| 1. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 2. |
- Abelev, Betty, et al.
(författare)
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Underlying Event measurements in pp collisions at root s=0.9 and 7 TeV with the ALICE experiment at the LHC
- 2012
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Ingår i: Journal of High Energy Physics. - 1029-8479. ; :7
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Tidskriftsartikel (refereegranskat)abstract
- We present measurements of Underlying Event observables in pp collisions at root s = 0 : 9 and 7 TeV. The analysis is performed as a function of the highest charged-particle transverse momentum p(T),L-T in the event. Different regions are defined with respect to the azimuthal direction of the leading (highest transverse momentum) track: Toward, Transverse and Away. The Toward and Away regions collect the fragmentation products of the hardest partonic interaction. The Transverse region is expected to be most sensitive to the Underlying Event activity. The study is performed with charged particles above three different p(T) thresholds: 0.15, 0.5 and 1.0 GeV/c. In the Transverse region we observe an increase in the multiplicity of a factor 2-3 between the lower and higher collision energies, depending on the track p(T) threshold considered. Data are compared to PYTHIA 6.4, PYTHIA 8.1 and PHOJET. On average, all models considered underestimate the multiplicity and summed p(T) in the Transverse region by about 10-30%.
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| 3. |
- Alonso-Mori, Roberto, et al.
(författare)
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Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:47, s. 19103-19107
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Tidskriftsartikel (refereegranskat)abstract
- The ultrabright femtosecond X-ray pulses provided by X-ray free-electron lasers open capabilities for studying the structure and dynamics of a wide variety of systems beyond what is possible with synchrotron sources. Recently, this probe-before-destroy approach has been demonstrated for atomic structure determination by serial X-ray diffraction of microcrystals. There has been the question whether a similar approach can be extended to probe the local electronic structure by X-ray spectroscopy. To address this, we have carried out femtosecond X-ray emission spectroscopy (XES) at the Linac Coherent Light Source using redox-active Mn complexes. XES probes the charge and spin states as well as the ligand environment, critical for understanding the functional role of redox-active metal sites. K beta(1,3) XES spectra of Mn-II and Mn-2(III,IV) complexes at room temperature were collected using a wavelength dispersive spectrometer and femtosecond X-ray pulses with an individual dose of up to > 100 MGy. The spectra were found in agreement with undamaged spectra collected at low dose using synchrotron radiation. Our results demonstrate that the intact electronic structure of redox active transition metal compounds in different oxidation states can be characterized with this shot-by-shot method. This opens the door for studying the chemical dynamics of metal catalytic sites by following reactions under functional conditions. The technique can be combined with X-ray diffraction to simultaneously obtain the geometric structure of the overall protein and the local chemistry of active metal sites and is expected to prove valuable for understanding the mechanism of important metalloproteins, such as photosystem II.
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| 4. |
- Anniyev, Toyli, et al.
(författare)
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Complementarity between high-energy photoelectron and L-edge spectroscopy for probing the electronic structure of 5d transition metal catalysts
- 2010
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 12:21, s. 5694-5700
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate the successful use of hard X-ray photoelectron spectroscopy (HAXPES) for selectively probing the platinum partial d-density of states (DOS) in a Pt-Cu nanoparticle catalyst which shows activity superior to pure Pt towards the oxygen-reduction reaction (ORR). The information about occupied Pt d-band states was complemented by Pt L-2-edge X-ray absorption near-edge spectroscopy (XANES), which probes unoccupied valence states. We found a significant electronic perturbation of the Pt projected d-DOS which was narrowed and shifted to higher binding energy compared to pure platinum. The effect of this electronic structure perturbation on the chemical properties of the nanoparticle surface is discussed in terms of the d-band model. We have thereby demonstrated that the combination of L-edge spectroscopy and HAXPES allows for an experimental derivation of the valence electronic structure in an element-specific way for 5d metal catalysts.
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| 5. |
- Bergmann, René, et al.
(författare)
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Prominent Binding of Human and Equine Fibrinogen to Streptococcus equi subsp. zooepidemicus Is Mediated by Specific SzM Types and Is a Distinct Phenotype of Zoonotic Isolates
- 2020
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Ingår i: Infection and Immunity. - 1098-5522. ; 88:1
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus equi subsp. zooepidemicus is an important pathogen in horses that causes severe diseases such as pneumonia and abortion. Furthermore, it is a zoonotic agent, and contact with horses is a known risk factor. In this study, we investigated the working hypothesis that the zoonotic potential varies among S. equi subsp. zooepidemicus strains in association with differences in M-like protein-mediated binding of host plasma proteins. We demonstrate via in-frame deletion mutagenesis of two different S. equi subsp. zooepidemicus strains that the M-like protein SzM is crucial for the binding of fibrinogen to the bacterial surface and for survival in equine and human blood. S. equi subsp. zooepidemicus isolates of equine and human origins were compared with regard to SzM sequences and binding of equine and human fibrinogens. The N-terminal 216 amino acids of the mature SzM were found to exhibit a high degree of diversity, but the majority of human isolates grouped in three distinct SzM clusters. Plasma protein absorption assays and flow cytometry analysis revealed that pronounced binding of human fibrinogen is a common phenotype of human S. equi subsp. zooepidemicus isolates but much less so in equine S. equi subsp. zooepidemicus isolates. Furthermore, binding of human fibrinogen is associated with specific SzM types. These results suggest that SzM-mediated binding of human fibrinogen is an important virulence mechanism of zoonotic S. equi subsp. zooepidemicus isolates.
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| 6. |
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| 7. |
- Bergmann, Uwe, et al.
(författare)
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Using X-ray free-electron lasers for spectroscopy of molecular catalysts and metalloenzymes
- 2021
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Ingår i: NATURE REVIEWS PHYSICS. - : Springer Nature. - 2522-5820. ; 3:4, s. 264-282
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Forskningsöversikt (refereegranskat)abstract
- X-ray lasers offer unprecedented capabilities, with their tunable, intense and short X-ray pulses. This Technical Review discusses the current and future use of X-ray lasers for probing molecular catalysts and metalloenzymes and their chemical reactions in real time and under functional conditions. The metal centres in metalloenzymes and molecular catalysts are responsible for the rearrangement of atoms and electrons during complex chemical reactions, and they enable selective pathways of charge and spin transfer, bond breaking/making and the formation of new molecules. Mapping the electronic structural changes at the metal sites during the reactions gives a unique mechanistic insight that has been difficult to obtain to date. The development of X-ray free-electron lasers (XFELs) enables powerful new probes of electronic structure dynamics to advance our understanding of metalloenzymes. The ultrashort, intense and tunable XFEL pulses enable X-ray spectroscopic studies of metalloenzymes, molecular catalysts and chemical reactions, under functional conditions and in real time. In this Technical Review, we describe the current state of the art of X-ray spectroscopy studies at XFELs and highlight some new techniques currently under development. With more XFEL facilities starting operation and more in the planning or construction phase, new capabilities are expected, including high repetition rate, better XFEL pulse control and advanced instrumentation. For the first time, it will be possible to make real-time molecular movies of metalloenzymes and catalysts in solution, while chemical reactions are taking place.
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| 8. |
- Bhowmick, Asmit, et al.
(författare)
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Going around the Kok cycle of the water oxidation reaction with femtosecond X-ray crystallography
- 2023
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Ingår i: IUCrJ. - : International Union Of Crystallography. - 2052-2525. ; 10:6, s. 642-655
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Forskningsöversikt (refereegranskat)abstract
- The water oxidation reaction in photosystem II (PS II) produces most of the molecular oxygen in the atmosphere, which sustains life on Earth, and in this process releases four electrons and four protons that drive the downstream process of CO2 fixation in the photosynthetic apparatus. The catalytic center of PS II is an oxygen-bridged Mn4Ca complex (Mn4CaO5) which is progressively oxidized upon the absorption of light by the chlorophyll of the PS II reaction center, and the accumulation of four oxidative equivalents in the catalytic center results in the oxidation of two waters to dioxygen in the last step. The recent emergence of X-ray free-electron lasers (XFELs) with intense femtosecond X-ray pulses has opened up opportunities to visualize this reaction in PS II as it proceeds through the catalytic cycle. In this review, we summarize our recent studies of the catalytic reaction in PS II by following the structural changes along the reaction pathway via room-temperature X-ray crystallography using XFELs. The evolution of the electron density changes at the Mn complex reveals notable structural changes, including the insertion of OX from a new water molecule, which disappears on completion of the reaction, implicating it in the O-O bond formation reaction. We were also able to follow the structural dynamics of the protein coordinating with the catalytic complex and of channels within the protein that are important for substrate and product transport, revealing well orchestrated conformational changes in response to the electronic changes at the Mn4Ca cluster.
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| 9. |
- Bhowmick, Asmit, et al.
(författare)
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Structural evidence for intermediates during O2 formation in photosystem II
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 617:7961, s. 629-636
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Tidskriftsartikel (refereegranskat)abstract
- In natural photosynthesis, the light-driven splitting of water into electrons, protons and molecular oxygen forms the first step of the solar-to-chemical energy conversion process. The reaction takes place in photosystem II, where the Mn4CaO5 cluster first stores four oxidizing equivalents, the S0 to S4 intermediate states in the Kok cycle, sequentially generated by photochemical charge separations in the reaction center and then catalyzes the O–O bond formation chemistry. Here, we report room temperature snapshots by serial femtosecond X-ray crystallography to provide structural insights into the final reaction step of Kok’s photosynthetic water oxidation cycle, the S3→[S4]→S0 transition where O2 is formed and Kok’s water oxidation clock is reset. Our data reveal a complex sequence of events, which occur over micro- to milliseconds, comprising changes at the Mn4CaO5 cluster, its ligands and water pathways as well as controlled proton release through the hydrogen-bonding network of the Cl1 channel. Importantly, the extra O atom Ox, which was introduced as a bridging ligand between Ca and Mn1 during the S2→S3 transition, disappears or relocates in parallel with Yz reduction starting at approximately 700 μs after the third flash. The onset of O2 evolution, as indicated by the shortening of the Mn1–Mn4 distance, occurs at around 1,200 μs, signifying the presence of a reduced intermediate, possibly a bound peroxide.
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| 10. |
- Bogacz, Isabel, et al.
(författare)
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Room temperature X-ray absorption spectroscopy of metalloenzymes with drop-on-demand sample delivery at XFELs
- 2023
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Ingår i: Pure and Applied Chemistry. - 0033-4545. ; 95:8, s. 891-897
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Tidskriftsartikel (refereegranskat)abstract
- X-ray crystallography and X-ray spectroscopy using X-ray free electron lasers plays an important role in understanding the interplay of structural changes in the protein and the chemical changes at the metal active site of metalloenzymes through their catalytic cycles. As a part of such an effort, we report here our recent development of methods for X-ray absorption spectroscopy (XAS) at XFELs to study dilute biological samples, available in limited volumes. Our prime target is Photosystem II (PS II), a multi subunit membrane protein complex, that catalyzes the light-driven water oxidation reaction at the Mn4CaO5 cluster. This is an ideal system to investigate how to control multi-electron/proton chemistry, using the flexibility of metal redox states, in coordination with the protein and the water network. We describe the method that we have developed to collect XAS data using PS II samples with a Mn concentration of <1 mM, using a drop-on-demand sample delivery method.
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| 11. |
- Chasman, Daniel I., et al.
(författare)
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Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
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Tidskriftsartikel (refereegranskat)abstract
- In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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| 12. |
- Chatterjee, Ruchira, et al.
(författare)
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XANES and EXAFS of dilute solutions of transition metals at XFELs
- 2019
-
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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| 13. |
- Chen, Chen, et al.
(författare)
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Solvation structures of protons and hydroxide ions in water
- 2013
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 138:15, s. 154506-
-
Tidskriftsartikel (refereegranskat)abstract
- X-ray Raman spectroscopy (XRS) combined with small-angle x-ray scattering (SAXS) were used to study aqueous solutions of HCl and NaOH. Hydrated structures of H+ and OH- are not simple mirror images of each other. While both ions have been shown to strengthen local hydrogen bonds in the hydration shell as indicated by XRS, SAXS suggests that H+ and OH- have qualitatively different long-range effects. The SAXS structure factor of HCl (aq) closely resembles that of pure water, while NaOH (aq) behaves similar to NaF (aq). We propose that protons only locally enhance hydrogen bonds while hydroxide ions induce tetrahedrality in the overall hydrogen bond network of water.
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| 14. |
- Fransson, Thomas, et al.
(författare)
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Effects of x-ray free-electron laser pulse intensity on the Mn K beta(1,3) x-ray emission spectrum in photosystem II-A case study for metalloprotein crystals and solutions
- 2021
-
Ingår i: Structural Dynamics. - : AIP Publishing. - 2329-7778. ; 8:6
-
Tidskriftsartikel (refereegranskat)abstract
- In the last ten years, x-ray free-electron lasers (XFELs) have been successfully employed to characterize metalloproteins at room temperature using various techniques including x-ray diffraction, scattering, and spectroscopy. The approach has been to outrun the radiation damage by using femtosecond (fs) x-ray pulses. An example of an important and damage sensitive active metal center is the Mn4CaO5 cluster in photosystem II (PS II), the catalytic site of photosynthetic water oxidation. The combination of serial femtosecond x-ray crystallography and K beta x-ray emission spectroscopy (XES) has proven to be a powerful multimodal approach for simultaneously probing the overall protein structure and the electronic state of the Mn4CaO5 cluster throughout the catalytic (Kok) cycle. As the observed spectral changes in the Mn4CaO5 cluster are very subtle, it is critical to consider the potential effects of the intense XFEL pulses on the K beta XES signal. We report here a systematic study of the effects of XFEL peak power, beam focus, and dose on the Mn K beta(1,3) XES spectra in PS II over a wide range of pulse parameters collected over seven different experimental runs using both microcrystal and solution PS II samples. Our findings show that for beam intensities ranging from & SIM;5 x 10(15) to 5 x 10(17) W/cm(2) at a pulse length of & SIM;35 fs, the spectral effects are small compared to those observed between S-states in the Kok cycle. Our results provide a benchmark for other XFEL-based XES studies on metalloproteins, confirming the viability of this approach.& nbsp;
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| 15. |
- Fransson, Thomas, et al.
(författare)
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Effects of x-ray free-electron laser pulse intensity on the Mn K β 1,3x-ray emission spectrum in photosystem II - A case study for metalloprotein crystals and solutions
- 2021
-
Ingår i: Structural Dynamics. - : American Institute of Physics (AIP). - 2329-7778. ; 8:6
-
Tidskriftsartikel (refereegranskat)abstract
- In the last ten years, x-ray free-electron lasers (XFELs) have been successfully employed to characterize metalloproteins at room temperature using various techniques including x-ray diffraction, scattering, and spectroscopy. The approach has been to outrun the radiation damage by using femtosecond (fs) x-ray pulses. An example of an important and damage sensitive active metal center is the Mn4CaO5 cluster in photosystem II (PS II), the catalytic site of photosynthetic water oxidation. The combination of serial femtosecond x-ray crystallography and Kβ x-ray emission spectroscopy (XES) has proven to be a powerful multimodal approach for simultaneously probing the overall protein structure and the electronic state of the Mn4CaO5 cluster throughout the catalytic (Kok) cycle. As the observed spectral changes in the Mn4CaO5 cluster are very subtle, it is critical to consider the potential effects of the intense XFEL pulses on the Kβ XES signal. We report here a systematic study of the effects of XFEL peak power, beam focus, and dose on the Mn Kβ1,3 XES spectra in PS II over a wide range of pulse parameters collected over seven different experimental runs using both microcrystal and solution PS II samples. Our findings show that for beam intensities ranging from ∼5 × 1015 to 5 × 1017 W/cm2 at a pulse length of ∼35 fs, the spectral effects are small compared to those observed between S-states in the Kok cycle. Our results provide a benchmark for other XFEL-based XES studies on metalloproteins, confirming the viability of this approach.
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| 16. |
- Friebel, Daniel, et al.
(författare)
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In situ x-ray probing reveals the importance of surface platinum oxide formation in fuel cell catalysis
- 2011
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 13:1, s. 262-266
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Tidskriftsartikel (refereegranskat)abstract
- In situ X-ray absorption spectroscopy (XAS) at the Pt L3 edge is a useful probe for Pt–O interactions at polymer electrolyte membrane fuel cell (PEMFC) cathodes. We show that XAS using the high energy resolution fluorescence detection (HERFD) mode, applied to a well-defined monolayer Pt/Rh(111) sample where the bulk penetrating hard X-rays probe only surface Pt atoms, provides a unique sensitivity to structure and chemical bonding at the Pt-electrolyte interface. Ab initio multiple-scattering calculations using the FEFF code and complementary extended X-ray absorption fine structure (EXAFS) results indicate that the commonly observed large increase of the white-line at high electrochemical potentials on PEMFC cathodes originates from platinum oxide formation, whereas previously proposed chemisorbed oxygen-containing species merely give rise to subtle spectral changes.
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| 17. |
- Fuller, Franklin D, et al.
(författare)
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Drop-on-demand sample delivery for studying biocatalysts in action at X-ray free-electron lasers
- 2017
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Ingår i: Nature Methods. - : Macmillan Publishers Ltd.. - 1548-7091 .- 1548-7105. ; 14, s. 443-449
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Tidskriftsartikel (refereegranskat)abstract
- X-ray crystallography at X-ray free-electron laser sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy, both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing insights into the interplay between the protein structure and dynamics and the chemistry at an active site. The implementation of such a multimodal approach can be compromised by conflicting requirements to optimize each individual method. In particular, the method used for sample delivery greatly affects the data quality. We present here a robust way of delivering controlled sample amounts on demand using acoustic droplet ejection coupled with a conveyor belt drive that is optimized for crystallography and spectroscopy measurements of photochemical and chemical reactions over a wide range of time scales. Studies with photosystem II, the phytochrome photoreceptor, and ribonucleotide reductase R2 illustrate the power and versatility of this method.
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| 18. |
- Fuller, Franklin D., et al.
(författare)
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Resonant X-ray emission spectroscopy from broadband stochastic pulses at an X-ray free electron laser
- 2021
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Ingår i: Communications Chemistry. - : Springer Nature. - 2399-3669. ; 4:1
-
Tidskriftsartikel (refereegranskat)abstract
- X-ray absorption and X-ray free electron lasers are important tools to study chemical and structural dynamics, but spectral details like pre-edge features are inherently hard to detect. Here, the authors show that stochastic spectroscopy can yield similar spectral information to monochromatic spectroscopies, while increasing signal yield and reducing acquisition time. Hard X-ray spectroscopy is an element specific probe of electronic state, but signals are weak and require intense light to study low concentration samples. Free electron laser facilities offer the highest intensity X-rays of any available light source. The light produced at such facilities is stochastic, with spikey, broadband spectra that change drastically from shot to shot. Here, using aqueous ferrocyanide, we show that the resonant X-ray emission (RXES) spectrum can be inferred by correlating for each shot the fluorescence intensity from the sample with spectra of the fluctuating, self-amplified spontaneous emission (SASE) source. We obtain resolved narrow and chemically rich information in core-to-valence transitions of the pre-edge region at the Fe K-edge. Our approach avoids monochromatization, provides higher photon flux to the sample, and allows non-resonant signals like elastic scattering to be simultaneously recorded. The spectra obtained match well with spectra measured using a monochromator. We also show that inaccurate measurements of the stochastic light spectra reduce the measurement efficiency of our approach.
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| 19. |
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| 20. |
- Glatzel, Pieter, et al.
(författare)
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Electronic Structural Changes of Mn in the Oxygen-Evolving Complex of Photosystem II during the Catalytic Cycle
- 2013
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 52:10, s. 5642-5644
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Tidskriftsartikel (refereegranskat)abstract
- The oxygen-evolving complex (OEC) in photosystem II (PS II) was studied in the S-0 through S-3 states using 1s2p resonant inelastic X-ray scattering spectroscopy. The spectral changes of the OEC during the S-state transitions are subtle, indicating that the electrons are strongly delocalized throughout the cluster. The result suggests that, in addition to the Mn ions, ligands are also playing an important role in the redox reactions. A series of Mn-IV coordination complexes were compared, particularly with the PS II S-3 state spectrum to understand its oxidation state. We find strong variations of the electronic structure within the series of Mn-IV model systems. The spectrum of the S-3 state best resembles those of the Mn-IV complexes (Mn3Ca2)-Ca-IV and saplnMn(2)(IV)(OH)(2). The current result emphasizes that the assignment of formal oxidation states alone is not sufficient for understanding the detailed electronic structural changes that govern the catalytic reaction in the OEC.
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| 21. |
- Hattne, Johan, et al.
(författare)
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Accurate macromolecular structures using minimal measurements from X-ray free-electron lasers
- 2014
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Ingår i: Nature Methods. - 1548-7091 .- 1548-7105. ; 11:5, s. 545-548
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Tidskriftsartikel (refereegranskat)abstract
- X-ray free-electron laser (XFEL) sources enable the use of crystallography to solve three-dimensional macromolecular structures under native conditions and without radiation damage. Results to date, however, have been limited by the challenge of deriving accurate Bragg intensities from a heterogeneous population of microcrystals, while at the same time modeling the X-ray spectrum and detector geometry. Here we present a computational approach designed to extract meaningful high-resolution signals from fewer diffraction measurements.
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| 22. |
- Hattne, Johan, et al.
(författare)
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Accurate macromolecular structures using minimal measurements from X-ray free-electron lasers
- 2014
-
Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 11:5, s. 545-548
-
Tidskriftsartikel (refereegranskat)abstract
- X-ray free-electron laser (XFEL) sources enable the use of crystallography to solve three-dimensional macromolecular structures under native conditions and without radiation damage. Results to date, however, have been limited by the challenge of deriving accurate Bragg intensities from a heterogeneous population of microcrystals, while at the same time modeling the X-ray spectrum and detector geometry. Here we present a computational approach designed to extract meaningful high-resolution signals from fewer diffraction measurements.
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| 23. |
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| 24. |
- Huang, Ningdong, et al.
(författare)
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X-ray Raman scattering provides evidence for interfacial acetonitrile-water dipole interactions in aqueous solutions
- 2011
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 135:16, s. 164509-
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Tidskriftsartikel (refereegranskat)abstract
- Aqueous solutions of acetonitrile (MeCN) have been studied with oxygen K-edge x-ray Raman scattering (XRS) which is found to be sensitive to the interaction between water and MeCN. The changes in the XRS spectra can be attributed to water directly interacting with MeCN and are reproduced by density functional theory calculations on small clusters of water and MeCN. The dominant structural arrangement features dipole interaction instead of H-bonds between the two species as revealed by the XRS spectra combined with spectrum calculations. Small-angle x-ray scattering shows the largest heterogeneity for a MeCN to water ratio of 0.4 in agreement with earlier small-angle neutron scattering data.
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| 25. |
- 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
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
-
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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| 26. |
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| 27. |
- Ibrahim, Mohamed, et al.
(författare)
-
Untangling the sequence of events during the S-2 -> S-3 transition in photosystem II and implications for the water oxidation mechanism
- 2020
-
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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| 28. |
- Ibrahim, Mohamed, et al.
(författare)
-
Untangling the sequence of events during the S2 -> S3 transition in photosystem II and implications for the water oxidation mechanism
- 2020
-
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
-
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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| 29. |
- Kern, Jan, et al.
(författare)
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Room temperature femtosecond X-ray diffraction of photosystem II microcrystals
- 2012
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:25, s. 9721-9726
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Tidskriftsartikel (refereegranskat)abstract
- Most of the dioxygen on earth is generated by the oxidation of water by photosystem II (PS II) using light from the sun. This lightdriven, four-photon reaction is catalyzed by the Mn4CaO5 cluster located at the lumenal side of PS II. Various X-ray studies have been carried out at cryogenic temperatures to understand the intermediate steps involved in the water oxidation mechanism. However, the necessity for collecting data at room temperature, especially for studying the transient steps during the O-O bond formation, requires the development of new methodologies. In this paper we report room temperature X-ray diffraction data of PS II microcrystals obtained using ultrashort (<50 fs) 9 keV X-ray pulses from a hard X-ray free electron laser, namely the Linac Coherent Light Source. The results presented here demonstrate that the probe before destroy approach using an X-ray free electron laser works even for the highly-sensitive Mn4CaO5 cluster in PS II at room temperature. We show that these data are comparable to those obtained in synchrotron radiation studies as seen by the similarities in the overall structure of the helices, the protein subunits and the location of the various cofactors. This work is, therefore, an important step toward future studies for resolving the structure of the Mn4CaO5 cluster without any damage at room temperature, and of the reaction intermediates of PS II during O-O bond formation.
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| 30. |
- Kern, Jan, et al.
(författare)
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Simultaneous Femtosecond X-ray Spectroscopy and Diffraction of Photosystem II at Room Temperature
- 2013
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 340:6131, s. 491-495
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Tidskriftsartikel (refereegranskat)abstract
- Intense femtosecond x-ray pulses produced at the Linac Coherent Light Source (LCLS) were used for simultaneous x-ray diffraction (XRD) and x-ray emission spectroscopy (XES) of microcrystals of photosystem II (PS II) at room temperature. This method probes the overall protein structure and the electronic structure of the Mn4CaO5 cluster in the oxygen-evolving complex of PS II. XRD data are presented from both the dark state (S-1) and the first illuminated state (S-2) of PS II. Our simultaneous XRD-XES study shows that the PS II crystals are intact during our measurements at the LCLS, not only with respect to the structure of PS II, but also with regard to the electronic structure of the highly radiation-sensitive Mn4CaO5 cluster, opening new directions for future dynamics studies.
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| 31. |
- Kern, Jan, et al.
(författare)
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Structures of the intermediates of Kok’s photosynthetic water oxidation clock
- 2018
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 563, s. 421-425
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Tidskriftsartikel (refereegranskat)abstract
- Inspired by the period-four oscillation in flash-induced oxygen evolution of photosystem II discovered by Joliot in 1969, Kok performed additional experiments and proposed a five-state kinetic model for photosynthetic oxygen evolution, known as Kok’s S-state clock or cycle1,2. The model comprises four (meta)stable intermediates (S0, S1, S2 and S3) and one transient S4 state, which precedes dioxygen formation occurring in a concerted reaction from two water-derived oxygens bound at an oxo-bridged tetra manganese calcium (Mn4CaO5) cluster in the oxygen-evolving complex3–7. This reaction is coupled to the two-step reduction and protonation of the mobile plastoquinone QB at the acceptor side of PSII. Here, using serial femtosecond X-ray crystallography and simultaneous X-ray emission spectroscopy with multi-flash visible laser excitation at room temperature, we visualize all (meta)stable states of Kok’s cycle as high-resolution structures (2.04–2.08 Å). In addition, we report structures of two transient states at 150 and 400 µs, revealing notable structural changes including the binding of one additional ‘water’, Ox, during the S2→S3 state transition. Our results suggest that one water ligand to calcium (W3) is directly involved in substrate delivery. The binding of the additional oxygen Ox in the S3 state between Ca and Mn1 supports O–O bond formation mechanisms involving O5 as one substrate, where Ox is either the other substrate oxygen or is perfectly positioned to refill the O5 position during O2 release. Thus, our results exclude peroxo-bond formation in the S3 state, and the nucleophilic attack of W3 onto W2 is unlikely.
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| 32. |
- Kern, Jan, et al.
(författare)
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Taking snapshots of photosynthetic water oxidation using femtosecond X-ray diffraction and spectroscopy
- 2014
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 4371-
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Tidskriftsartikel (refereegranskat)abstract
- The dioxygen we breathe is formed by light-induced oxidation of water in photosystem II. O-2 formation takes place at a catalytic manganese cluster within milliseconds after the photosystem II reaction centre is excited by three single-turnover flashes. Here we present combined X-ray emission spectra and diffraction data of 2-flash (2F) and 3-flash (3F) photosystem II samples, and of a transient 3F' state (250 mu s after the third flash), collected under functional conditions using an X-ray free electron laser. The spectra show that the initial O-O bond formation, coupled to Mn reduction, does not yet occur within 250 mu s after the third flash. Diffraction data of all states studied exhibit an anomalous scattering signal from Mn but show no significant structural changes at the present resolution of 4.5 angstrom. This study represents the initial frames in a molecular movie of the structural changes during the catalytic reaction in photosystem II.
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| 33. |
- Kjær, Kasper S., et al.
(författare)
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Ligand manipulation of charge transfer excited state relaxation and spin crossover in [Fe(2,2'-bipyridine)2(CN)2]
- 2017
-
Ingår i: Structural Dynamics. - : AIP Publishing. - 2329-7778. ; 4:4
-
Tidskriftsartikel (refereegranskat)abstract
- We have used femtosecond resolution UV-visible and Kβ x-ray emission spectroscopy to characterize the electronic excited state dynamics of [Fe(bpy)2(CN)2], where bpy=2,20-bipyridine, initiated by metal-to-ligand charge transfer (MLCT) excitation. The excited-state absorption in the transient UV-visible spectra, associated with the 2,20-bipyridine radical anion, provides a robust marker for the MLCT excited state, while the transient Kβ x-ray emission spectra provide a clear measure of intermediate and high spin metal-centered excited states. From these measurements, we conclude that the MLCT state of [Fe(bpy)2(CN)2] undergoes ultrafast spin crossover to a metalcentered quintet excited state through a short lived metal-centered triplet transient species. These measurements of [Fe(bpy)2(CN)2] complement prior measurement performed on [Fe(bpy)3]2+ and [Fe(bpy)(CN)4]2- in dimethylsulfoxide solution and help complete the chemical series [Fe(bpy)N(CN)6-2N]2N-4, whereN=1-3. The measurements confirm that simple ligand modifications can significantly change the relaxation pathways and excited state lifetimes and support the further investigation of light harvesting and photocatalytic applications of 3d transition metal complexes.
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| 34. |
- Kolz, Melanie, et al.
(författare)
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Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations
- 2009
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000504-
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2×10−201), ABCG2 (p = 3.1×10−26), SLC17A1 (p = 3.0×10−14), SLC22A11 (p = 6.7×10−14), SLC22A12 (p = 2.0×10−9), SLC16A9 (p = 1.1×10−8), GCKR (p = 1.4×10−9), LRRC16A (p = 8.5×10−9), and near PDZK1 (p = 2.7×10−9). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0×10−26) and propionyl-L-carnitine (p = 5.0×10−8) concentrations, which in turn were associated with serum UA levels (p = 1.4×10−57 and p = 8.1×10−54, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.
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| 35. |
- Kubin, Markus, et al.
(författare)
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Probing the oxidation state of transition metal complexes : a case study on how charge and spin densities determine Mn L-edge X-ray absorption energies
- 2018
-
Ingår i: Chem. Sci.. - : The Royal Society of Chemistry. ; 9:33, s. 6813-6829
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Tidskriftsartikel (refereegranskat)abstract
- Transition metals in inorganic systems and metalloproteins can occur in different oxidation states, which makes them ideal redox-active catalysts. To gain a mechanistic understanding of the catalytic reactions, knowledge of the oxidation state of the active metals, ideally in operando, is therefore critical. L-edge X-ray absorption spectroscopy (XAS) is a powerful technique that is frequently used to infer the oxidation state via a distinct blue shift of L-edge absorption energies with increasing oxidation state. A unified description accounting for quantum-chemical notions whereupon oxidation does not occur locally on the metal but on the whole molecule and the basic understanding that L-edge XAS probes the electronic structure locally at the metal has been missing to date. Here we quantify how charge and spin densities change at the metal and throughout the molecule for both redox and core-excitation processes. We explain the origin of the L-edge XAS shift between the high-spin complexes MnII(acac)2 and MnIII(acac)3 as representative model systems and use ab initio theory to uncouple effects of oxidation-state changes from geometric effects. The shift reflects an increased electron affinity of MnIII in the core-excited states compared to the ground state due to a contraction of the Mn 3d shell upon core-excitation with accompanied changes in the classical Coulomb interactions. This new picture quantifies how the metal-centered core hole probes changes in formal oxidation state and encloses and substantiates earlier explanations. The approach is broadly applicable to mechanistic studies of redox-catalytic reactions in molecular systems where charge and spin localization/delocalization determine reaction pathways.
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| 36. |
- Kubin, Markus, et al.
(författare)
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Soft x-ray absorption spectroscopy of metalloproteins and high-valent metal-complexes at room temperature using free-electron lasers
- 2017
-
Ingår i: Structural Dynamics. - : AMER INST PHYSICS. - 2329-7778. ; 4:5
-
Tidskriftsartikel (refereegranskat)abstract
- X-ray absorption spectroscopy at the L-edge of 3d transition metals provides unique information on the local metal charge and spin states by directly probing 3d-derived molecular orbitals through 2p-3d transitions. However, this soft x-ray technique has been rarely used at synchrotron facilities for mechanistic studies of metalloenzymes due to the difficulties of x-ray-induced sample damage and strong background signals from light elements that can dominate the low metal signal. Here, we combine femtosecond soft x-ray pulses from a free-electron laser with a novel x-ray fluorescence-yield spectrometer to overcome these difficulties. We present L-edge absorption spectra of inorganic high-valent Mn complexes (Mn similar to 6-15 mmol/l) with no visible effects of radiation damage. We also present the first L-edge absorption spectra of the oxygen evolving complex (Mn4CaO5) in Photosystem II (Mn < 1 mmol/l) at room temperature, measured under similar conditions. Our approach opens new ways to study metalloenzymes under functional conditions. (C) 2017 Author(s).
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| 37. |
- Luederitz, Christopher, et al.
(författare)
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Learning through Evaluation: A Tentative Evaluative Scheme for Sustainability Transition Experiments
- 2017
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Ingår i: Journal of Cleaner Production. - 0959-6526. ; 169, s. 61-76
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Tidskriftsartikel (refereegranskat)abstract
- Transitions towards sustainability are urgently needed to address the interconnected challenges of economic development, ecological integrity, and social justice, from local to global scales. Around the world, collaborative science-society initiatives are forming to conduct experiments in support of sustainability transitions. Such experiments, if carefully designed, provide significant learning opportunities for making progress on transition efforts. Yet, there is no broadly applicable evaluative scheme available to capture this critical information across a large number of cases, and to guide the design of transition experiments. To address this gap, the article develops such a scheme, in a tentative form, drawing on evaluative research and sustainability transitions scholarship, alongside insights from empirical cases. We critically discuss the scheme's key features of being generic, comprehensive, operational, and formative. Furthermore, we invite scholars and practitioners to apply, reflect and further develop the proposed tentative scheme – making evaluation and experiments objects of learning.
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| 38. |
- Lundberg, Marcus, et al.
(författare)
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Metal-ligand Covalency of Iron Complexes from High-Resolution Resonant Inelastic X-ray Scattering
- 2013
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Ingår i: Journal of the American Chemical Society. - Washington : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 135:45, s. 17121-17134
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Tidskriftsartikel (refereegranskat)abstract
- Data from Kα resonant inelastic X-ray scattering (RIXS) have been used to extract electronic structure information, i.e., the covalency of metal–ligand bonds, for four iron complexes using an experimentally based theoretical model. Kα RIXS involves resonant 1s→3d excitation and detection of the 2p→1s (Kα) emission. This two-photon process reaches similar final states as single-photon L-edge (2p→3d) X-ray absorption spectroscopy (XAS), but involves only hard X-rays and can therefore be used to get high-resolution L-edge-like spectra for metal proteins, solution catalysts and their intermediates. To analyze the information content of Kα RIXS spectra, data have been collected for four characteristic σ-donor and π-back-donation complexes: ferrous tacn [FeII(tacn)2]Br2, ferrocyanide [FeII(CN)6]K4, ferric tacn [FeIII(tacn)2]Br3 and ferricyanide [FeIII(CN)6]K3. From these spectra metal–ligand covalencies can be extracted using a charge-transfer multiplet model, without previous information from the L-edge XAS experiment. A direct comparison of L-edge XAS and Kα RIXS spectra show that the latter reaches additional final states, e.g., when exciting into the eg (σ*) orbitals, and the splitting between final states of different symmetry provides an extra dimension that makes Kα RIXS a more sensitive probe of σ-bonding. Another key difference between L-edge XAS and Kα RIXS is the π-back-bonding features in ferro- and ferricyanide that are significantly more intense in L-edge XAS compared to Kα RIXS. This shows that two methods are complementary in assigning electronic structure. The Kα RIXS approach can thus be used as a stand-alone method, in combination with L-edge XAS for strongly covalent systems that are difficult to probe by UV/vis spectroscopy, or as an extension to conventional absorption spectroscopy for a wide range of transition metal enzymes and catalysts.
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| 39. |
- Mitzner, Rolf, et al.
(författare)
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L-Edge X-ray Absorption Spectroscopy of Dilute Systems Relevant to Metalloproteins Using an X-ray Free-Electron Laser
- 2013
-
Ingår i: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 4:21, s. 3641-3647
-
Tidskriftsartikel (refereegranskat)abstract
- L-edge spectroscopy of 3d transition metals provides important electronic structure information and has been used in many fields. However, the use of this method for studying dilute aqueous systems, such as metalloenzymes, has not been prevalent because of severe radiation damage and the lack of suitable detection systems. Here we present spectra from a dilute Mn aqueous solution using a high-transmission zone-plate spectrometer at the Linac Coherent Light Source (LCLS). The spectrometer has been optimized for discriminating the Mn L-edge signal from the overwhelming 0 K-edge background that arises from water and protein itself, and the ultrashort LCLS X-ray pulses can outrun X-ray induced damage. We show that the deviations of the partial-fluorescence yield-detected spectra from the true absorption can be well modeled using the state-dependence of the fluorescence yield, and discuss implications for the application of our concept to biological samples.
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| 40. |
- Newton-Cheh, Christopher, et al.
(författare)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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| 41. |
- Ohmer, Christopher J., et al.
(författare)
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XFEL serial crystallography reveals the room temperature structure of methyl-coenzyme M reductase
- 2022
-
Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 230, s. 111768-
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Tidskriftsartikel (refereegranskat)abstract
- Methyl-Coenzyme M Reductase (MCR) catalyzes the biosynthesis of methane in methanogenic archaea, using a catalytic Ni-centered Cofactor F430 in its active site. It also catalyzes the reverse reaction, that is, the anaerobic activation and oxidation, including the cleavage of the C-H bond in methane. Because methanogenesis is the major source of methane on earth, understanding the reaction mechanism of this enzyme can have massive implications in global energy balances. While recent publications have proposed a radical-based catalytic mechanism as well as novel sulfonate-based binding modes of MCR for its native substrates, the structure of the active state of MCR, as well as a complete characterization of the reaction, remain elusive. Previous attempts to structurally characterize the active MCR-Ni(I) state have been unsuccessful due to oxidation of the redox- sensitive catalytic Ni center. Further, while many cryo structures of the inactive Ni(II)-enzyme in various substrates bound forms have been published, no room temperature structures have been reported, and the structure and mechanism of MCR under physiologically relevant conditions is not known. In this study, we report the first room temperature structure of the MCRred1-silent Ni(II) form using an X-ray Free-Electron Laser (XFEL), with simultaneous X-ray Emission Spectroscopy (XES) and X-ray Diffraction (XRD) data collection. In celebration of the seminal contributions of inorganic chemist Dick Holm to our understanding of nickel-based catalysis, we are honored to announce our findings in this special issue dedicated to this remarkable pioneer of bioinorganic chemistry.
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| 42. |
- O'Seaghdha, Conall M., et al.
(författare)
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Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations
- 2013
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:9, s. e1003796-
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Tidskriftsartikel (refereegranskat)abstract
- Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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| 43. |
- Parsa, Afshin, et al.
(författare)
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Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
- 2013
-
Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:12, s. 2105-2117
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Tidskriftsartikel (refereegranskat)abstract
- Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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| 44. |
- Pattaro, Cristian, et al.
(författare)
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Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function
- 2012
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002584-
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
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| 45. |
- Pushkar, Yulia, et al.
(författare)
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Structure and orientation of the Mn4Ca cluster in plant photosystem II membranes studied by polarized range-extended X-ray absorption spectroscopy
- 2007
-
Ingår i: Journal of Biological Chemistry. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0021-9258 .- 1083-351X. ; 282:10, s. 7198-7208
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Tidskriftsartikel (refereegranskat)abstract
- X-ray absorption spectroscopy has provided important insights into the structure and function of the Mn4Ca cluster in the oxygen-evolving complex of Photosystem II (PS II). The range of manganese extended x-ray absorption fine structure data collected from PS II until now has been, however, limited by the presence of iron in PS II. Using a crystal spectrometer with high energy resolution to detect solely the manganese K alpha fluorescence, we are able to extend the extended x-ray absorption fine structure range beyond the onset of the iron absorption edge. This results in improvement in resolution of the manganese-backscatterer distances in PS II from 0.14 to 0.09 angstrom. The high resolution data obtained from oriented spinach PS II membranes in the S-1 state show that there are three di-mu-oxo-bridged manganese-manganese distances of similar to 2.7 and similar to 2.8 angstrom in a 2:1 ratio and that these three manganese-manganese vectors are aligned at an average orientation of similar to 60 degrees relative to the membrane normal. Furthermore, we are able to observe the separation of the Fourier peaks corresponding to the similar to 3.2 angstrom manganese-manganese and the similar to 3.4 angstrom manganese-calcium interactions in oriented PS II samples and determine their orientation relative to the membrane normal. The average of the manganese-calcium vectors at similar to 3.4 angstrom is aligned along the membrane normal, while the similar to 3.2 angstrom manganese-manganese vector is oriented near the membrane plane. A comparison of this structural information with the proposed Mn4Ca cluster models based on spectroscopic and diffraction data provides input for refining and selecting among these models.
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| 46. |
- 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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| 47. |
- Ried, Janina S., et al.
(författare)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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| 48. |
- Sauter, Nicholas K., et al.
(författare)
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No observable conformational changes in PSII
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 533:7603, s. E1-E2
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Tidskriftsartikel (refereegranskat)
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| 49. |
- Schreck, Simon, et al.
(författare)
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Reabsorption of Soft X-Ray Emission at High X-Ray Free-Electron Laser Fluences
- 2014
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 113:15, s. 153002-
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Tidskriftsartikel (refereegranskat)abstract
- We report on oxygen K-edge soft x-ray emission spectroscopy from a liquid water jet at the Linac Coherent Light Source. We observe significant changes in the spectral content when tuning over a wide range of incident x-ray fluences. In addition the total emission yield decreases at high fluences. These modifications result from reabsorption of x-ray emission by valence-excited molecules generated by the Auger cascade. Our observations have major implications for future x-ray emission studies at intense x-ray sources. We highlight the importance of the x-ray pulse length with respect to the core-hole lifetime.
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| 50. |
- Sellberg, Jonas A., et al.
(författare)
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X-ray emission spectroscopy of bulk liquid water in no-man's land
- 2015
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 142:4
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Tidskriftsartikel (refereegranskat)abstract
- The structure of bulk liquid water was recently probed by x-ray scattering below the temperature limit of homogeneous nucleation (T-H) of similar to 232 K [J. A. Sellberg et al., Nature 510, 381-384 (2014)]. Here, we utilize a similar approach to study the structure of bulk liquid water below T-H using oxygen K-edge x-ray emission spectroscopy (XES). Based on previous XES experiments [T. Tokushima et al., Chem. Phys. Lett. 460, 387-400 (2008)] at higher temperatures, we expected the ratio of the 1b(1)' and 1b(1) peaks associated with the lone-pair orbital in water to change strongly upon deep supercooling as the coordination of the hydrogen (H-) bonds becomes tetrahedral. In contrast, we observed only minor changes in the lone-pair spectral region, challenging an interpretation in terms of two interconverting species. A number of alternative hypotheses to explain the results are put forward and discussed. Although the spectra can be explained by various contributions from these hypotheses, we here emphasize the interpretation that the line shape of each component changes dramatically when approaching lower temperatures, where, in particular, the peak assigned to the proposed disordered component would become more symmetrical as vibrational interference becomes more important.
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