| 1. |
- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 2. |
- Jones, Benedict C, et al.
(författare)
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To which world regions does the valence-dominance model of social perception apply?
- 2021
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Ingår i: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
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Tidskriftsartikel (refereegranskat)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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| 3. |
- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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| 4. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 5. |
- Crous, P. W., et al.
(författare)
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Fungal Planet description sheets: 1478-1549
- 2023
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Ingår i: Persoonia. - 0031-5850. ; 50, s. 158-310
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Tidskriftsartikel (refereegranskat)abstract
- Novel species of fungi described in this study include those from various countries as follows: Australia, Aschersonia mackerrasiae on whitefly, Cladosporium corticola on bark of Melaleuca quinquenervia, Penicillium nudgee from soil under Melaleuca quinquenervia, Pseudocercospora blackwoodiae on leaf spot of Persoonia fal- cata, and Pseudocercospora dalyelliae on leaf spot of Senna alata. Bolivia, Aspicilia lutzoniana on fully submersed siliceous schist in high-mountain streams, and Niesslia parviseta on the lower part and apothecial discs of Erioderma barbellatum on a twig. Brazil, Cyathus bonsai on decaying wood, Geastrum albofibrosum from moist soil with leaf litter, Laetiporus pratigiensis on a trunk of a living unknown hardwood tree species, and Scytalidium synnematicum on dead twigs of unidentified plant. Bulgaria, Amanita abscondita on sandy soil in a plantation of Quercus suber. Canada, Penicillium acericola on dead bark of Acer saccharum, and Penicillium corticola on dead bark of Acer saccharum. China, Colletotrichum qingyuanense on fruit lesion of Capsicum annuum. Denmark, Helminthosphaeria leptospora on corticioid Neohypochnicium cremicolor. Ecuador (Galapagos), Phaeosphaeria scalesiae on Scalesia sp. Finland, Inocybe jacobssonii on calcareous soils in dry forests and park habitats. France, Cortinarius rufomyr- rheus on sandy soil under Pinus pinaster, and Periconia neominutissima on leaves of Poaceae. India, Coprinopsis fragilis on decaying bark of logs, Filoboletus keralensis on unidentified woody substrate, Penicillium sankaranii from soil, Physisporinus tamilnaduensis on the trunk of Azadirachta indica, and Poronia nagaraholensis on elephant dung. Iran, Neosetophoma fici on infected leaves of Ficus elastica. Israel, Cnidariophoma eilatica (incl. Cnidario- phoma gen. nov.) from Stylophora pistillata. Italy, Lyophyllum obscurum on acidic soil. Namibia, Aureobasidium faidherbiae on dead leaf of Faidherbia albida, and Aureobasidium welwitschiae on dead leaves of Welwitschia mirabilis. Netherlands, Gaeumannomycella caricigena on dead culms of Carex elongata, Houtenomyces caricicola (incl. Houtenomyces gen. nov.) on culms of Carex disticha, Neodacampia ulmea (incl. Neodacampia gen. nov.) on branch of Ulmus laevis, Niesslia phragmiticola on dead standing culms of Phragmites australis, Pseudopyricularia caricicola on culms of Carex disticha, and Rhodoveronaea nieuwwulvenica on dead bamboo sticks. Norway, Arrhenia similis half-buried and moss-covered pieces of rotting wood in grass-grown path. Pakistan, Mallocybe ahmadii on soil. Poland, Beskidomyces laricis (incl. Beskidomyces gen. nov.) from resin of Larix decidua ssp. polonica, Lapi- domyces epipinicola from sooty mould community on Pinus nigra, and Leptographium granulatum from a gallery of Dendroctonus micans on Picea abies. Portugal, Geoglossum azoricum on mossy areas of laurel forest areas planted with Cryptomeria japonica, and Lunasporangiospora lusitanica from a biofilm covering a biodeteriorated limestone wall. Qatar, Alternaria halotolerans from hypersaline sea water, and Alternaria qatarensis from water sample collected from hypersaline lagoon. South Africa, Alfaria thamnochorti on culm of Thamnochortus fraternus, Knufia aloeicola on Aloe gariepensis, Muriseptatomyces restionacearum (incl. Muriseptatomyces gen. nov. ) on culms of Restionaceae, Neocladosporium arctotis on nest of cases of bag worm moths (Lepidoptera, Psychidae) on Arctotis auriculata, Neodevriesia scadoxi on leaves of Scadoxus puniceus, Paraloratospora schoenoplecti on stems of Schoenoplectus lacustris, Tulasnella epidendrea from the roots of Epidendrum x obrienianum, and Xenoidriella cinnamomi (incl. Xenoidriella gen. nov.) on leaf of Cinnamomum camphora. South Korea, Lemonniera fraxinea on decaying leaves of Fraxinus sp. from pond. Spain, Atheniella lauri on the bark of fallen trees of Laurus nobilis, Halocryptovalsa endophytica from surface-sterilised, asymptomatic roots of Salicornia patula, Inocybe amygda- liolens on soil in mixed forest, Inocybe pityusarum on calcareous soil in mixed forest, Inocybe roseobulbipes on acidic soils, Neonectria borealis from roots of Vitis berlandieri x Vitis rupestris, Sympoventuria eucalyptorum on leaves of Eucalyptus sp., and Tuber conchae from soil. Sweden, Inocybe bidumensis on calcareous soil. Thailand, Cordyceps sandindaengensis on Lepidoptera pupa, buried in soil, Ophiocordyceps kuchinaraiensis on Coleoptera larva, buried in soil, and Samsoniella winandae on Lepidoptera pupa, buried in soil. Taiwan region (China), Neo- phaeosphaeria livistonae on dead leaf of Livistona rotundifolia. Turkiye, Melanogaster anatolicus on clay loamy soils. UK, Basingstokeomyces allii (incl. Basingstokeomyces gen. nov.) on leaves of Allium schoenoprasum. Ukraine, Xenosphaeropsis corni on recently dead stem of Cornus alba. USA, Nothotrichosporon aquaticum (incl. Nothotrichosporon gen. nov.) from water, and Periconia philadelphiana from swab of coil surface. Morphological and culture characteristics for these new taxa are supported by DNA barcodes.
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| 6. |
- Dickinson, S., et al.
(författare)
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Recent advances on containment iodine chemistry
- 2010
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Ingår i: Progress in Nuclear Energy. - : Elsevier BV. - 0149-1970. ; 52:1, s. 128-135
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Konferensbidrag (refereegranskat)abstract
- The 5th FWP EURSAFE Project highlighted iodine chemistry in the containment as one of the issues requiring further research in order to reduce source term uncertainties. Consequently, a series of studies was launched in the 6th FWP SARNET Project aimed at improving the predictability of iodine behaviour during severe accidents via a better understanding of the complex chemical phenomena in the containment. In particular, SARNET has striven to foster common interpretation of integral and separate effect test data, production of new or improved models where necessary, and compilation of the existing knowledge of the subject. The work has been based on a substantial amount of experimental information made available from bench-scale projects (PARIS and EPICUR), via intermediate-scale tests (CAIMAN) to large-scale facilities (SISYPHE, THAI and PHEBUS-FP). In the experimental field, particular attention has been paid to two specific issues: the effects of radiation on both aqueous and gaseous iodine chemistry, and the mass transfer of iodine between aqueous and gaseous phases. Comparisons between calculations and results of the EPICUR and CAIMAN experiments suggest that the aqueous phase chemistry is reasonably well understood, although there are still some areas of uncertainty. Interpretation of integral experiments, like PHEBUS-FPT2, indicated that radiation-induced conversion of molecular iodine into particulate species (IxOy) could be responsible for the gaseous iodine depletion observed in the long-term. However, the results of much simpler, small-scale experiments have shown that further improvements in understanding and modelling are still needed. Mass transfer modelling has been extended to cover evaporating sump conditions based on SISYPHE data; however, application of this model to the larger scale THAI experiments seems not to be straightforward. In addition to these two major issues, some specific studies have been carried out concerning the potential effect of passive autocatalytic hydrogen recombiners on iodine volatility. The RECI analytical experiments have shown that metal iodides (namely Csl and Cdl(2)) are not stable and yield gaseous iodine when heated, in a humid atmosphere, at temperatures representative of recombiner operation. Another important undertaking successfully carried out has been the compilation of an Iodine Data Book, which provides a critical review of the experimental data and modelling approaches that have been used in the development of iodine source term methodologies. This should assist in a proper use of such models, and inform their future development.
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| 7. |
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| 8. |
- Kwong, Y. L., et al.
(författare)
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Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma
- 2018
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 29:1, s. 256-263
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Tidskriftsartikel (refereegranskat)abstract
- Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT+RT; RT+CT) and concurrent modalities (CCRT; CCRT+CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P=0.027), prognostic index for NK/T-cell lymphoma (PINK) (P=0.026) and types of initial treatment (P=0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P=0.021) and PINK-EBV DNA (PINK-E) (P=0.002) significantly impacted on PFS; whereas ECOG performance score (P=0.008) and stage (P<0.001) significantly impacted on OS. For comparing CCRT6CT and sequential CT+RT, CCRT6CT patients (n=190) were similar to sequential CT+RT patients (n=54) in all evaluated clinicopathologic parameters except two significantly superior features (higher proportion of undetectable circulating EBV DNA on diagnosis and lower PINK-E scores). Despite more favorable pre-treatment characteristics, CCRT6CT patients had CR rate, PFS and OS comparable with sequential CT+RT patients on multivariate and Cox regression analyses. Conclusions: In stage I/II NK/T-cell lymphomas, when effective chemotherapeutic regimens were used, CCRT and sequential CT+RT gave similar outcome.
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| 9. |
- Richter, M. C., et al.
(författare)
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NiFe2O4 and Fe3O4 studied by XMCD and resonant photoemission
- 2009
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Ingår i: The European Physical Journal. Special Topics. - : Springer Science and Business Media LLC. - 1951-6355 .- 1951-6401. ; 169, s. 175-180
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Tidskriftsartikel (refereegranskat)abstract
- X-ray magnetic circular dichroism and resonant photoemission at the Fe and Ni L-2,L-3 edges have been used to investigate the electronic structure of NiFe2O4 (NFO) thin films. The results, when compared to those obtained on Fe3O4, indicate that in a 12 nm NFO film the Ni atoms occupy mainly B sites, as in bulk NFO, and that a decrease in the thickness of the film results in a modi. cation of the nickel hybridization.
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| 10. |
- Wu, Chuanyan, et al.
(författare)
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Elevated circulating follistatin associates with an increased risk of type 2 diabetes
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04-1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09-1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Chatterjee, Ruchira, et al.
(författare)
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XANES and EXAFS of dilute solutions of transition metals at XFELs
- 2019
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Ingår i: Journal of Synchrotron Radiation. - : INT UNION CRYSTALLOGRAPHY. - 0909-0495 .- 1600-5775. ; 26, s. 1716-1724
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Tidskriftsartikel (refereegranskat)abstract
- This work has demonstrated that X-ray absorption spectroscopy (XAS), both Mn XANES and EXAFS, of solutions with millimolar concentrations of metal is possible using the femtosecond X-ray pulses from XFELs. Mn XAS data were collected using two different sample delivery methods, a Rayleigh jet and a drop-on-demand setup, with varying concentrations of Mn. Here, a new method for normalization of XAS spectra based on solvent scattering that is compatible with data collection from a highly variable pulsed source is described. The measured XANES and EXAFS spectra of such dilute solution samples are in good agreement with data collected at synchrotron sources using traditional scanning protocols. The procedures described here will enable XFEL-based XAS on dilute biological samples, especially metalloproteins, with low sample consumption. Details of the experimental setup and data analysis methods used in this XANES and EXAFS study are presented. This method will also benefit XAS performed at high-repetition-rate XFELs such as the European XFEL, LCLS-II and LCLS-II-HE.
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| 15. |
- Dawed, Adem Y., et al.
(författare)
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Pharmacogenomics of GLP-1 receptor agonists : a genome- wide analysis of observational data and large randomised controlled trials
- 2023
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 11:1, s. 33-41
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods:In this genome-wide analysis we included adults (aged & GE;18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings:4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G & RARR;A (Gly168Ser) in the GLP1R (0.08% [95% CI 0.04-0.12] or 0.9 mmol/mol lower reduction in HbA1c per serine, p=6.0 x 10-5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6.7 x 10-8), largely driven by rs140226575G & RARR;A (Thr370Met; 0.25% [SE 0.06] or 2.7 mmol/mol [SE 0.7] greater HbA1c reduction per methionine, p=5.2 x 10-6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation:This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.
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| 16. |
- Gudmundsdottir, Valborg, et al.
(författare)
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Whole blood co-expression modules associate with metabolic traits and type 2 diabetes : an IMI-DIRECT study
- 2020
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Ingår i: Genome Medicine. - : BioMed Central. - 1756-994X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D.Methods: Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts.Results: We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling.Conclusions: Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
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| 17. |
- Hong, Mun-Gwan, et al.
(författare)
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Evidence that the gene encoding insulin degrading enzyme influences human lifespan.
- 2008
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 17:15, s. 2370-8
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Tidskriftsartikel (refereegranskat)abstract
- Studies in model organisms have demonstrated that components of insulin and insulin-like signaling pathways are involved in the regulation of lifespan but the relevance of those findings to humans has remained obscure. Here we provide evidence suggesting that variants of the gene encoding insulin-degrading enzyme (IDE) may be influencing human lifespan. We have employed a variety of models and diverse samples that reproducibly indicate the relative change in IDE genotype frequency across the age spectrum as well as allow the detection of association with age-at-death. A tenable molecular basis of this is suggested by the observation of genetic association with both fasting plasma insulin levels and IDE mRNA expression. Across populations the emergent genetic model is indicative of over-dominance, where heterozygotes of critical markers have increased IDE mRNA expression and insulin levels, and this is reflected in diminished heterozygosity at advanced age. A critical and replicating feature of this study is that change in IDE genotype frequency with advancing age appears to be occurring only in men, and this is supported in that insulin levels are only associated with IDE in men. Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans, but over-dominance and gender specificity will be important parameters to consider clarifying the biological importance of these findings.
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| 18. |
- Hussein, Rana, et al.
(författare)
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Structural dynamics in the water and proton channels of photosystem II during the S2 to S3 transition
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Light-driven oxidation of water to molecular oxygen is catalyzed by the oxygen-evolving complex (OEC) in Photosystem II (PS II). This multi-electron, multi-proton catalysis requires the transport of two water molecules to and four protons from the OEC. A high-resolution 1.89 Å structure obtained by averaging all the S states and refining the data of various time points during the S2 to S3 transition has provided better visualization of the potential pathways for substrate water insertion and proton release. Our results indicate that the O1 channel is the likely water intake pathway, and the Cl1 channel is the likely proton release pathway based on the structural rearrangements of water molecules and amino acid side chains along these channels. In particular in the Cl1 channel, we suggest that residue D1-E65 serves as a gate for proton transport by minimizing the back reaction. The results show that the water oxidation reaction at the OEC is well coordinated with the amino acid side chains and the H-bonding network over the entire length of the channels, which is essential in shuttling substrate waters and protons.
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| 19. |
- Ibrahim, Mohamed, et al.
(författare)
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Untangling the sequence of events during the S-2 -> S-3 transition in photosystem II and implications for the water oxidation mechanism
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 117:23, s. 12624-12635
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Tidskriftsartikel (refereegranskat)abstract
- In oxygenic photosynthesis, light-driven oxidation of water to molecular oxygen is carried out by the oxygen-evolving complex (OEC) in photosystem II (PS II). Recently, we reported the room-temperature structures of PS II in the four (semi)stable S-states, S-1, S-2, S-3, and S-0, showing that a water molecule is inserted during the S-2 -> S-3 transition, as a new bridging O(H)-ligand between Mn1 and Ca. To understand the sequence of events leading to the formation of this last stable intermediate state before O-2 formation, we recorded diffraction and Mn X-ray emission spectroscopy (XES) data at several time points during the S-2 -> S-3 transition. At the electron acceptor site, changes due to the two-electron redox chemistry at the quinones, QA and QB, are observed. At the donor site, tyrosine YZ and His190 H-bonded to it move by 50 mu s after the second flash, and Glu189 moves away from Ca. This is followed by Mn1 and Mn4 moving apart, and the insertion of OX(H) at the open coordination site of Mn1. This water, possibly a ligand of Ca, could be supplied via a "water wheel"-like arrangement of five waters next to the OEC that is connected by a large channel to the bulk solvent. XES spectra show that Mn oxidation (t of similar to 350 mu s) during the S-2 -> S-3 transition mirrors the appearance of OX electron density. This indicates that the oxidation state change and the insertion of water as a bridging atom between Mn1 and Ca are highly correlated.
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| 20. |
- Ibrahim, Mohamed, et al.
(författare)
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Untangling the sequence of events during the S2 -> S3 transition in photosystem II and implications for the water oxidation mechanism
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:23, s. 12624-12635
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Tidskriftsartikel (refereegranskat)abstract
- In oxygenic photosynthesis, light-driven oxidation of water to molecular oxygen is carried out by the oxygen-evolving complex (OEC) in photosystem II (PS II). Recently, we reported the room-temperature structures of PS II in the four (semi)stable S-states, S1, S2, S3, and S0, showing that a water molecule is inserted during the S2 -> S3 transition, as a new bridging O(H)-ligand between Mn1 and Ca. To understand the sequence of events leading to the formation of this last stable intermediate state before O2 formation, we recorded diffraction and Mn X-ray emission spectroscopy (XES) data at several time points during the S2 -> S3 transition. At the electron acceptor site, changes due to the two-electron redox chemistry at the quinones, QA and QB, are observed. At the donor site, tyrosine YZ and His190 H-bonded to it move by 50 μs after the second flash, and Glu189 moves away from Ca. This is followed by Mn1 and Mn4 moving apart, and the insertion of OX(H) at the open coordination site of Mn1. This water, possibly a ligand of Ca, could be supplied via a "water wheel"-like arrangement of five waters next to the OEC that is connected by a large channel to the bulk solvent. XES spectra show that Mn oxidation (τ of ∼350 μs) during the S2 -> S3 transition mirrors the appearance of OX electron density. This indicates that the oxidation state change and the insertion of water as a bridging atom between Mn1 and Ca are highly correlated.
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| 21. |
- Keable, Stephen M., et al.
(författare)
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Room temperature XFEL crystallography reveals asymmetry in the vicinity of the two phylloquinones in photosystem I
- 2021
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Photosystem I (PS I) has a symmetric structure with two highly similar branches of pigments at the center that are involved in electron transfer, but shows very different efficiency along the two branches. We have determined the structure of cyanobacterial PS I at room temperature (RT) using femtosecond X-ray pulses from an X-ray free electron laser (XFEL) that shows a clear expansion of the entire protein complex in the direction of the membrane plane, when compared to previous cryogenic structures. This trend was observed by complementary datasets taken at multiple XFEL beamlines. In the RT structure of PS I, we also observe conformational differences between the two branches in the reaction center around the secondary electron acceptors A1A and A1B. The π-stacked Phe residues are rotated with a more parallel orientation in the A-branch and an almost perpendicular confirmation in the B-branch, and the symmetry breaking PsaB-Trp673 is tilted and further away from A1A. These changes increase the asymmetry between the branches and may provide insights into the preferential directionality of electron transfer.
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| 22. |
- Rabe, Patrick, et al.
(författare)
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X-ray free-electron laser studies reveal correlated motion during isopenicillin N synthase catalysis
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:34
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Tidskriftsartikel (refereegranskat)abstract
- Isopenicillin N synthase (IPNS) catalyzes the unique reaction of L-delta-(alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) with dioxygen giving isopenicillin N (IPN), the precursor of all natural penicillins and cephalosporins. X-ray free-electron laser studies including time-resolved crystallography and emission spectroscopy reveal how reaction of IPNS:Fe(II):ACV with dioxygen to yield an Fe(III) superoxide causes differences in active site volume and unexpected conformational changes that propagate to structurally remote regions. Combined with solution studies, the results reveal the importance of protein dynamics in regulating intermediate conformations during conversion of ACV to IPN. The results have implications for catalysis by multiple IPNS-related oxygenases, including those involved in the human hypoxic response, and highlight the power of serial femtosecond crystallography to provide insight into long-range enzyme dynamics during reactions presently impossible for nonprotein catalysts.
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