| 1. |
- Locke, Adam E, et al.
(author)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Journal article (peer-reviewed)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
|
|
| 2. |
- Schafmayer, Clemens, et al.
(author)
-
Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
- 2019
-
In: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 68:5, s. 854-865
-
Journal article (peer-reviewed)abstract
- Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p< 0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10-10 and 0.002 (OR allelic = 1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). Conclusion I n silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
|
|
| 3. |
- Shungin, Dmitry, et al.
(author)
-
New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
-
Journal article (peer-reviewed)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
|
|
| 4. |
- Bellenberg, Sören, et al.
(author)
-
Automated Microscopic Analysis of Metal Sulfide Colonization by Acidophilic Microorganisms
- 2018
-
In: Applied and Environmental Microbiology. - : American society for microbiology. - 0099-2240 .- 1098-5336. ; 84:20
-
Journal article (peer-reviewed)abstract
- Industrial biomining processes are currently focused on metal sulfides and their dissolution, which is catalyzed by acidophilic iron(II)- and/or sulfur-oxidizing microorganisms. Cell attachment on metal sulfides is important for this process. Biofilm formation is necessary for seeding and persistence of the active microbial community in industrial biomining heaps and tank reactors, and it enhances metal release. In this study, we used a method for direct quantification of the mineral-attached cell population on pyrite or chalcopyrite particles in bioleaching experiments by coupling high-throughput, automated epifluorescence microscopy imaging of mineral particles with algorithms for image analysis and cell quantification, thus avoiding human bias in cell counting. The method was validated by quantifying cell attachment on pyrite and chalcopyrite surfaces with axenic cultures of Acidithiobacillus caldus, Leptospirillum ferriphilum, and Sulfobacillus thermosulfidooxidans. The method confirmed the high affinity of L. ferriphilum cells to colonize pyrite and chalcopyrite surfaces and indicated that biofilm dispersal occurs in mature pyrite batch cultures of this species. Deep neural networks were also applied to analyze biofilms of different microbial consortia. Recent analysis of the L. ferriphilum genome revealed the presence of a diffusible soluble factor (DSF) family quorum sensing system. The respective signal compounds are known as biofilm dispersal agents. Biofilm dispersal was confirmed to occur in batch cultures of L. ferriphilum and S. thermosulfidooxidans upon the addition of DSF family signal compounds. IMPORTANCE The presented method for the assessment of mineral colonization allows accurate relative comparisons of the microbial colonization of metal sulfide concentrate particles in a time-resolved manner. Quantitative assessment of the mineral colonization development is important for the compilation of improved mathematical models for metal sulfide dissolution. In addition, deep-learning algorithms proved that axenic or mixed cultures of the three species exhibited characteristic biofilm patterns and predicted the biofilm species composition. The method may be extended to the assessment of microbial colonization on other solid particles and may serve in the optimization of bioleaching processes in laboratory scale experiments with industrially relevant metal sulfide concentrates. Furthermore, the method was used to demonstrate that DSF quorum sensing signals directly influence colonization and dissolution of metal sulfides by mineral-oxidizing bacteria, such as L. ferriphilum and S. thermosulfidooxidans.
|
|
| 5. |
|
|
| 6. |
- Buetti-Dinh, Antoine, 1984-, et al.
(author)
-
Deep neural networks outperform human expert's capacity in characterizing bioleaching bacterial biofilm composition
- 2019
-
In: Biotechnology Reports. - : Elsevier. - 2215-017X. ; 22, s. 1-5
-
Journal article (peer-reviewed)abstract
- Background: Deep neural networks have been successfully applied to diverse fields of computer vision. However, they only outperform human capacities in a few cases. Methods: The ability of deep neural networks versus human experts to classify microscopy images was tested on biofilm colonization patterns formed on sulfide minerals composed of up to three different bioleaching bacterial species attached to chalcopyrite sample particles. Results: A low number of microscopy images per category (<600) was sufficient for highly efficient computational analysis of the biofilm's bacterial composition. The use of deep neural networks reached an accuracy of classification of ∼90% compared to ∼50% for human experts. Conclusions: Deep neural networks outperform human experts’ capacity in characterizing bacterial biofilm composition involved in the degradation of chalcopyrite. This approach provides an alternative to standard, time-consuming biochemical methods. © 2019 The Author
|
|
| 7. |
- Christel, Stephan, et al.
(author)
-
Multi-omics reveal the lifestyle of the acidophilic, mineral-oxidizing model species Leptospirillum ferriphilumT
- 2018
-
In: Applied and Environmental Microbiology. - : American society for microbiology. - 0099-2240 .- 1098-5336. ; 4:3
-
Journal article (peer-reviewed)abstract
- Leptospirillum ferriphilum plays a major role in acidic, metal rich environments where it represents one of the most prevalent iron oxidizers. These milieus include acid rock and mine drainage as well as biomining operations. Despite its perceived importance, no complete genome sequence of this model species' type strain is available, limiting the possibilities to investigate the strategies and adaptations Leptospirillum ferriphilumT applies to survive and compete in its niche. This study presents a complete, circular genome of Leptospirillum ferriphilumT DSM 14647 obtained by PacBio SMRT long read sequencing for use as a high quality reference. Analysis of the functionally annotated genome, mRNA transcripts, and protein concentrations revealed a previously undiscovered nitrogenase cluster for atmospheric nitrogen fixation and elucidated metabolic systems taking part in energy conservation, carbon fixation, pH homeostasis, heavy metal tolerance, oxidative stress response, chemotaxis and motility, quorum sensing, and biofilm formation. Additionally, mRNA transcript counts and protein concentrations were compared between cells grown in continuous culture using ferrous iron as substrate and bioleaching cultures containing chalcopyrite (CuFeS2). Leptospirillum ferriphilumT adaptations to growth on chalcopyrite included a possibly enhanced production of reducing power, reduced carbon dioxide fixation, as well as elevated RNA transcripts and proteins involved in heavy metal resistance, with special emphasis on copper efflux systems. Finally, expression and translation of genes responsible for chemotaxis and motility were enhanced.
|
|
| 8. |
- Christel, Stephan, et al.
(author)
-
Systems Biology of Acidophile Biofilms for Efficient Metal Extraction
- 2015
-
In: Biotechnologies in Mining Industry and Environmental Engineering. - 9783038356783 ; , s. 312-315
-
Conference paper (peer-reviewed)abstract
- This European Union ERASysApp funded study will investigate one of the major drawbacks of bioleaching of the copper containing mineral chalcopyrite, namely the long lag phase between construction and inoculation of bioleaching heaps and the release of dissolved metals. In practice, this lag phase can be up to three years and the long time period adds to the operating expenses of bioheaps for chalcopyrite dissolution. One of the major time determining factors in bioleaching heaps is suggested to be the speed of mineral colonization by the acidophilic microorganisms present. By applying confocal microscopy, metatranscriptomics, metaproteomics, bioinformatics, and computer modeling the authors aim to investigate the processes leading up to, and influencing the attachment of three moderately thermophilic sulfur-and/or iron-oxidizing model species:Acidithiobacillus caldus, Leptospirillum ferriphilum, and Sulfobacillus thermosulfidooxidans. Stirred tank reactors containing chalcopyrite concentrate will be inoculated with these species in various orders and proportions and the effects on the lag phase and rates of metal release will be compared. Meanwhile, confocal microscopy studies of cell attachment to chalcopyrite mineral particles, as well as metatranscriptomics and metaproteomics of the formed biofilms will further increase understanding of the attachment process and help develop a model thereof. By fulfilling our goal to decrease the length of the lag phase of chalcopyrite bioleaching heaps we hope to increase their economic feasibility and therefore, industrial interest in bioleaching as a sustainable technology.
|
|
| 9. |
- Christel, Stephan, et al.
(author)
-
Weak Iron Oxidation by Sulfobacillus thermosulfidooxidans Maintains a Favorable Redox Potential for Chalcopyrite Bioleaching
- 2018
-
In: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 9
-
Journal article (peer-reviewed)abstract
- Bioleaching is an emerging technology, describing the microbially assisted dissolution of sulfidicores that provides a more environmentally friendly alternative to many traditional metal extractionmethods, such as roasting or smelting. Industrial interest increases steadily and today, circa 15-20%of the world’s copper production can be traced back to this method. However, bioleaching of theworld’s most abundant copper mineral chalcopyrite suffers from low dissolution rates, oftenattributed to passivating layers, which need to be overcome to use this technology to its full potential.To prevent these passivating layers from forming, leaching needs to occur at a lowoxidation/reduction potential (ORP), but chemical redox control in bioleaching heaps is difficult andcostly. As an alternative, selected weak iron-oxidizers could be employed that are incapable ofscavenging exceedingly low concentrations of iron and therefore, raise the ORP just above the onsetof bioleaching, but not high enough to allow for the occurrence of passivation. In this study, wereport that microbial iron oxidation by Sulfobacillus thermosulfidooxidans meets these specifications.Chalcopyrite concentrate bioleaching experiments with S. thermosulfidooxidans as the sole ironoxidizer exhibited significantly lower redox potentials and higher release of copper compared tocommunities containing the strong iron oxidizer Leptospirillum ferriphilum. Transcriptomic responseto single and co-culture of these two iron oxidizers was studied and revealed a greatly decreasednumber of mRNA transcripts ascribed to iron oxidation in S. thermosulfidooxidans when cultured inthe presence of L. ferriphilum. This allowed for the identification of genes potentially responsible forS. thermosulfidooxidans’ weaker iron oxidation to be studied in the future, as well as underlined theneed for mechanisms to control the microbial population in bioleaching heaps
|
|
| 10. |
- Dand, Nick, et al.
(author)
-
Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling
- 2017
-
In: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:21, s. 4301-4313
-
Journal article (peer-reviewed)abstract
- Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.
|
|
