riska Shannon K. McDonnell Daniel J. Schaid William J. Catalona S. Lilly Zheng Kathleen A. Cooney Anna M. Ray Kimberly A. Zuhlke Ethan M. Lange Graham G. Giles Melissa C. Southey Liesel M. Fitzgerald Antje Rinckleb Manuel Luedeke Christiane Maier Janet L. Stanford Elaine A. Ostrander Elina M. Kaikkonen Csilla Sipeky Teuvo Tammela Johanna Schleutker Kathleen E. Wiley Sarah D. Isaacs Patrick C. Walsh William B. Isaacs Jianfeng Xu Geraldine Cancel-Tassin Olivier Cussenot Diptasri Mandal Cecelia Laurie Cathy Laurie The PRACTICAL consortium International Consortium for Prostate Cancer Genetics Stephen N. Thibodeau Rosalind A. Eeles Zsofia Kote-Jarai Lisa Cannon-Albright 《Human genetics》2016,135(8):923-938
34.
Aaltje Y. Adema Frans J. van Ittersum Joost G. Hoenderop Martin H. de Borst Prabath W. Nanayakkara Piet M. Ter Wee Annemieke C. Heijboer Marc G. Vervloet NIGRAM consortium 《PloS one》2016,11(1)
The CKD-associated decline in soluble α-Klotho levels is considered detrimental. Some in vitro and in vivo animal studies have shown that anti-oxidant therapy can upregulate the expression of α-Klotho in the kidney. We examined the effect of anti-oxidant therapy on α-Klotho concentrations in a clinical cohort with mild tot moderate chronic kidney disease (CKD). We performed a post-hoc analysis of a prospective randomized trial involving 62 patients with mild to moderate CKD (the ATIC study), all using an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for 12 months. On top of that, the intervention group received anti-oxidative therapy consisting of the combination of pravastatin (40 mg/d) and vitamin E (α-tocopherol acetate, 300 mg/d) while the placebo was not treated with anti-oxidants. α-Klotho concentrations were measured at baseline and after 12 months of anti-oxidant therapy. Data were analysed using T-tests and Generalized Estimating Equations, adjusting for potential confounders such as vitamin D, parathyroid hormone, fibroblast-growth-factor 23 (FGF23) and eGFR. The cohort existed of 62 patients with an eGFR (MDRD) of 35 ± 14 ml/min/1.72m2, 34 were male and mean age was 53.0 ± 12.5 years old. Anti-oxidative therapy did successfully reduce oxLDL and LDL concentrations (P <0.001). α-Klotho concentrations did not change in patients receiving either anti-oxidative therapy (476.9 ± 124.3 to 492.7 ± 126.3 pg/mL, P = 0.23) nor in those receiving placebo 483.2 ± 142.5 to 489.6 ± 120.3 pg/mL, P = 0.62). Changes in α-Klotho concentrations were not different between both groups (p = 0.62). No evidence was found that anti-oxidative therapy affected α-Klotho concentrations in patients with mild-moderate CKD. 相似文献
35.
Hui-Young Lee Kyeong-Hoon Jeong Cheol Soo Choi International Mouse Phenotyping Consortium 《Mammalian genome》2014,25(9-10):508-521
The world-wide prevalence of obesity and diabetes has increased sharply during the last two decades. Accordingly, the metabolic phenotyping of genetically engineered mouse models is critical for evaluating the functional roles of target genes in obesity and diabetes, and for developing new therapeutic targets. In this review, we discuss the practical meaning of metabolic phenotyping, the strategy of choosing appropriate tests, and considerations when designing and performing metabolic phenotyping in mice. 相似文献
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37.
Tia DiTommaso Lynelle K. Jones Denny L. Cottle The WTSI Mouse Genetics Program Anna-Karin Gerdin Valerie E. Vancollie Fiona M. Watt Ramiro Ramirez-Solis Allan Bradley Karen P. Steel John P. Sundberg Jacqueline K. White Ian M. Smyth 《PLoS genetics》2014,10(10)
The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute''s Mouse Genetics Project (Sanger-MGP). A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1), while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1). The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation. 相似文献
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39.
Bharat Thyagarajan Mary Wojczynski Ryan L Minster Jason Sanders Sandra Barral Lene Christiansen R Graham Barr CHARGE consortium SpiroMeta consortium Anne Newman 《Respiratory research》2014,15(1)
Background
Reduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals with exceptional longevity have not been identified.Method
We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia. The association between SNPs and FEV1 and FEV1/FVC was analyzed using a linear mixed effects model adjusted for age, age2, sex, height, field center, ancestry principal components and kinship structure to adjust for family relationships separately for ever smokers and never smokers. In the linkage analysis, we used the residuals of the FEV1 and FEV1/FVC, adjusted for age, sex, height, ancestry principal components (PCs), smoking status, pack-years, and field center.Results
We identified nine SNPs in strong linkage disequilibrium in the CYP2U1 gene to be associated with FEV1 and a novel SNP (rs889574) associated with FEV1/FVC, none of which were replicated in the CHARGE/SpiroMeta consortia. Using linkage analysis, we identified a novel linkage peak in chromosome 2 at 219 cM for FEV1/FVC (LOD: 3.29) and confirmed a previously reported linkage peak in chromosome 6 at 28 cM (LOD: 3.33) for FEV1.Conclusion
Future studies need to identify the rare genetic variants underlying the linkage peak in chromosome 6 for FEV1.Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0134-x) contains supplementary material, which is available to authorized users. 相似文献40.
Robin J. Pakeman Jan Lepš Michael Kleyer Sandra Lavorel Eric Garnier the VISTA consortium 《植被学杂志》2009,20(1):148-159
Objective: To identify the relative roles of climatic, edaphic and management factors in controlling the weighted mean traits of vegetation. Location: Eleven sites in Europe and one in Israel undergoing transitions in land use. Material and Methods: Standardised methods were used to collect information on species traits and attributes from plots covering a range of land uses at each site. This was combined with abundance data to create a plot × trait matrix. Variance partitioning was used to identify the relative roles of climate, soil and management on the weighted and unweighted mean traits of the vegetation in the full data set, and the data set divided into vegetative traits (including life‐form, clonality, defence and a range of leaf traits) and traits linked to regeneration via seeds (including seed mass, dispersal and pollination mechanism). Results: Variance partitioning of the full data set showed that climate (18.7%), explained more variance in the weighted mean traits of the vegetation than climate and soil together (9.2), soil (6.9) and management (6.1). There was a similar distribution of variance explained for both vegetative and regeneration via seed traits, although more variance was explained for the latter. This restricted set of climatic, edaphic and management variables could explain 45‐50% of the variance in the weighted mean traits of the vegetation between plots. There were only small differences between analyses of the weighted and unweighted data. Conclusions: Despite large variations in climate and soils between sites, there was still a separate and recognisable impact of management on the mean weighted traits of the vegetation. There was also a degree of shared variation between the three groups of factors, indicating that the response of plant traits to one group of factors may not be predictable because they may be modulated by their response to other groups. 相似文献