| 1. |
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| 2. |
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| 3. |
- Elhai, M, et al.
(författare)
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Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
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Tidskriftsartikel (refereegranskat)abstract
- To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice.MethodsWe performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab.Results254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83–9.62]; p=0.019 as compared with controls vs 3 [0.66–5.35]; p=0.012).ConclusionRituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
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| 4. |
- Hajkova, V., et al.
(författare)
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X-ray laser-induced ablation of lead compounds
- 2011
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Ingår i: DAMAGE TO VUV, EUV, AND X-RAY OPTICS III. - : SPIE.
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Konferensbidrag (refereegranskat)abstract
- The recent commissioning of a X-ray free-electron laser triggered an extensive research in the area of X-ray ablation of high-Z, high-density materials. Such compounds should be used to shorten an effective attenuation length for obtaining clean ablation imprints required for the focused beam analysis. Compounds of lead (Z=82) represent the materials of first choice. In this contribution, single-shot ablation thresholds are reported for PbWO(4) and PbI(2) exposed to ultra-short pulses of extreme ultraviolet radiation and X-rays at FLASH and LCLS facilities, respectively. Interestingly, the threshold reaches only 0.11 J/cm(2) at 1.55 nm in lead tungstate although a value of 0.4 J/cm(2) is expected according to the wavelength dependence of an attenuation length and the threshold value determined in the XUV spectral region, i.e., 79 mJ/cm(2) at a FEL wavelength of 13.5 nm. Mechanisms of ablation processes are discussed to explain this discrepancy. Lead iodide shows at 1.55 nm significantly lower ablation threshold than tungstate although an attenuation length of the radiation is in both materials quite the same. Lower thermal and radiation stability of PbI(2) is responsible for this finding.
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| 5. |
- Vinko, S. M., et al.
(författare)
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Electronic Structure of an XUV Photogenerated Solid-Density Aluminum Plasma
- 2010
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 104:22, s. 225001-
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Tidskriftsartikel (refereegranskat)abstract
- By use of high intensity XUV radiation from the FLASH free-electron laser at DESY, we have created highly excited exotic states of matter in solid-density aluminum samples. The XUV intensity is sufficiently high to excite an inner-shell electron from a large fraction of the atoms in the focal region. We show that soft-x-ray emission spectroscopy measurements reveal the electronic temperature and density of this highly excited system immediately after the excitation pulse, with detailed calculations of the electronic structure, based on finite-temperature density functional theory, in good agreement with the experimental results.
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| 6. |
- Hong, S. J., et al.
(författare)
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TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
- 2021
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:10, s. 1628-1640
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Kurilshikov, Alexander, et al.
(författare)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 11. |
- Nelson, A. J., et al.
(författare)
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Soft x-ray free electron laser microfocus for exploring matter under extreme conditions
- 2009
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Ingår i: Optics Express. - 1094-4087. ; 17:20, s. 18271-18278
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Tidskriftsartikel (refereegranskat)abstract
- We have focused a beam (BL3) of FLASH (Free-electron LASer in Hamburg: lambda = 13.5 nm, pulse length 15 fs, pulse energy 10-40 mu J, 5Hz) using a fine polished off-axis parabola having a focal length of 270 mm and coated with a Mo/Si multilayer with an initial reflectivity of 67% at 13.5 nm. The OAP was mounted and aligned with a picomotor controlled six-axis gimbal. Beam imprints on poly(methyl methacrylate) -PMMA were used to measure focus and the focused beam was used to create isochoric heating of various slab targets. Results show the focal spot has a diameter of <= 1 mu m. Observations were correlated with simulations of best focus to provide further relevant information.
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| 12. |
- Pannee, Josef, 1979, et al.
(författare)
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The global Alzheimer's Association round robin study on plasma amyloid beta methods
- 2021
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Blood-based assays to measure brain amyloid beta (A beta) deposition are an attractive alternative to the cerebrospinal fluid (CSF)-based assays currently used in clinical settings. In this study, we examined different blood-based assays to measure A beta and how they compare among centers and assays. Methods Aliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass-spectrometric methods were used to measure plasma A beta concentrations. Results Correlations were weak for A beta 42 while A beta 40 correlations were stronger. The ratio A beta 42/A beta 40 did not improve the correlations and showed weak correlations. Discussion The poor correlations for A beta 42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre-analytical sample handling and specificity, and cross-reactivity of different antibodies. Different methods might also measure different pools of plasma A beta 42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study.
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| 13. |
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| 14. |
- Andreasson, A., et al.
(författare)
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Fosfomycin versus Ciprofloxacin as transrectal prostatebiopsy antibiotic prophylaxis an open randomized controlled multicenter drug trial
- 2023
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 83:Suppl. 1, s. S180-S180
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction & Objectives: Antibiotic prophylaxis are administered as a routine to decrease the risk for septic complications following transrectal prostate biopsy. Fosfomycin administered 1 h or more prior to biopsy has equal or better infectious complication rates as compared to Ciprofloxacin in both prospective and retrospective studies from countries with high rates of antibiotic resistance. The aim of this study was to investigate if Fosfomycin administered immediately prior to prostate biopsy was as effective as Ciprofloxacin in Sweden, a country with low rates of antibiotic resistance.Materials & Methods: A randomized, controlled, open, multicenter, non-inferiority-study including men of all ages undergoing transrectal prostate biopsy was performed in the urology departments of three Swedish hospitals. The total number of patients were planned for 3448, divided into low and high infection risk groups. The low-risk group was randomized to either one dose of Fosfomycin 3g or Ciprofloxacin 750mg before biopsy. The high-risk group was randomized to either two doses of Fosfomycin 3g prior to biopsy and one more 24 h after biopsy or Ciprofloxacin 500mg once prior to biopsy and then twice daily for three days. The drugs were administered orally. All patients had a rectal swab for culture before and after biopsy. The endpoint was hospitalisation due to urinary tract infection within 14 days from biopsy, follow-up was performed with a phone interview.Results: The safety board prematurely interrupted the study after 42 included patients due to an unusual high number of hospitalisations. Four out of 20 patients (20%), three in the low-risk group and one in the high-risk group, had been hospitalised due to urosepsis in the Fosfomycin group. One further patient described fever symptoms but did not seek health care. No patient in the Ciprofloxacin group (n=21) described symptoms of infection from the urinary tract. One patient was lost to follow-up. A one-sided binomial test showed a p-value of <0.001. Two of the four hospitalised patients had a positive blood culture for Pseudomonas Aeruginosa and one had a positive rectal swab culture for Pseudomonas species both before and after biopsy.Conclusions: The study does not support the use of Fosfomycin administered immediately prior to prostate biopsy. The results may have been affected by the unexpected high number of Pseudomonas infections, a bacteria where Fosfomycin often lack effect. If Fosfomycin is to be used it should be with caution if Pseudomonas has been seen in earlier cultures
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| 15. |
- Barty, A., et al.
(författare)
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Self-terminating diffraction gates femtosecond X-ray nanocrystallography measurements
- 2012
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Ingår i: Nature Photonics. - 1749-4885 .- 1749-4893. ; 6:1, s. 35-40
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Tidskriftsartikel (refereegranskat)abstract
- X-ray free-electron lasers have enabled new approaches to the structural determination of protein crystals that are too small or radiation-sensitive for conventional analysis1. For sufficiently short pulses, diffraction is collected before significant changes occur to the sample, and it has been predicted that pulses as short as 10 fs may be required to acquire atomic-resolution structural information1, 2, 3, 4. Here, we describe a mechanism unique to ultrafast, ultra-intense X-ray experiments that allows structural information to be collected from crystalline samples using high radiation doses without the requirement for the pulse to terminate before the onset of sample damage. Instead, the diffracted X-rays are gated by a rapid loss of crystalline periodicity, producing apparent pulse lengths significantly shorter than the duration of the incident pulse. The shortest apparent pulse lengths occur at the highest resolution, and our measurements indicate that current X-ray free-electron laser technology5 should enable structural determination from submicrometre protein crystals with atomic resolution.
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| 16. |
- Cryan, J P, et al.
(författare)
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Molecular frame Auger electron energy spectrum from N2
- 2012
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Ingår i: Journal of Physics B. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 45:5, s. 055601-
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Tidskriftsartikel (refereegranskat)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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| 17. |
- Glownia, James M., et al.
(författare)
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Time-resolved pump-probe experiments at the LCLS
- 2010
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Ingår i: Optics Express. - 1094-4087. ; 18:17, s. 17620-17630
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Tidskriftsartikel (refereegranskat)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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| 18. |
- Bos, I., et al.
(författare)
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Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:5, s. 644-654
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We investigated relations between amyloid-beta (A beta) status, apolipoprotein E (APOE) e4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau). Methods: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with A beta status (Ab beta- vs. A beta+), clinical diagnosis APOE epsilon 4 carriership, baseline cognition, and change in cognition. Results: Ng and T-tau distinguished between A beta+ from A beta- individuals in each clinical group, whereas NFL and YKL-40 were associated with A beta+ in nondemented individuals only. APOE epsilon 4 carriership did not influence NFL, Ng, and YKL-40 in A beta+ individuals. NFL was the best predictor of cognitive decline in A beta+ individuals across the cognitive spectrum. Discussion: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 19. |
- Camu, W., et al.
(författare)
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Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial
- 2020
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 59
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects. Methods: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759. Findings: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3–4·9) and 1 MIU ES=3·5 (IC95%: 2·1–4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels. Interpretation: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression. Funding: : The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA). © 2020 The Authors
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| 20. |
- Cryan, James P., et al.
(författare)
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Auger Electron Angular Distribution of Double Core-Hole States in the Molecular Reference Frame
- 2010
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 105:8, s. 083004-
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Tidskriftsartikel (refereegranskat)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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| 21. |
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| 22. |
- Lewczuk, Piotr, et al.
(författare)
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Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.
- 2018
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Ingår i: The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. - : Informa UK Limited. - 1814-1412. ; 19:4, s. 244-328
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Tidskriftsartikel (refereegranskat)abstract
- In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.
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| 23. |
- Shi, Liu, et al.
(författare)
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Replication study of plasma proteins relating to Alzheimer's pathology.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 17:9, s. 1452-1464
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Tidskriftsartikel (refereegranskat)abstract
- This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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| 24. |
- Wohlfarth, C., et al.
(författare)
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miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3'UTR binding sites. The novel isoform HTR4b_2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.
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| 25. |
- Andreasson, Jakob, et al.
(författare)
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Saturated ablation in metal hydrides and acceleration of protons and deuterons to keV energies with a soft-x-ray laser
- 2011
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Ingår i: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics. - 1539-3755 .- 1550-2376. ; 83:1, s. 016403-
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Tidskriftsartikel (refereegranskat)abstract
- Studies of materials under extreme conditions have relevance to a broad area of research, including planetary physics, fusion research, materials science, and structural biology with x-ray lasers. We study such extreme conditions and experimentally probe the interaction between ultrashort soft x-ray pulses and solid targets (metals and their deuterides) at the FLASH free-electron laser where power densities exceeding 1017 W/cm2 were reached. Time-of-flight ion spectrometry and crater analysis were used to characterize the interaction. The results show the onset of saturation in the ablation process at power densities above 1016 W/cm2. This effect can be linked to a transiently induced x-ray transparency in the solid by the femtosecond x-ray pulse at high power densities. The measured kinetic energies of protons and deuterons ejected from the surface reach several keV and concur with predictions from plasma-expansion models. Simulations of the interactions were performed with a nonlocal thermodynamic equilibrium code with radiation transfer. These calculations return critical depths similar to the observed crater depths and capture the transient surface transparency at higher power densities.
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| 26. |
- Boza-Serrano, A., et al.
(författare)
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Galectin-3 is elevated in CSF and is associated with A beta deposits and tau aggregates in brain tissue in Alzheimer's disease
- 2022
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533.
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer's disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around A beta plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients (n=119) compared to control individuals (n= 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-beta. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-beta positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/-) (A + T +N+/-) groups compared to the A + T-N- group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.
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| 27. |
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| 28. |
- Eriksson, S, et al.
(författare)
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Complex formation of myrosinase isoenzymes in Brassica napus seeds are dependent on the presence of myrosinase binding proteins
- 2002
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Ingår i: Plant Physiology. - 1532-2548. ; 129:4, s. 1592-1599
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Tidskriftsartikel (refereegranskat)abstract
- The enzyme myrosinase (EC 3.2.3.1) degrades the secondary compounds glucosinolates upon wounding and serves as a defense to generalist pests in Capparales. Certain myrosinases are present in complexes together with other proteins such as myrosinase-binding proteins (MBP) in extracts of oilseed rape (Brassica napus) seeds. Immunhistochemical analysis of wild-type seeds showed that MBPs were present in most cells but not in the myrosin cells, indicating that the complex formation observed in extracts is initiated upon tissue disruption. To study the role of MBP in complex formation and defense, oilseed rape antisense plants lacking the seed MBPs were produced. Western blotting and immunohistochemical staining confirmed depletion of MBP in the transgenic seeds. The exclusive expression of myrosinase in idioblasts (myrosin cells) of the seed was not affected by the down-regulation of MBP. Using size-exclusion chromatography, we have shown that myrosinases with subunit molecular masses of 62 to 70 kD were present as free dimers from the antisense seed extract, whereas in the wild type, they formed complexes. In accordance with this, MBPs are necessary for myrosinase complex formation of the 62- to 70-kD myrosinases. The product formed from sinalbin hydrolysis by myrosinase was the same whether MBP was present or not. The performance of a common beetle generalist (Tenebrio molitor) fed with seeds, herbivory by flea beetles (Phyllotreta undulata) on cotyledons, or growth rate of the Brassica fungal pathogens Alternaria brassicae or Lepthosphaeria maculans in the presence of seed extracts were not affected by the down-regulation of MBP, leaving the physiological function of this protein family open.
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| 29. |
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| 30. |
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| 31. |
- Hellwig, K., et al.
(författare)
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Neurogranin and YKL-40: independent markers of synaptic degeneration and neuroinflammation in Alzheimer's disease
- 2015
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neuroinflammation and synaptic degeneration are major neuropathological hallmarks in Alzheimer's disease (AD). Neurogranin and YKL-40 in cerebrospinal fluid (CSF) are newly discovered markers indicating synaptic damage and microglial activation, respectively. Methods: CSF samples from 95 individuals including 39 patients with AD dementia (AD-D), 13 with mild cognitive impairment (MCI) due to AD (MCI-AD), 29 with MCI not due to AD (MCI-o) and 14 patients with non-AD dementias (non-AD-D) were analyzed for neurogranin and YKL-40. Results: Patients with dementia or MCI due to AD showed elevated levels of CSF neurogranin (p < 0.001 for AD-D and p < 0.05 for MCI-AD) and YKL-40 (p < 0.05 for AD-D and p = 0.15 for MCI-AD) compared to mildly cognitively impaired subjects not diagnosed with AD. CSF levels of neurogranin and YKL-40 did not differ between MCI not due to AD and non-AD dementias. In AD subjects no correlation between YKL-40 and neurogranin was found. The CSF neurogranin levels correlated moderately with tau and p-tau but not with A beta 42 or the MMSE in AD samples. No relevant associations between YKL-40 and MMSE or the core AD biomarkers, A beta 42, t-tau and p-tau were found in AD subjects. Conclusions: Neurogranin and YKL-40 are promising AD biomarkers, independent of and complementary to the established core AD biomarkers, reflecting additional pathological changes in the course of AD.
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| 32. |
- Henstrom, M., et al.
(författare)
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome
- 2018
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 67:2, s. 263-270
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Tidskriftsartikel (refereegranskat)abstract
- Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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| 33. |
- Herrfurth, O., et al.
(författare)
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Transient birefringence and dichroism in ZnO studied with fs-time-resolved spectroscopic ellipsometry
- 2021
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Ingår i: Physical Review Research. - : American Physical Society. - 2643-1564. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- The full transient dielectric-function (DF) tensor of ZnO after UV-laser excitation in the spectral range 1.4–3.6 eV is obtained by measuring an m-plane-oriented ZnO thin film with femtosecond (fs)-time-resolved spectroscopic ellipsometry. From the merits of the method, we can distinguish between changes in the real and the imaginary part of the DF as well as changes in birefringence and dichroism, respectively. We find pump-induced switching from positive to negative birefringence in almost the entire measured spectral range for about 1 ps. Simultaneously, weak dichroism in the spectral range below 3.0 eV hints at contributions of inter-valence-band transitions. Line-shape analysis of the DF above the band gap based on discrete exciton, exciton-continuum, and exciton-phonon-complex contributions shows a maximal dynamic increase in the transient exciton energy by 80 meV. The absorption coefficient below the band gap reveals an exponential line shape attributed to Urbach-rule absorption mediated by exciton–longitudinal-optic-phonon interaction. The transient DF is supported by first-principles calculations for 1020cm−3 excited electron-hole pairs in ideal bulk ZnO.
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| 34. |
- Iwan, Bianca S, et al.
(författare)
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TOF-OFF : A method for determining focal positions in tightly focused free-electron laser experiments by measurement of ejected ions
- 2011
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Ingår i: High Energy Density Physics. - : Elsevier BV. - 1574-1818. ; 7:4, s. 336-342
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Tidskriftsartikel (refereegranskat)abstract
- Pulse intensities greater than 1017 Watt/cm2 were reached at the FLASH soft X-ray laser in Hamburg, Germany, using an off-axis parabolic mirror to focus 15 fs pulses of 5–70 μJ energy at 13.5 nm wavelength to a micron-sized spot. We describe the interaction of such pulses with niobium and vanadium targets and their deuterides. The beam produced craters in the solid targets, and we measured the kinetic energy of ions ejected from these craters. Ions with several keV kinetic energy were observed from craters approaching 5 μm in depth when the sample was at best focus. We also observed the onset of saturation in both ion acceleration and ablation with pulse intensities exceeding 1016 W/cm2, when the highest detected ion energies and the crater depths tend to saturate with increasing intensity. A general difficulty in working with micron and sub-micron focusing optics is finding the exact focus of the beam inside a vacuum chamber. Here we propose a direct method to measure the focal position to a resolution better than the Rayleigh length. The method is based on the correlation between the energies of ejected ions and the physical dimensions of the craters. We find that the focus position can be quickly determined from the ion time-of-flight (TOF) data as the target is scanned through the expected focal region. The method does not require external access to the sample or venting the vacuum chamber. Profile fitting employed to analyze the TOF data can extend resolution beyond the actual scanning step size.
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| 35. |
- Lewczuk, P., et al.
(författare)
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Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease
- 2018
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10:71
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Tidskriftsartikel (refereegranskat)abstract
- Background: A growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer's disease (AD). Methods: With a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD; n = 33), and in nondemented controls (n = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid beta (A beta) 1-42, A beta 42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions. Results: NfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 degrees C. Compared with the control group of nondemented subjects (22.0 +/- 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 +/- 15.9 pg/mL, p < 0.005) and even further elevated in the ADD group (49.1 +/- 28.4 pg/mL; p < 0.001). A significant association between NfL and age (p = 0.65, p < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant (r = -0.49, p < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups. Conclusions: This study confirms increased concentrations of plasma NfL in patients with Alzheimer's disease compared with nondemented controls.
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| 36. |
- Liwing, J., et al.
(författare)
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Is multiple myeloma a chronic disease?
- 2012
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Ingår i: Haematologica. - : Fondazione Ferrata Storti. - 0390-6078 .- 1592-8721. ; 97, s. 345-346
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 37. |
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| 38. |
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| 39. |
- Mattsson, Niklas, 1979, et al.
(författare)
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CSF biomarker variability in the Alzheimer's Association quality control program
- 2013
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 9:3, s. 251-261
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Tidskriftsartikel (refereegranskat)abstract
- Background The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.
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| 40. |
- Munke, Anna, et al.
(författare)
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Data Descriptor : Coherent diffraction of single Rice Dwarf virus particles using hard X-rays at the Linac Coherent Light Source
- 2016
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Ingår i: Scientific Data. - : Nature Publishing Group. - 2052-4463. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Single particle diffractive imaging data from Rice Dwarf Virus (RDV) were recorded using the Coherent X-ray Imaging (CXI) instrument at the Linac Coherent Light Source (LCLS). RDV was chosen as it is a wellcharacterized model system, useful for proof-of-principle experiments, system optimization and algorithm development. RDV, an icosahedral virus of about 70 nm in diameter, was aerosolized and injected into the approximately 0.1 mu m diameter focused hard X-ray beam at the CXI instrument of LCLS. Diffraction patterns from RDV with signal to 5.9 angstrom ngstrom were recorded. The diffraction data are available through the Coherent X-ray Imaging Data Bank (CXIDB) as a resource for algorithm development, the contents of which are described here.
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| 41. |
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| 42. |
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| 43. |
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| 44. |
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| 45. |
- Panneman, Daan M., et al.
(författare)
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Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis
- 2023
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.
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| 46. |
- Paterson, R W, et al.
(författare)
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A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology.
- 2016
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previously validated multiplexed 10-min, targeted proteomic assay to assess 54 candidate cerebrospinal fluid (CSF) biomarkers in two independent cohorts comprising individuals with neurodegenerative dementias and healthy controls. Individuals were classified as 'AD' or 'non-AD' on the basis of their CSF T-tau and amyloid Aβ1-42 profile measured using enzyme-linked immunosorbent assay; biomarkers of interest were compared using univariate and multivariate analyses. In all, 35/31 individuals in Cohort 1 and 46/36 in Cohort 2 fulfilled criteria for AD/non-AD profile CSF, respectively. After adjustment for multiple comparisons, five proteins were elevated significantly in AD CSF compared with non-AD CSF in both cohorts: malate dehydrogenase; total APOE; chitinase-3-like protein 1 (YKL-40); osteopontin and cystatin C. In an independent multivariate orthogonal projection to latent structures discriminant analysis (OPLS-DA), these proteins were also identified as major contributors to the separation between AD and non-AD in both cohorts. Independent of CSF Aβ1-42 and tau, a combination of these biomarkers differentiated AD and non-AD with an area under curve (AUC)=0.88. This targeted proteomic multiple reaction monitoring (MRM)-based assay can simultaneously and rapidly measure multiple candidate CSF biomarkers. Applying this technique to AD we demonstrate differences in proteins involved in glucose metabolism and neuroinflammation that collectively have potential clinical diagnostic utility.
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| 47. |
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| 48. |
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| 49. |
- Vinko, S. M., et al.
(författare)
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Time-Resolved XUV Opacity Measurements of Warm Dense Aluminum
- 2020
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Ingår i: Physical Review Letters. - : American Physical Society. - 1079-7114 .- 0031-9007. ; 124:22
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Tidskriftsartikel (refereegranskat)abstract
- The free-free opacity in plasmas is fundamental to our understanding of energy transport in stellar interiors and for inertial confinement fusion research. However, theoretical predictions in the challenging dense plasma regime are conflicting and there is a dearth of accurate experimental data to allow for direct model validation. Here we present time-resolved transmission measurements in solid-density Al heated by an XUV free-electron laser. We use a novel functional optimization approach to extract the temperature-dependent absorption coefficient directly from an oversampled pool of single-shot measurements, and find a pronounced enhancement of the opacity as the plasma is heated to temperatures of order of the Fermi energy. Plasma heating and opacity enhancement are observed on ultrafast timescales, within the duration of the femtosecond XUV pulse. We attribute further rises in the opacity on ps timescales to melt and the formation of warm dense matter.
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