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| 12. |
- Abdo, A. A., et al.
(författare)
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The on-orbit calibration of the Fermi Large Area Telescope
- 2009
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Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 32:3-4, s. 193-219
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Tidskriftsartikel (refereegranskat)abstract
- The Large Area Telescope (LAT) on-board the Fermi Gamma-ray Space Telescope began its on-orbit operations on June 23, 2008. Calibrations, defined in a generic sense, correspond to synchronization of trigger signals, optimization of delays for latching data, determination of detector thresholds, gains and responses, evaluation of the perimeter of the South Atlantic Anomaly (SAA), measurements of live time, of absolute time, and internal and spacecraft boresight alignments. Here we describe on-orbit calibration results obtained using known astrophysical sources, galactic cosmic rays, and charge injection into the front-end electronics of each detector. Instrument response functions will be described in a separate publication. This paper demonstrates the stability of calibrations and describes minor changes observed since launch. These results have been used to calibrate the LAT datasets to be publicly released in August 2009.
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| 13. |
- Hussein, A. E., et al.
(författare)
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Laser-wakefield accelerators for high-resolution X-ray imaging of complex microstructures
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Laser-wakefield accelerators (LWFAs) are high acceleration-gradient plasma-based particle accelerators capable of producing ultra-relativistic electron beams. Within the strong focusing fields of the wakefield, accelerated electrons undergo betatron oscillations, emitting a bright pulse of X-rays with a micrometer-scale source size that may be used for imaging applications. Non-destructive X-ray phase contrast imaging and tomography of heterogeneous materials can provide insight into their processing, structure, and performance. To demonstrate the imaging capability of X-rays from an LWFA we have examined an irregular eutectic in the aluminum-silicon (Al-Si) system. The lamellar spacing of the Al-Si eutectic microstructure is on the order of a few micrometers, thus requiring high spatial resolution. We present comparisons between the sharpness and spatial resolution in phase contrast images of this eutectic alloy obtained via X-ray phase contrast imaging at the Swiss Light Source (SLS) synchrotron and X-ray projection microscopy via an LWFA source. An upper bound on the resolving power of 2.7 ± 0.3 μm of the LWFA source in this experiment was measured. These results indicate that betatron X-rays from laser wakefield acceleration can provide an alternative to conventional synchrotron sources for high resolution imaging of eutectics and, more broadly, complex microstructures.
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| 14. |
- Akhtar, M., et al.
(författare)
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Evaluation of the safety and immunogenicity of the oral inactivated multivalent enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi adults in a double-blind, randomized, placebo-controlled Phase I trial using electrochemiluminescence and ELISA assays for immunogenicity analyses
- 2019
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X. ; 37:37, s. 5645-5656
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Tidskriftsartikel (refereegranskat)abstract
- The safety and immunogenicity of the second generation oral enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX, consisting of inactivated recombinant E. coli strains over-expressing the colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the heat labile toxoid LCTBA, were evaluated in Bangladeshi volunteers. To enable analysis of antibody responses against multiple vaccine antigens for subsequent use in small sample volumes from children, a sensitive electrochemiluminescence (ECL) assay for analysis of intestine-derived antibody-secreting cell responses using the antibodies in lymphocyte secretions (ALS) assay was established using Meso Scale Discovery technology. Three groups of Bangladeshi adults (n = 15 per group) received two oral doses of ETVAX with or without double mutant LT (dmLT) adjuvant or placebo in the initial part of a randomized, double-blind, placebo-controlled, age-descending, dose-escalation trial. CF- and LTB-specific ALS and plasma IgA responses were analyzed by ECL and/or ELISA. ETVAX was safe and well tolerated in the adults. Magnitudes of IgA ALS responses determined by ECL and ELISA correlated well (r = 0.85 to 0.98 for the five primary antigens, P < 0.001) and ECL was selected as the ALS readout method. ALS IgA responses against each of the primary antigens were detected in 87-100% of vaccinees after the first and in 100% after the second vaccine dose. Plasma IgA responses against different CFs and LTB were observed in 62-93% and 100% of vaccinees, respectively. No statistically significant adjuvant effect of dmLT on antibody responses to any antigen was detected, but the overall anti-genic breadth of the plasma IgA response tended to favor the adjuvanted vaccine when responses to 4 or more or 5 vaccine antigens were considered. Responses in placebo recipients were infrequent and mainly detected against single antigens. The promising results in adults supported testing ETVAX in descending age groups of children.
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| 15. |
- Kettle, B., et al.
(författare)
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Single-Shot Multi-keV X-Ray Absorption Spectroscopy Using an Ultrashort Laser-Wakefield Accelerator Source
- 2019
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Ingår i: Physical Review Letters. - 0031-9007. ; 123:25
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Tidskriftsartikel (refereegranskat)abstract
- Single-shot absorption measurements have been performed using the multi-keV x rays generated by a laser-wakefield accelerator. A 200 TW laser was used to drive a laser-wakefield accelerator in a mode which produced broadband electron beams with a maximum energy above 1 GeV and a broad divergence of ≈15 mrad FWHM. Betatron oscillations of these electrons generated 1.2±0.2×106 photons/eV in the 5 keV region, with a signal-to-noise ratio of approximately 300 1. This was sufficient to allow high-resolution x-ray absorption near-edge structure measurements at the K edge of a titanium sample in a single shot. We demonstrate that this source is capable of single-shot, simultaneous measurements of both the electron and ion distributions in matter heated to eV temperatures by comparison with density functional theory simulations. The unique combination of a high-flux, large bandwidth, few femtosecond duration x-ray pulse synchronized to a high-power laser will enable key advances in the study of ultrafast energetic processes such as electron-ion equilibration.
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| 16. |
- Maitrallain, A., et al.
(författare)
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Parametric study of high-energy ring-shaped electron beams from a laser wakefield accelerator
- 2022
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Ingår i: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Laser wakefield accelerators commonly produce on-axis, low-divergence, high-energy electron beams. However, a high charge, annular shaped beam can be trapped outside the bubble and accelerated to high energies. Here we present a parametric study on the production of low-energy-spread, ultra-relativistic electron ring beams in a two-stage gas cell. Ring-shaped beams with energies higher than 750 MeV are observed simultaneously with on axis, continuously injected electrons. Often multiple ring shaped beams with different energies are produced and parametric studies to control the generation and properties of these structures were conducted. Particle tracking and particle-in-cell simulations are used to determine properties of these beams and investigate how they are formed and trapped outside the bubble by the wake produced by on-axis injected electrons. These unusual femtosecond duration, high-charge, high-energy, ring electron beams may find use in beam driven plasma wakefield accelerators and radiation sources.
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| 17. |
- Spesyvtsev, R., et al.
(författare)
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Generation of electron high energy beams with a ring-like structure by a dual stage laser wakefield accelerator
- 2019
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Ingår i: Relativistic Plasma Waves and Particle Beams as Coherent and Incoherent Radiation Sources III. - : SPIE. - 9781510627383 ; 11036
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Konferensbidrag (refereegranskat)abstract
- The laser wake-field accelerator (LWFA) traditionally produces high brightness, quasi-monoenergetic electron beams with Gaussian-like spatial and angular distributions. In the present work we investigate the generation of ultra-relativistic beams with ring-like structures in the blowout regime of the LWFA using a dual stage accelerator. A density down-ramp triggers injection after the first stage and is used to produce ring-like electron spectra in the 300 - 600 MeV energy range. These well defined, annular beams are observed simultaneously with the on-axis, high energy electron beams, with a divergence of a few milliradians. The rings have quasi-monoenergetic energy spectra with an RMS spread estimated to be less than 5%. Particle-in-cell simulations confirm that off-axis injection provides the electrons with the initial transverse momentum necessary to undertake distinct betatron oscillations within the plasma bubble during their acceleration process.
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| 18. |
- Streeter, M. J.V., et al.
(författare)
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Characterization of laser wakefield acceleration efficiency with octave spanning near-IR spectrum measurements
- 2022
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Ingår i: Physical Review Accelerators and Beams. - 2469-9888. ; 25:10
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Tidskriftsartikel (refereegranskat)abstract
- We report on experimental measurements of energy transfer efficiencies in a GeV-class laser wakefield accelerator. Both the transfer of energy from the laser to the plasma wakefield and from the plasma to the accelerated electron beam was diagnosed by simultaneous measurement of the deceleration of laser photons and the acceleration of electrons as a function of plasma length. The extraction efficiency, which we define as the ratio of the energy gained by the electron beam to the energy lost by the self-guided laser mode, was maximized at 19±3% by tuning the plasma density and length. The additional information provided by the octave-spanning laser spectrum measurement allows for independent optimization of the plasma efficiency terms, which is required for the key goal of improving the overall efficiency of laser wakefield accelerators.
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| 19. |
- Aalbers, J., et al.
(författare)
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A next-generation liquid xenon observatory for dark matter and neutrino physics
- 2023
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Ingår i: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 50:1
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Forskningsöversikt (refereegranskat)abstract
- The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector.
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| 20. |
- Aalbers, Jelle, et al.
(författare)
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Solar neutrino detection sensitivity in DARWIN via electron scattering
- 2020
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 80:12
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Tidskriftsartikel (refereegranskat)abstract
- We detail the sensitivity of the proposed liquid xenon DARWIN observatory to solar neutrinos via elastic electron scattering. We find that DARWIN will have the potential to measure the fluxes of five solar neutrino components: pp, 7Be, 13N, 15O and pep. The precision of the 13N, 15O and pep components is hindered by the double-beta decay of 136Xe and, thus, would benefit from a depleted target. A high-statistics observation of pp neutrinos would allow us to infer the values of the electroweak mixing angle, sin2 theta w, and the electron-type neutrino survival probability, Pee, in the electron recoil energy region from a few keV up to 200 keV for the first time, with relative precision of 5% and 4%, respectively, with 10 live years of data and a 30 tonne fiducial volume. An observation of pp and 7Be neutrinos would constrain the neutrino-inferred solar luminosity down to 0.2%. A combination of all flux measurements would distinguish between the high- (GS98) and low-metallicity (AGS09) solar models with 2.1-2.5 sigma significance, independent of external measurements from other experiments or a measurement of 8B neutrinos through coherent elastic neutrino-nucleus scattering in DARWIN. Finally, we demonstrate that with a depleted target DARWIN may be sensitive to the neutrino capture process of 131Xe.
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| 21. |
- Dahl-Jensen, D., et al.
(författare)
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Eemian interglacial reconstructed from a Greenland folded ice core
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 493:7433, s. 489-494
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Tidskriftsartikel (refereegranskat)abstract
- Efforts to extract a Greenland ice core with a complete record of the Eemian interglacial (130,000 to 115,000 years ago) have until now been unsuccessful. The response of the Greenland ice sheet to the warmer-than-present climate of the Eemian has thus remained unclear. Here we present the new North Greenland Eemian Ice Drilling ('NEEM') ice core and show only a modest ice-sheet response to the strong warming in the early Eemian. We reconstructed the Eemian record from folded ice using globally homogeneous parameters known from dated Greenland and Antarctic ice-core records. On the basis of water stable isotopes, NEEM surface temperatures after the onset of the Eemian (126,000 years ago) peaked at 8 +/- 4 degrees Celsius above the mean of the past millennium, followed by a gradual cooling that was probably driven by the decreasing summer insolation. Between 128,000 and 122,000 years ago, the thickness of the northwest Greenland ice sheet decreased by 400 +/- 250 metres, reaching surface elevations 122,000 years ago of 130 +/- 300 metres lower than the present. Extensive surface melt occurred at the NEEM site during the Eemian, a phenomenon witnessed when melt layers formed again at NEEM during the exceptional heat of July 2012. With additional warming, surface melt might become more common in the future.
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| 22. |
- Maier, N., et al.
(författare)
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Efficacy of an Enterotoxigenic Escherichia coli (ETEC) Vaccine on the Incidence and Severity of Traveler's Diarrhea (TD): Evaluation of Alternative Endpoints and a TD Severity Score
- 2023
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Ingår i: Microorganisms. - 2076-2607. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- The efficacy of an Oral Whole Cell ETEC Vaccine (OEV) against Travelers' Diarrhea (TD) was reexamined using novel outcome and immunologic measures. More specifically, a recently developed disease severity score and alternative clinical endpoints were evaluated as part of an initial validation effort to access the efficacy of a vaccine intervention for the first time in travelers to an ETEC endemic area. A randomized, double-blind, placebo-controlled trial followed travelers to Guatemala or Mexico up to 28 days after arrival in the country following vaccination (two doses two weeks apart) with an ETEC vaccine. Fecal samples were collected upon arrival, departure, and during TD for pathogen identification. Serum was collected in a subset of subjects to determine IgA cholera toxin B subunit (CTB) antibody titers upon their arrival in the country. The ETEC vaccine's efficacy, utilizing a TD severity score and other alternative endpoints, including the relationship between antibody levels and TD risk, was assessed and compared to the per-protocol primary efficacy endpoint. A total of 1435 subjects completed 7-28 days of follow-up and had available data. Vaccine efficacy was higher against more severe (>= 5 unformed stools/24 h) ETEC-attributable TD and when accounting for immunologic take (PE >= 50%; p < 0.05). The vaccine protected against less severe (3 and 4 unformed stools/24 h) ETEC-attributable TD when accounting for symptom severity or change in activity (PE = 76.3%, p = 0.01). Immunologic take of the vaccine was associated with a reduced risk of infection with ETEC and other enteric pathogens, and with lower TD severity. Clear efficacy was observed among vaccinees with a TD score of >= 4 or >= 5, regardless of immunologic take (PE = 72.0% and 79.0%, respectively, p <= 0.03). The vaccine reduced the incidence and severity of ETEC, and this warrants accelerated evaluation of the improved formulation (designated ETVAX), currently undergoing advanced field testing. Subjects with serum IgA titers to CTB had a lower risk of infection with ETEC and Campylobacter jejuni/coli. Furthermore, the TD severity score provided a more robust descriptor of disease severity and should be included as an endpoint in future studies.
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| 23. |
- Qadri, F., et al.
(författare)
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Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial
- 2020
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Ingår i: Lancet Infectious Diseases. - : Elsevier BV. - 1473-3099. ; 20:2, s. 208-219
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Tidskriftsartikel (refereegranskat)abstract
- Background Enterotoxigenic Escherichia coil causes diarrhoea, leading to substantial mortality and morbidity in children, but no specific vaccine exists. This trial tested an oral, inactivated, enterotoxigenic E coli vaccine (ETVAX), which has been previously shown to be safe and highly immuongenic in Swedish and Bangladeshi adults. We tested the safety and immunogenicity of ETVAX, consisting of four E coli strains overexpressing the most prevalent colonisation factors (CFA/I, CS3, CSS, and CS6) and a toxoid (LCTBA) administered with or without a double-mutant heat-labile enterotoxin (dmLT) as an adjuvant, in Bangladeshi children. Methods We did a randomised, double-blind, placebo-controlled, dose-escalation, age-descending, phase 1/2 trial in Dhaka, Bangladesh. Healthy children in one of three age groups (24-59 months, 12-23 months, and 6-11 months) were eligible. Children were randomly assigned with block randomisation to receive either ETVAX, with or without dmLT, or placebo. ETVAX (half [5.5 x 10(10) cells], quarter [2.5 x 10(10) cells], or eighth [1.25 x 10(10) cells] adult dose), with or without dmLT adjuvant (2.5 mu g, 5.0 mu g, or 10.0 mu g), or placebo were administered orally in two doses 2 weeks apart. Investigators and participants were masked to treatment allocation. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunisation, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov , NCT02531802. Findings Between Dec 7, 2015, and Jan 10, 2017, we screened 1500 children across the three age groups, of whom 430 were enrolled and randomly assigned to the different treatment groups (130 aged 24-59 months, 100 aged 12-23 months, and 200 aged 6-11 months). All participants received at least one dose of vaccine. No solicited adverse events occurred that were greater than moderate in severity, and most were mild. The most common solicited event was vomiting (ten [8%] of 130 patients aged 24-59 months, 13 [13%] of 100 aged 12-23 months, and 29 115%1 of 200 aged 6-11 months; mostly of mild severity), which appeared related to dose and age. The addition of dmLT did not modify the safety profile. Three serious adverse events occurred but they were not considered related to the study drug. Mucosal IgA antibody responses in lymphocyte secretions were detected against all primary vaccine antigens (CFA/I, CS3, CSS, CS6, and the LCTBA toxoid) in most participants in the two older age groups, whereas such responses to four of the five antigens were less frequent and of lower magnitude in infants aged 6-11 months than in older children. Faecal secretory IgA immune responses were recorded against all vaccine antigens in infants aged 6-11 months. 78 (56%) of 139 infants aged 6-11 months who were vaccinated developed mucosal responses against at least three of the vaccine antigens versus 14 (29%) of 49 of the infants given placebo. Addition of the adjuvant dmLT enhanced the magnitude, breadth, and kinetics (based on number of responders after the first dose of vaccine) of immune responses in infants. Interpretation The encouraging safety and immunogenicity of ETVAX and benefit of dmLT adjuvant in young children support its further assessment for protective efficacy in children in enterotoxigenic E coli-endemic areas. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.
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| 24. |
- Enerbäck, Sven, 1958, et al.
(författare)
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Acidosis and Deafness in Patients with Recessive Mutations in FOXI1
- 2018
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Ingår i: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 29:3, s. 1041-1048
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Tidskriftsartikel (refereegranskat)abstract
- Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.
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| 25. |
- Fisher, D. A., et al.
(författare)
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The effects of flowline length evolution on chemistry - δ18O profiles from Penny Ice Cap, Baffin Island, Canada
- 2002
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Ingår i: Annals of Glaciology. - : International Glaciological Society. - 0260-3055 .- 1727-5644. ; 35:1, s. 150-156
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Tidskriftsartikel (refereegranskat)abstract
- The isotopic and chemical signatures for ice-age and Holocene ice from Summit, Greenland, and Penny Ice Cap, Baffin Island, Canada, are compared. The usual pattern of low δ180, high Ca2+ and high Cl- is presented in the Summit records, but Penny Ice Cap has lower than present Cl- in its ice-age ice. A simple extension of the Hansson model (Hansson, 1994) is developed and used to simulate these signatures. The low ice age Cl- from Penny Ice Cap is explained by having the ice-age ice originating many thousands of km inland near the centre of the Laurentide ice sheet and much further from the marine sources. Summit's flowlines all start close to the present site. The Penny Ice Cap early-Holocene δ180's had to be corrected to offset the Laurentide meltwater distortion.The analysis suggests that presently the Summit and Penny Ice Cap marine impurity ori ginates about 500 km away, and that presently Penny Ice Cap receives a significant amountoflocal continental impurity.
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| 26. |
- Holmgren, Jan, 1944, et al.
(författare)
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Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant
- 2013
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 31:20, s. 2457-2464
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Tidskriftsartikel (refereegranskat)abstract
- A first-generation oral inactivated whole-cell enterotoxigenic Escherichia coli (ETEC) vaccine, comprising formalin-killed ETEC bacteria expressing different colonization factor (CF) antigens combined with cholera toxin B subunit (CTB), when tested in phase III studies did not significantly reduce overall (generally mild) ETEC diarrhea in travelers or children although it reduced more severe ETEC diarrhea in travelers by almost 80%. We have now developed a novel more immunogenic ETEC vaccine based on recombinant non-toxigenic E. coli strains engineered to express increased amounts of CF antigens, including CS6 as well as an ETEC-based B subunit protein (LCTB. A), and the optional combination with a nontoxic double-mutant heat-labile toxin (LT) molecule (dmLT) as an adjuvant.Two test vaccines were prepared under GMP: (1) A prototype E. coli CFA/I-only formalin-killed whole-cell. +. LCTB. A vaccine, and (2) A "complete" inactivated multivalent ETEC-CF (CFA/I, CS3, CS5 and CS6 antigens) whole-cell. +. LCTB. A vaccine. These vaccines, when given intragastrically alone or together with dmLT in mice, were well tolerated and induced strong intestinal-mucosal IgA antibody responses as well as serum IgG and IgA responses to each of the vaccine CF antigens as well as to LT B subunit (LTB). Both mucosal and serum responses were further enhanced (adjuvanted) when the vaccines were co-administered with dmLT. We conclude that the new multivalent oral ETEC vaccine, both alone and especially in combination with the dmLT adjuvant, shows great promise for further testing in humans.
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| 27. |
- Lundgren, Anna, 1974, et al.
(författare)
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Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein.
- 2013
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Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 31:8, s. 1163-1170
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a new oral vaccine against enterotoxigenic Escherichia coli (ETEC) diarrhea containing killed recombinant E. coli bacteria expressing increased levels of ETEC colonization factors (CFs) and a recombinant protein (LCTBA), i.e. a hybrid between the binding subunits of E. coli heat labile toxin (LTB) and cholera toxin (CTB). We describe a randomized, comparator controlled, double-blind phase I trial in 60 adult Swedish volunteers of a prototype of this vaccine. The safety and immunogenicity of the prototype vaccine, containing LCTBA and an E. coli strain overexpressing the colonization factor CFA/I, was compared to a previously developed oral ETEC vaccine, consisting of CTB and inactivated wild type ETEC bacteria expressing CFA/I (reference vaccine). Groups of volunteers were given two oral doses of either the prototype or the reference vaccine; the prototype vaccine was administered at the same or a fourfold higher dosage than the reference vaccine. The prototype vaccine was found to be safe and equally well-tolerated as the reference vaccine at either dosage tested. The prototype vaccine induced mucosal IgA (fecal secretory IgA and intestine-derived IgA antibody secreting cell) responses to both LTB and CFA/I, as well as serum IgA and IgG antibody responses to LTB. Immunization with LCTBA resulted in about twofold higher mucosal and systemic IgA responses against LTB than a comparable dose of CTB. The higher dose of the prototype vaccine induced significantly higher fecal and systemic IgA responses to LTB and fecal IgA responses to CFA/I than the reference vaccine. These results demonstrate that CF over-expression and inclusion of the LCTBA hybrid protein in an oral inactivated ETEC vaccine does not change the safety profile when compared to a previous generation of such a vaccine and that the prototype vaccine induces significant dose dependent mucosal immune responses against CFA/I and LTB.
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| 28. |
- Lundgren, Anna, 1974, et al.
(författare)
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Safety and immunogenicity of an improved oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine administered alone and together with dmLT adjuvant in a double-blind, randomized, placebo-controlled Phase I study
- 2014
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X. ; 32:52, s. 7077-7084
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have developed a new oral vaccine against enterotoxigenic Escherichia coli (ETEC), which is the most common cause of bacterial diarrhea in children in developing countries and in travelers. Methods: The vaccine was tested for safety and immunogenicity alone and together with double-mutant heat-labile toxin (dmLT) adjuvant in a double-blind, placebo-controlled Phase I study in 129 Swedish adults. The vaccine consists of four inactivated recombinant E. coli strains overexpressing the major ETEC colonization factors (CFs) CFA/I, CS3, CS5, and CS6 mixed with an LT B-subunit related toxoid, LCTBA. Volunteers received two oral doses of vaccine alone, vaccine plus 10 mu g or 25 mu g dmLT or placebo. Secretory IgA antibody responses in fecal samples and IgA responses in secretions from circulating intestine-derived antibody secreting cells were assessed as primary measures of vaccine immunogenicity. Results: The vaccine was safe and well tolerated; adverse events were few and generally mild with no significant differences between subjects receiving placebo or vaccine with or without adjuvant. As many as 74% of subjects receiving vaccine alone and 83% receiving vaccine plus 10 mu g dmLT showed significant mucosal IgA responses to all five primary vaccine antigens and about 90% of all vaccinees responded to at least four of the antigens. Subjects receiving vaccine plus 10 mu g dmLT responded with significantly increased intestine-derived anti-CS6 responses compared to subjects receiving vaccine alone. Conclusions: The vaccine was safe and broadly immunogenic. dmLT further enhanced mucosal immune responses to CF antigens present in low amounts in the vaccine. Based on these encouraging results, the vaccine will be tested for safety and immunogenicity in different age groups including infants in Bangladesh and for protective efficacy in travelers. (C) 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.
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| 29. |
- Pérez-Andreu, V., et al.
(författare)
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miR-133a regulates Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), a key protein in the Vitamin K cycle
- 2012
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Ingår i: Molecular Medicine. - : Springer Science and Business Media LLC. - 1076-1551 .- 1528-3658. ; 18:11, s. 1466-1472
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Tidskriftsartikel (refereegranskat)abstract
- Regulation of key proteins by microRNAs (miRNAs) is an emergent field in biomedicine. Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is a relevant molecule for cardiovascular diseases, since it is the target of oral anticoagulant drugs and plays a role in soft tissue calcification. The objective of this study was to determine the influence of miRNAs on the expression of VKORC1. Potential miRNAs targeting VKORC1 mRNA were searched by using online algorithms. Validation studies were carried out in HepG2 cells by using miRNA precursors; direct miRNA interaction was investigated with reporter assays. In silico studies identified two putative conserved binding sites for miR-133a and miR-137 on VKORC1 mRNA. Ex vivo studies showed that only miR-133a was expressed in liver; transfection of miRNA precursors of miR-133a in HepG2 cells reduced VKORC1 mRNA expression in a dosedependent manner, as assessed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) as well as protein expression. Reporter assays in HEK293T cells showed that miR-133a interacts with the 3′UTR of VKORC1. Additionally, miR-133a levels correlated inversely with VKORC1 mRNA levels in 23 liver samples from healthy subjects. In conclusion, miR-133a appears to have a direct regulatory effect on expression of VKORC1 in humans; this regulation may have potential importance for anticoagulant therapy or aortic calcification.
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| 30. |
- Schüpbach, S., et al.
(författare)
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Greenland records of aerosol source and atmospheric lifetime changes from the Eemian to the Holocene
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The Northern Hemisphere experienced dramatic changes during the last glacial, featuring vast ice sheets and abrupt climate events, while high northern latitudes during the last interglacial (Eemian) were warmer than today. Here we use high-resolution aerosol records from the Greenland NEEM ice core to reconstruct the environmental alterations in aerosol source regions accompanying these changes. Separating source and transport effects, we find strongly reduced terrestrial biogenic emissions during glacial times reflecting net loss of vegetated area in North America. Rapid climate changes during the glacial have little effect on terrestrial biogenic aerosol emissions. A strong increase in terrestrial dust emissions during the coldest intervals indicates higher aridity and dust storm activity in East Asian deserts. Glacial sea salt aerosol emissions in the North Atlantic region increase only moderately (50%), likely due to sea ice expansion. Lower aerosol concentrations in Eemian ice compared to the Holocene are mainly due to shortened atmospheric residence time, while emissions changed little.
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| 31. |
- Svennerholm, Ann-Mari, 1947, et al.
(författare)
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Induction of mucosal and systemic immune responses against the common O78 antigen of an oral inactivated ETEC vaccine in Bangladeshi children and infants
- 2022
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X. ; 40:2, s. 380-389
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Tidskriftsartikel (refereegranskat)abstract
- We tested an oral enterotoxigenic Escherichia coli (ETEC) vaccine, ETVAX, consisting of inactivated E. coli overexpressing the most prevalent ETEC colonization factors (CFs) and a toxoid (LCTBA), in Bangladeshi children for capacity to induce mucosal and plasma immune responses against O78 lipopolysaccharide (LPS) expressed on the vaccine strains. The vaccine was given +/- double-mutant heat-labile toxin (dmLT) adjuvant. We evaluated the impact of dmLT on anti-O78 LPS immune responses and whether such responses can predict responses against the CFs as a marker for vaccine "take". Two fractionated doses of ETVAX +/- different amounts of dmLT were administered biweekly to groups of children 24-59 (n = 125), 12-23 (n = 97) and 6-11 (n = 158) months of age. Immune responses were evaluated in antibody in lymphocyte supernatants (ALS), fecal extracts and plasma. ALS IgA responses against O78 LPS were induced in 44-49% of the children aged 12-59 months. The magnitudes of the ALS responses were significantly higher in children receiving a half-dose (5 x 10(10) bacteria) of ETVAX +/- dmLT than in placebo recipients. <10% of the vaccinees aged 6-11 months mounted ALS responses against O78 LPS. However, 49% of the infants developed fecal secretory IgA responses which were significantly more frequent in those receiving a quarter-dose (2.5 x 10(10) bacteria) of vaccine + dmLT (62%) compared to a quarter-dose alone (36%). Plasma IgA antibody responses were induced in 80% of older children and 36% of infants. The frequencies of O78 LPS responses in plasma and feces were comparable or higher than against the vaccine CFs in infants. Our findings show that ETVAX induced mucosal and systemic immune responses against O78 LPS in all age groups and that dmLT improved intestinal immune responses among infants. These observations may have implications for more successful use of other oral vaccines based on O antigens in children. (C) 2021 Published by Elsevier Ltd.
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| 32. |
- Wang, X.-Y., et al.
(författare)
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Ultrastructural injury to interstitial cells of Cajal and communication with mast cells in Crohn's disease
- 2007
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 19:5, s. 349-364
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Tidskriftsartikel (refereegranskat)abstract
- Crohn's disease associated dysmotility has been attributed to fibrosis and damage to enteric nerves but injury to interstitial cells of Cajal (ICC) could also be involved. We assessed ICC in specimens obtained from patients with Crohn's disease and determined the relation between ICC and the inflammatory infiltrate, particularly mast cells (MC) using quantitative immunohistochemistry and electron microscopy. Ultrastructural injury to ICC was patchy in all ICC subtypes but ICC-Auerbach's plexus (AP) showed damage more frequently, i.e. swelling of mitochondria, decreased electron density, autophagosomes and partial depletion of the cytoplasm. Light microscopy confirmed a significant decrease in c-kit immunoreactivity for ICC-AP and an increased number of MC in the muscularis externa. Electron microscopy showed MC exhibiting piecemeal degranulation and making frequent and selective membrane-to-membrane contact with all types of injured ICC which suggests chronic release of granule content to affect ICC. Extent of ICC injury was not associated with duration of the disease. In conclusion, ultrastructural injury and loss of ICC-AP is evident in Crohn's disease. Epidemiological and morphological data suggest that ICC have the capacity to regenerate in spite of the chronic insult. The muscularis hosts a marked number of MC that exhibit piecemeal degranulation associated with ICC and may facilitate ICC maintenance. © 2007 The Authors.
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