| 1. |
- Niemi, MEK, et al.
(author)
-
- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 3. |
- Aaltonen, T., et al.
(author)
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Combination of Tevatron Searches for the Standard Model Higgs Boson in the W+W- Decay Mode
- 2010
-
In: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 104:6, s. 061802-
-
Journal article (peer-reviewed)abstract
- We combine searches by the CDF and D0 Collaborations for a Higgs boson decaying to W+W-. The data correspond to an integrated total luminosity of 4.8 (CDF) and 5.4 (D0) fb(-1) of p (p) over bar collisions at root s = 1.96 TeV at the Fermilab Tevatron collider. No excess is observed above background expectation, and resulting limits on Higgs boson production exclude a standard model Higgs boson in the mass range 162-166 GeV at the 95% C.L.
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| 4. |
- Aaltonen, T., et al.
(author)
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Evidence for a Particle Produced in Association with Weak Bosons and Decaying to a Bottom-Antibottom Quark Pair in Higgs Boson Searches at the Tevatron
- 2012
-
In: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 109:7, s. 071804-
-
Journal article (peer-reviewed)abstract
- We combine searches by the CDF and D0 Collaborations for the associated production of a Higgs boson with a W or Z boson and subsequent decay of the Higgs boson to a bottom-antibottom quark pair. The data, originating from Fermilab Tevatron p (p) over bar collisions at root s = 1.96 TeV, correspond to integrated luminosities of up to 9.7 fb(-1). The searches are conducted for a Higgs boson with mass in the range 100-150 GeV/c(2). We observe an excess of events in the data compared with the background predictions, which is most significant in the mass range between 120 and 135 GeV/c(2). The largest local significance is 3.3 standard deviations, corresponding to a global significance of 3.1 standard deviations. We interpret this as evidence for the presence of a new particle consistent with the standard model Higgs boson, which is produced in association with a weak vector boson and decays to a bottom-antibottom quark pair.
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| 5. |
- Aaltonen, T., et al.
(author)
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Combination of CDF and D0 measurements of the W boson helicity in top quark decays
- 2012
-
In: Physical Review D. - 1550-7998 .- 1550-2368. ; 85:7, s. 071106-
-
Journal article (peer-reviewed)abstract
- We report the combination of recent measurements of the helicity of the W boson from top quark decay by the CDF and D0 collaborations, based on data samples corresponding to integrated luminosities of 2.7-5.4 fb(-1) of p (p) over bar collisions collected during Run II of the Fermilab Tevatron collider. Combining measurements that simultaneously determine the fractions of W bosons with longitudinal (f(0)) and right-handed (f(+)) helicities, we find f(0) = 0.722 +/- 0.081[+/- 0.062(stat) +/- 0.052(syst)] and f(+) = -0.033 +/- 0.046[+/- 0.034(stat) +/- 0.031(syst)]. Combining measurements where one of the helicity fractions is fixed to the value expected in the standard model, we find f(0) = 0.682 +/- 0.057[+/- 0.035(stat) +/- 0.046(syst)] for fixed f(+) and f(+) = -0.015 +/- 0.035[+/- 0.018(stat) +/- 0.030(syst)] for fixed f(0). The results are consistent with standard model expectations.
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| 6. |
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| 7. |
- Dornelas, M., et al.
(author)
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BioTIME: A database of biodiversity time series for the Anthropocene
- 2018
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In: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 27:7, s. 760-786
-
Journal article (peer-reviewed)abstract
- Motivation: The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene. Main types of variables included: The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record. Spatial location and grain: BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km(2) (158 cm(2)) to 100 km(2) (1,000,000,000,000 cm(2)). Time period and grainBio: TIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year. Major taxa and level of measurement: BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.
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| 8. |
- Ederle, Joerg, et al.
(author)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
-
In: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
-
Journal article (peer-reviewed)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 9. |
- Abe, K., et al.
(author)
-
J-PARC Neutrino Beamline Upgrade Technical Design Report
- 2019
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Reports (peer-reviewed)abstract
- In this document, technical details of the upgrade plan of the J-PARC neutrino beamline for the extension of the T2K experiment are described. T2K has proposed to accumulate data corresponding to 2×1022 protons-on-target in the next decade, aiming at an initial observation of CP violation with 3σ or higher significance in the case of maximal CP violation. Methods to increase the neutrino beam intensity, which are necessary to achieve the proposed data increase, are described.
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| 10. |
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| 11. |
- Ortigoza-Escobar, J. D., et al.
(author)
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Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors
- 2017
-
In: Annals of Neurology. - : Wiley. - 0364-5134. ; 82:3, s. 317-330
-
Journal article (peer-reviewed)abstract
- Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317–330. © 2017 American Neurological Association
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| 12. |
- Lakens, Daniel, et al.
(author)
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Justify your alpha
- 2018
-
In: Nature Human Behaviour. - : Nature Publishing Group. - 2397-3374. ; 2:3, s. 168-171
-
Journal article (peer-reviewed)abstract
- In response to recommendations to redefine statistical significance to P ≤ 0.005, we propose that researchers should transparently report and justify all choices they make when designing a study, including the alpha level.
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| 13. |
- Vogel, G. F., et al.
(author)
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Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants
- 2023
-
In: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 25:6
-
Journal article (peer-reviewed)abstract
- Purpose: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. Conclusion: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.
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| 14. |
- Bolognesi, P., et al.
(author)
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A study of the dynamical energy flow in uracil
- 2015
-
In: Journal of Physics, Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 635
-
Journal article (peer-reviewed)abstract
- The time resolved photoionization of C 1s in uracil following excitation of the neutral molecule by 260 nm pulses has been studied at LCLS.
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| 15. |
- Fritz, D. M., et al.
(author)
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Ultrafast bond softening in bismuth : Mapping a solid's interatomic potential with X-rays
- 2007
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 315:5812, s. 633-636
-
Journal article (peer-reviewed)abstract
- Intense femtosecond laser excitation can produce transient states of matter that would otherwise be inaccessible to laboratory investigation. At high excitation densities, the interatomic forces that bind solids and determine many of their properties can be substantially altered. Here, we present the detailed mapping of the carrier density-dependent interatomic potential of bismuth approaching a solid-solid phase transition. Our experiments combine stroboscopic techniques that use a high-brightness linear electron accelerator-based x-ray source with pulse-by-pulse timing reconstruction for femtosecond resolution, allowing quantitative characterization of the interatomic potential energy surface of the highly excited solid.
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| 16. |
- Natali, S. M., et al.
(author)
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Large loss of CO2 in winter observed across the northern permafrost region
- 2019
-
In: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 9:11, s. 852-857
-
Journal article (peer-reviewed)abstract
- Recent warming in the Arctic, which has been amplified during the winter(1-3), greatly enhances microbial decomposition of soil organic matter and subsequent release of carbon dioxide (CO2)(4). However, the amount of CO2 released in winter is not known and has not been well represented by ecosystem models or empirically based estimates(5,6). Here we synthesize regional in situ observations of CO2 flux from Arctic and boreal soils to assess current and future winter carbon losses from the northern permafrost domain. We estimate a contemporary loss of 1,662 TgC per year from the permafrost region during the winter season (October-April). This loss is greater than the average growing season carbon uptake for this region estimated from process models (-1,032 TgC per year). Extending model predictions to warmer conditions up to 2100 indicates that winter CO2 emissions will increase 17% under a moderate mitigation scenario-Representative Concentration Pathway 4.5-and 41% under business-as-usual emissions scenario-Representative Concentration Pathway 8.5. Our results provide a baseline for winter CO2 emissions from northern terrestrial regions and indicate that enhanced soil CO2 loss due to winter warming may offset growing season carbon uptake under future climatic conditions.
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| 17. |
- Erdinc, Direnis, et al.
(author)
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Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- 2023
-
In: Embo Molecular Medicine. - 1757-4676. ; 15:5
-
Journal article (peer-reviewed)abstract
- Topoisomerase 3 alpha (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
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| 18. |
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| 19. |
- Bomprezzi, R, et al.
(author)
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Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease
- 2003
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 12:17, s. 2191-2199
-
Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) and other T cell-mediated autoimmune diseases develop in individuals carrying a complex susceptibility trait, probably following exposure to various environmental triggers. Owing to the presumed weak influence of single genes on disease predisposition and the recognized genetic heterogeneity of autoimmune disorders in humans, candidate gene searches in MS have been difficult. In an attempt to identify molecular markers indicative of disease status rather than susceptibility genes for MS, we show that gene expression profiling of peripheral blood mononuclear cells by cDNA microarrays can distinguish MS patients from healthy controls. Our findings support the concept that the activation of autoreactive T cells is of primary importance for this complex organ-specific disorder and prompt further investigations on gene expression in peripheral blood cells aimed at characterizing disease phenotypes.
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| 20. |
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| 21. |
- Farrell, J. P., et al.
(author)
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Ultrafast X-ray probe of nucleobase photoprotection
- 2012
-
In: Quantum Electronics and Laser Science Conference. - 9781467318396 ; , s. 6327153-
-
Conference paper (peer-reviewed)abstract
- We will present first results of a UV-pump X-ray-probe study of the photoprotection mechanism of thymine. The experiment used element specific Auger spectroscopy and was carried out at the LCLS.
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| 22. |
- Glownia, James M., et al.
(author)
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Time-resolved pump-probe experiments at the LCLS
- 2010
-
In: Optics Express. - 1094-4087. ; 18:17, s. 17620-17630
-
Journal article (peer-reviewed)abstract
- The first time-resolved x-ray/optical pump-probe experiments at the SLAC Linac Coherent Light Source (LCLS) used a combination of feedback methods and post-analysis binning techniques to synchronize an ultrafast optical laser to the linac-based x-ray laser. Transient molecular nitrogen alignment revival features were resolved in time-dependent x-ray-induced fragmentation spectra. These alignment features were used to find the temporal overlap of the pump and probe pulses. The strong-field dissociation of x-ray generated quasi-bound molecular dications was used to establish the residual timing jitter. This analysis shows that the relative arrival time of the Ti:Sapphire laser and the x-ray pulses had a distribution with a standard deviation of approximately 120 fs. The largest contribution to the jitter noise spectrum was the locking of the laser oscillator to the reference RF of the accelerator, which suggests that simple technical improvements could reduce the jitter to better than 50 fs.
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| 23. |
- Janko, Matthew R., et al.
(author)
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In-situ bypass is associated with superior infection-free survival compared with extra-anatomic bypass for the management of secondary aortic graft infections without enteric involvement
- 2022
-
In: Journal of Vascular Surgery. - : Elsevier. - 0741-5214 .- 1097-6809. ; 76:2, s. 546-
-
Journal article (peer-reviewed)abstract
- Objective: The optimal revascularization modality following complete resection of aortic graft infection (AGI) without enteric involvement remains unclear. The purpose of this investigation is to determine the revascularization approach associated with the lowest morbidity and mortality using real-world data in patients undergoing complete excision of AGI. Methods: A retrospective, multi-institutional study of AGI from 2002 to 2014 was performed using a standardized database. Baseline demographics, comorbidities, and perioperative variables were recorded. The primary outcome was infection-free survival. Descriptive statistics, Kaplan-Meier survival analysis, and univariate and multivariable analyses were performed. Results: A total of 241 patients at 34 institutions from seven countries presented with AGI during the study period (median age, 68 years; 75% male). The initial aortic procedures that resulted in AGI were 172 surgical grafts (71%), 66 endografts (27%), and three unknown (2%). Of the patients, 172 (71%) underwent complete excision of infected aortic graft material followed by in situ (in-line) bypass (ISB), including antibiotic-treated prosthetic graft (35%), autogenous femoral vein (neo-aortoiliac surgery) (24%), and cryopreserved allograft (41%). Sixty-nine patients (29%) underwent extra-anatomic bypass (EAB). Overall median Kaplan-Meier estimated survival was 5.8 years. Perioperative mortality was 16%. When stratified by ISB vs EAB, there was a significant difference in Kaplan-Meier estimated infection-free survival (2910 days; interquartile range, 391-3771 days vs 180 days; interquartile range, 27-3750 days; P <.001). There were otherwise no significant differences in presentation, comorbidities, or perioperative variables. Multivariable Cox regression showed lower infection-free survival among patients with EAB (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.6-3.6; P <.001), polymicrobial infection (HR, 2.2; 95% CI, 1.4-3.5; P = .001), methicillin-resistant Staphylococcus aureus infection (HR, 1.7; 95% CI, 1.1-2.7; P = .02), as well as the protective effect of omental/muscle flap coverage (HR, 0.59; 95% CI, 0.37-0.92; P = .02). Conclusions: After complete resection of AGI, perioperative mortality is 16% and median overall survival is 5.8 years. EAB is associated with nearly a two and one-half-fold higher reinfection/mortality compared with ISB. Omental and/or muscle flap coverage of the repair appear protective.
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| 24. |
- Persson, Örjan, 1974, et al.
(author)
-
Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions
- 2019
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
-
Journal article (peer-reviewed)abstract
- Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in mitochondrial DNA replication factors, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process in vitro using only purified mitochondrial proteins and defined DNA templates. Based on our in vivo and in vitro findings, we conclude that mtDNA deletion formation involves copy-choice recombination during replication of the mtDNA light strand.
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| 25. |
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| 26. |
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| 27. |
- Zhaunerchyk, Vitali, et al.
(author)
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Disentangling formation of multiple-core holes in aminophenol molecules exposed to bright X-FEL radiation
- 2015
-
In: Journal of Physics B. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 48:24
-
Journal article (peer-reviewed)abstract
- Competing multi-photon ionization processes, some leading to the formation of double core hole states, have been examined in 4-aminophenol. The experiments used the linac coherent light source (LCLS) x-ray free electron laser, in combination with a time-of-flight magnetic bottle electron spectrometer and the correlation analysis method of covariance mapping. The results imply that 4-aminophenol molecules exposed to the focused x-ray pulses of the LCLS sequentially absorb more than two x-ray photons, resulting in the formation of multiple core holes as well as in the sequential removal of photoelectrons and Auger electrons (so-called PAPA sequences).
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| 28. |
- Cryan, James P., et al.
(author)
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Auger Electron Angular Distribution of Double Core-Hole States in the Molecular Reference Frame
- 2010
-
In: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 105:8, s. 083004-
-
Journal article (peer-reviewed)abstract
- The Linac Coherent Light Source free electron laser is a source of high brightness x rays, 2×1011 photons in a ∼5 fs pulse, that can be focused to produce double core vacancies through rapid sequential ionization. This enables double core vacancy Auger electron spectroscopy, an entirely new way to study femtosecond chemical dynamics with Auger electrons that probe the local valence structure of molecules near a specific atomic core. Using 1.1 keV photons for sequential x-ray ionization of impulsively aligned molecular nitrogen, we observed a rich single-site double core vacancy Auger electron spectrum near 413 eV, in good agreement with ab initio calculations, and we measured the corresponding Auger electron angle dependence in the molecular frame.
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| 29. |
- Cryan, J P, et al.
(author)
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Molecular frame Auger electron energy spectrum from N2
- 2012
-
In: Journal of Physics B. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 45:5, s. 055601-
-
Journal article (peer-reviewed)abstract
- Here we present the first angle-resolved, non-resonant (normal) Auger spectra for impulsively aligned nitrogen molecules. We have measured the angular pattern of Auger electron emission following K -shell photoionization by 1.1 keV photons from the Linac Coherent Light Source (LCLS). Using strong-field-induced molecular alignment to make molecular frame measurements is equally effective for both repulsive and quasi-bound final states. The capability to resolve Auger emission angular distributions in the molecular frame of reference provides a new tool for spectral assignments in congested Auger electron spectra that takes advantage of the symmetries of the final diction states. Based on our experimental results and theoretical predictions, we propose the assignment of the spectral features in the Auger electron spectrum.
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| 30. |
- Kang, Po Wei, et al.
(author)
-
Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening
- 2024
-
Other publication (other academic/artistic)abstract
- Calmodulin (CaM) and PIP2 are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the IKs current important for repolarization of cardiac action potentials. Although cryo-EM structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully-activated state allows PIP2 to compete with CaM for binding to VSD, leading to the conformational change that alters the VSD-pore coupling. We identify a motif in the KCNQ1 cytosolic domain which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2 and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its function in the heart.
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| 31. |
- Kang, Po Wei, et al.
(author)
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Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening
- 2020
-
In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:50
-
Journal article (peer-reviewed)abstract
- Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PIP2) are potent regulators of the voltage-gated potassium channel KCNQ1 (K(v)7.1), which conducts the cardiac I-Ks current. Although cryo-electron microscopy structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully activated state allows PIP 2 to compete with CaM for binding to VSD. This leads to conformational changes that alter VSD-pore coupling to stabilize open states. We identify a motif in the KCNQ1 cytosolic domain, which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2 and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its physiological function.
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| 32. |
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| 33. |
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| 34. |
- McFarland, B. K., et al.
(author)
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Probing nucleobase photoprotection with soft x-rays
- 2013
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In: XVIIITH INTERNATIONAL CONFERENCE ON ULTRAFAST PHENOMENA. - : EDP Sciences. - 9782759809561 ; , s. 07004-
-
Conference paper (peer-reviewed)abstract
- Nucleobases absorb strongly in the ultraviolet region, leading to molecular excitation into reactive states. The molecules avoid the photoreactions by funnelling the electronic energy into less reactive states on an ultrafast timescale via non-Born-Oppenheimer dynamics. Current theory on the nucleobase thymine discusses two conflicting pathways for the photoprotective dynamics. We present our first results of our free electron laser based UV-pump soft x-ray-probe study of the photoprotection mechanism of thymine. We use the high spatial sensitivity of the Auger electrons emitted after the soft x-ray pulse induced core ionization. Our transient spetra show two timescales on the order of 200 fs and 5 ps, in agreement with previous (all UV) ultrafast experiments. The timescales appear at different Auger kinetic energies which will help us to decipher the molecular dynamics.
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| 35. |
- McFarland, B. K., et al.
(author)
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Ultrafast X-ray Auger probing of photoexcited molecular dynamics
- 2014
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 4235-
-
Journal article (peer-reviewed)abstract
- Molecules can efficiently and selectively convert light energy into other degrees of freedom. Disentangling the underlying ultrafast motion of electrons and nuclei of the photoexcited molecule presents a challenge to current spectroscopic approaches. Here we explore the photoexcited dynamics of molecules by an interaction with an ultrafast X-ray pulse creating a highly localized core hole that decays via Auger emission. We discover that the Auger spectrum as a function of photoexcitation-X-ray-probe delay contains valuable information about the nuclear and electronic degrees of freedom from an element-specific point of view. For the nucleobase thymine, the oxygen Auger spectrum shifts towards high kinetic energies, resulting from a particular C-O bond stretch in the pi pi* photoexcited state. A subsequent shift of the Auger spectrum towards lower kinetic energies displays the electronic relaxation of the initial photoexcited state within 200 fs. Ab-initio simulations reinforce our interpretation and indicate an electronic decay to the n pi* state.
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| 36. |
- Murphy, B. F., et al.
(author)
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Femtosecond X-ray-induced explosion of C-60 at extreme intensity
- 2014
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5
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Journal article (peer-reviewed)abstract
- Understanding molecular femtosecond dynamics under intense X-ray exposure is critical to progress in biomolecular imaging and matter under extreme conditions. Imaging viruses and proteins at an atomic spatial scale and on the time scale of atomic motion requires rigorous, quantitative understanding of dynamical effects of intense X-ray exposure. Here we present an experimental and theoretical study of C-60 molecules interacting with intense X-ray pulses from a free-electron laser, revealing the influence of processes not previously reported. Our work illustrates the successful use of classical mechanics to describe all moving particles in C-60, an approach that scales well to larger systems, for example, biomolecules. Comparisons of the model with experimental data on C-60 ion fragmentation show excellent agreement under a variety of laser conditions. The results indicate that this modelling is applicable for X-ray interactions with any extended system, even at higher X-ray dose rates expected with future light sources.
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| 37. |
- Peciulyte, Ausra, 1986, et al.
(author)
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Redox processes acidify and decarboxylate steam-pretreated lignocellulosic biomass and are modulated by LPMO and catalase
- 2018
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In: Biotechnology for Biofuels. - : Springer Science and Business Media LLC. - 1754-6834 .- 1754-6834. ; 11:1
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Journal article (peer-reviewed)abstract
- Background: The bioconversion of lignocellulosic feedstocks to ethanol is being commercialised, but further process development is required to improve their economic feasibility. Efficient saccharification of lignocellulose to fermentable sugars requires oxidative cleavage of glycosidic linkages by lytic polysaccharide monooxygenases (LPMOs). However, a proper understanding of the catalytic mechanism of this enzyme class and the interaction with other redox processes associated with the saccharification of lignocellulose is still lacking. The in-use stability of LPMO-containing enzyme cocktails is increased by the addition of catalase implying that hydrogen peroxide (H2O2) is generated in the slurry during incubation. Therefore, we sought to characterize the effects of enzymatic and abiotic sources of H2O2on lignocellulose hydrolysis to identify parameters that could improve this process. Moreover, we studied the abiotic redox reactions of steam-pretreated wheat straw as a function of temperature and dry-matter (DM) content. Results: Abiotic reactions in pretreated wheat straw consume oxygen, release carbon dioxide (CO2) to the slurry, and decrease the pH. The magnitude of these reactions increased with temperature and with DM content. The presence of LPMO during saccharification reduced the amount of CO2liberated, while the effect on pH was insignificant. Catalase led to increased decarboxylation through an unknown mechanism. Both in situ-generated and added H2O2caused a decrease in pH. Conclusions: Abiotic redox processes similar to those that occur in natural water-logged environments also affect the saccharification of pretreated lignocellulose. Heating of the lignocellulosic material and adjustment of pH trigger rapid oxygen consumption and acidification of the slurry. In industrial settings, it will be of utmost importance to control these processes. LPMOs interact with the surrounding redox compounds and redirect abiotic electron flow from decarboxylating reactions to fuel the oxidative cleavage of glycosidic bonds in cellulose.
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| 38. |
- Vogt, N. M., et al.
(author)
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Gut microbiome alterations in Alzheimer's disease
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is the most common form of dementia. However, the etiopathogenesis of this devastating disease is not fully understood. Recent studies in rodents suggest that alterations in the gut microbiome may contribute to amyloid deposition, yet the microbial communities associated with AD have not been characterized in humans. Towards this end, we characterized the bacterial taxonomic composition of fecal samples from participants with and without a diagnosis of dementia due to AD. Our analyses revealed that the gut microbiome of AD participants has decreased microbial diversity and is compositionally distinct from control age-and sex-matched individuals. We identified phylum-through genus-wide differences in bacterial abundance including decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium in the microbiome of AD participants. Furthermore, we observed correlations between levels of differentially abundant genera and cerebrospinal fluid (CSF) biomarkers of AD. These findings add AD to the growing list of diseases associated with gut microbial alterations, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.
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| 39. |
- Yang, Xin, et al.
(author)
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Cancer risks associated with germline PALB2 pathogenic variants : An international study of 524 families
- 2020
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In: Journal of Clinical Oncology. - 0732-183X. ; 38:7, s. 674-685
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Journal article (peer-reviewed)abstract
- PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.
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