| 1. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 2. |
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| 3. |
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| 4. |
- Veres, P., et al.
(författare)
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Observation of inverse Compton emission from a long gamma-ray burst
- 2019
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 575:7783, s. 459-
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Tidskriftsartikel (refereegranskat)abstract
- Long-duration gamma-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectron volt-to-mega electronvoltband, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission(1,2). Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands(1-6). The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock(7-9). Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C(10,11). Here we report multifrequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 x 10(-6) to 10(12) electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.
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| 5. |
- Chibueze, J. O., et al.
(författare)
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A MeerKAT, e-MERLIN, HESS, and Swift search for persistent and transient emission associated with three localized FRBs
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 515:1, s. 1365-1379
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Tidskriftsartikel (refereegranskat)abstract
- We report on a search for persistent radio emission from the one-off fast radio burst (11(B) 20190714A, as well as from two repeating FRBs, 20190711A and 20171019A, using the MeerKAT radio telescope. For FRB 20171019A, we also conducted simultaneous observations with the High-Energy Stereoscopic System (H.E.S.S.) in very high-energy gamma rays and searched for signals in the ultraviolet, optical, and X-ray bands. For this FRB, we obtain a UV flux upper limit of 1.39 x 10(-16) erg cm(-2) s(-1) angstrom(-1), X-ray limit of similar to 6.6 x 10(-14) erg cm(-2) s(-1) and a limit on the very high energy gamma-ray flux Phi(E > 120 GeV) < 1.7 x 10(-12) erg cm(-2) S-1. We obtain a radio upper limit of similar to 15 mu Jy beam(-1) for persistent emission at the locations of both FRBs 20190711A and 20171019A with MeerKAT. However, we detected an almost unresolved (ratio of integrated flux to peak flux is similar to 1.7 beam) radio emission, where the synthesized beam size was similar to 8 arcsec size with a peak brightness of similar to 53 mu Jy beam(-1) at MeerKAT and similar to 86 mu Jy beam(-1) at e-MERLIN, possibly associated with FRB 20190714A at z = 0.2365. This represents the first detection of persistent continuum radio emission potentially associated with a (as-yet) non- repeating FRB. If the association is confirmed, one of the strongest remaining distinction between repeaters and non-repeaters would no longer be applicable. A parallel search for repeat bursts from these FRBs revealed no new detections down to a fluence of 0.08 Jy ms for a 1 ms duration burst.
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| 6. |
- Heywood, I., et al.
(författare)
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Inflation of 430-parsec bipolar radio bubbles in the Galactic Centre by an energetic event
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 573:7773, s. 235-237
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Tidskriftsartikel (refereegranskat)abstract
- The Galactic Centre contains a supermassive black hole with a mass of four million Suns1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings2. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts3, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone4 at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas5, a high cosmic-ray ionization rate6, unusual gas chemistry, enhanced synchrotron emission7,8, and a multitude of radio-emitting magnetized filaments9, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 1052 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.
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| 7. |
- Davis, P. E. D., et al.
(författare)
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Suppressed basal melting in the eastern Thwaites Glacier grounding zone
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 614:7948
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Tidskriftsartikel (refereegranskat)abstract
- Thwaites Glacier is one of the fastest-changing ice-ocean systems in Antarctica(1-3). Much of the ice sheet within the catchment of Thwaites Glacier is grounded below sea level on bedrock that deepens inland(4), making it susceptible to rapid and irreversible ice loss that could raise the global sea level by more than half a metre(2,3,5). The rate and extent of ice loss, and whether it proceeds irreversibly, are set by the ocean conditions and basal melting within the grounding-zone region where Thwaites Glacier first goes afloat(3,6), both of which are largely unknown. Here we show-using observations from a hot-water-drilled access hole-that the grounding zone of Thwaites Eastern Ice Shelf (TEIS) is characterized by a warm and highly stable water column with temperatures substantially higher than the in situ freezing point. Despite these warm conditions, low current speeds and strong density stratification in the ice-ocean boundary layer actively restrict the vertical mixing of heat towards the ice base(7,8), resulting in strongly suppressed basal melting. Our results demonstrate that the canonical model of ice-shelf basal melting used to generate sea-level projections cannot reproduce observed melt rates beneath this critically important glacier, and that rapid and possibly unstable grounding-line retreat may be associated with relatively modest basal melt rates.
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| 8. |
- Jarvis, M.J., et al.
(författare)
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The discovery of a z = 0.7092 OH megamaser with the MIGHTEE survey
- 2024
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Ingår i: Monthly Notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 529:4, s. 3484-3494
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Tidskriftsartikel (refereegranskat)abstract
- We present the discovery of the most distant OH megamaser (OHM) to be observed in the main lines, using data from the MeerKAT International Giga-Hertz Tiered Extragalactic Exploration (MIGHTEE) survey. At a newly measured redshift of z = 0.7092, the system has strong emission in both the 1665 MHz (L ≈ 2500 L-) and 1667 MHz (L ≈ 4.5 × 104 L-) transitions, with both narrow and broad components. We interpret the broad line as a high-velocity-dispersion component of the 1667 MHz transition, with velocity v ∼330 km s-1 with respect to the systemic velocity. The host galaxy has a stellar mass of M = 2.95 × 1010 M- and a star formation rate of SFR = 371 M- yr-1, placing it ∼1.5 dex above the main sequence for star-forming galaxies at this redshift, and can be classified as an ultraluminous infrared galaxy. Alongside the optical imaging data, which exhibit evidence for a tidal tail, this suggests that the OHM arises from a system that is currently undergoing a merger, which is stimulating star formation and providing the necessary conditions for pumping the OH molecule to saturation. The OHM is likely to be lensed, with a magnification factor of ∼2.5, and perhaps more if the maser emitting region is compact and suitably offset relative to the centroid of its host galaxy's optical light. This discovery demonstrates that spectral line mapping with the new generation of radio interferometers may provide important information on the cosmic merger history of galaxies.
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| 9. |
- Russell, T. D., et al.
(författare)
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Disk-Jet Coupling in the 2017/2018 Outburst of the Galactic Black Hole Candidate X-Ray Binary MAXI J1535-571
- 2019
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 883:2
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Tidskriftsartikel (refereegranskat)abstract
- MAXI J1535-571 is a Galactic black hole candidate X-ray binary that was discovered going into outburst in 2017 September. In this paper, we present comprehensive radio monitoring of this system using the Australia Telescope Compact Array, as well as the MeerKAT radio observatory, showing the evolution of the radio jet during its outburst. Our radio observations show the early rise and subsequent quenching of the compact jet as the outburst brightened and then evolved toward the soft state. We constrain the compact jet quenching factor to be more than 3.5 orders of magnitude. We also detected and tracked (for 303 days) a discrete, relativistically moving jet knot that was launched from the system. From the motion of the apparently superluminal knot, we constrain the jet inclination (at the time of ejection) and speed to = 0.69 c, respectively. Extrapolating its motion back in time, our results suggest that the jet knot was ejected close in time to the transition from the hard intermediate state to soft intermediate state. The launching event also occurred contemporaneously with a short increase in X-ray count rate, a rapid drop in the strength of the X-ray variability, and a change in the type-C quasi-periodic oscillation (QPO) frequency that occurs >2.5 days before the first appearance of a possible type-B QPO.
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| 10. |
- Graham, Robert M., et al.
(författare)
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Southern Ocean fronts : Controlled by wind or topography?
- 2012
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 117
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Tidskriftsartikel (refereegranskat)abstract
- The location of fronts has a direct influence on both the physical and biological processes in the Southern Ocean. Here we explore the relative importance of bottom topography and winds for the location of Southern Ocean fronts, using 100 years of a control and climate change simulation from the high resolution coupled climate model HiGEM. Topography has primary control on the number and intensity of fronts at each longitude. However, there is no strong relationship between the position or spacing of jets and underlying topographic gradients because of the effects of upstream and downstream topography. The Southern Hemisphere Westerlies intensify and shift south by 1.3 degrees in the climate change simulation, but there is no comparable meridional displacement of the Antarctic Circumpolar Current's (ACC) path or the fronts within its boundaries, even over flat topography. Instead, the current contracts meridionally and weakens. North of the ACC, the Subtropical Front (STF) shifts south gradually, even over steep topographic ridges. We suggest the STF reacts more strongly to the wind shift because it is strongly surface intensified. In contrast, fronts within the ACC are more barotropic and are therefore more sensitive to the underlying topography. An assessment of different methods for identifying jets reveals that maxima of gradients in the sea surface height field are the most reliable. Approximating the position of fronts using sea surface temperature gradients is ineffective at high latitudes while using sea surface height contours can give misleading results when studying the temporal variability of front locations.
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| 11. |
- Hallqvist, Jenny, et al.
(författare)
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A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning
- 2023
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Ingår i: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - 1661-6596 .- 1422-0067. ; 24:18
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Tidskriftsartikel (refereegranskat)abstract
- As disease-modifying therapies are now available for Alzheimer's disease (AD), accessible, accurate and affordable biomarkers to support diagnosis are urgently needed. We sought to develop a mass spectrometry-based urine test as a high-throughput screening tool for diagnosing AD. We collected urine from a discovery cohort (n = 11) of well-characterised individuals with AD (n = 6) and their asymptomatic, CSF biomarker-negative study partners (n = 5) and used untargeted proteomics for biomarker discovery. Protein biomarkers identified were taken forward to develop a high-throughput, multiplexed and targeted proteomic assay which was tested on an independent cohort (n = 21). The panel of proteins identified are known to be involved in AD pathogenesis. In comparing AD and controls, a panel of proteins including MIEN1, TNFB, VCAM1, REG1B and ABCA7 had a classification accuracy of 86%. These proteins have been previously implicated in AD pathogenesis. This suggests that urine-targeted mass spectrometry has potential utility as a diagnostic screening tool in AD.
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| 12. |
- Heywood, W. E., et al.
(författare)
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Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay
- 2015
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Currently there are no effective treatments for many neurodegenerative diseases. Reliable biomarkers for identifying and stratifying these diseases will be important in the development of future novel therapies. Lewy Body Dementia (LBD) is considered an under diagnosed form of dementia for which markers are needed to discriminate LBD from other forms of dementia such as Alzheimer's Disease (AD). This work describes a Label-Free proteomic profiling analysis of cerebral spinal fluid (CSF) from non-neurodegenerative controls and patients with LBD. Using this technology we identified several potential novel markers for LBD. These were then combined with other biomarkers from previously published studies, to create a 10 min multiplexed targeted and translational MRM-LC-MS/MS assay. This test was used to validate our new assay in a larger cohort of samples including controls and the other neurodegenerative conditions of Alzheimer's and Parkinson's disease (PD). Results: Thirty eight proteins showed significantly (p < 0.05) altered expression in LBD CSF by proteomic profiling. The targeted MRM-LC-MS/MS assay revealed 4 proteins that were specific for the identification of AD from LBD: ectonucleotide pyrophosphatase/phosphodiesterase 2 (p < 0.0001), lysosome-associated membrane protein 1 (p < 0.0001), pro-orexin (p < 0.0017) and transthyretin (p < 0.0001). Nineteen proteins were elevated significantly in both AD and LBD versus the control group of which 4 proteins are novel (malate dehydrogenase 1, serum amyloid A4, GM2-activator protein, and prosaposin). Protein-DJ1 was only elevated significantly in the PD group and not in either LBD or AD samples. Correlations with Alzheimer-associated amyloid beta-42 levels, determined by ELISA, were observed for transthyretin, GM2 activator protein and IGF2 in the AD disease group (r(2) >= 0.39, p <= 0.012). Cystatin C, ubiquitin and osteopontin showed a strong significant linear relationship (r(2) >= 0.4, p <= 0.03) with phosphorylated-tau levels in all groups, whilst malate dehydrogenase and apolipoprotein E demonstrated a linear relationship with phosphorylated-tau and total-tau levels in only AD and LBD disease groups. Conclusions: Using proteomics we have identified several potential and novel markers of neurodegeneration and subsequently validated them using a rapid, multiplexed mass spectral test. This targeted proteomic platform can measure common markers of neurodegeneration that correlate with existing diagnostic makers as well as some that have potential to show changes between AD from LBD.
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| 13. |
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| 14. |
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| 15. |
- Andersson, Staffan, 1969-, et al.
(författare)
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The Politics of Perception: Use and Abuse of Transparency International’s Approach to Measuring Corruption
- 2009
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Ingår i: Political Studies. - : Blackwell Publishing. - 0032-3217 .- 1467-9248. ; 57:4, s. 746-767
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Tidskriftsartikel (refereegranskat)abstract
- The annual Corruption Perceptions Index (CPI), published by Transparency International (TI), has had a pivotal role in focusing attention on corruption. Despite recent critiques of the CPI, it remains highly influential on research into the causes of corruption and is also extensively used to galvanise support for measures to fight corruption. In this article we explore the CPI in more depth in order to highlight how the index has been used for political ends which may not always turn out to be supportive of anti-corruption efforts. The argument is developed in four sections: in the first, we focus on Transparency International's definition of corruption, highlighting some conceptual difficulties with the approach adopted and its relationship to the promotion of ‘good governance’ as the principal means of combating corruption. In the second section, we outline some methodological difficulties in the design of the Corruption Perceptions Index. Although the CPI has been much criticised, we demonstrate in the third section that the index continues to exercise great influence both in academic research and in the politics of anti-corruption efforts, particularly as exercised by Transparency International itself. In the final section we argue that the CPI contributes to the risk of creating a ‘corruption trap’ in countries where corruption is deeply embedded, as development aid is increasingly made conditional on the implementation of reforms which are impossible to achieve without that aid.
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| 16. |
- Azaneu, M., et al.
(författare)
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Influence of Shelf Break Processes on the Transport of Warm Waters Onto the Eastern Amundsen Sea Continental Shelf
- 2023
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Ingår i: Journal of Geophysical Research-Oceans. - 2169-9275. ; 128:5
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Tidskriftsartikel (refereegranskat)abstract
- The heat transported onto the continental shelf by Circumpolar Deep Water (CDW) is the main driver of ice shelf basal melting in the Amundsen Sea. Here, we investigate the slope current system and the variability of the heat transported through the Pine Island-Thwaites central and eastern troughs using data from five moorings deployed in the region between 5 March 2012 and 7 February 2016. Substantial variability on intermonthly time scales (3-4 months) is observed in the onshore heat flux, driven primarily by zonal wind stress north of the shelf break. Heat content, onshore flow, and heat flux are highly correlated between central and eastern troughs, which are most likely dynamically linked by the zonal wind stress forcing. This is the first time this dynamic link between troughs is observed. In the eastern the Amundsen Sea, during the El Nino of 2015/2016, strong eastward winds led to lower temperatures over the continental shelf while the onshore heat flux is intensified. We hypothesize that this anti-correlation between heat content and heat flux results from a strengthened eastward undercurrent leading to upwelling of a colder and deeper CDW variety. These results highlight the complex and heterogeneous response of this region to environmental and the importance of velocity data for understanding the dynamics in this region. It also suggests that the hypothesized link between large-scale atmospheric forcing (e.g., El Nino-Southern Oscillation) and ice-shelf melt is not produced via changes in heat content, but instead via changes in onshore heat flux.
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| 17. |
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| 18. |
- Dotto, T. S., et al.
(författare)
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Ocean variability beneath Thwaites Eastern Ice Shelf driven by the Pine Island Bay Gyre strength
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- West Antarctic ice-shelf thinning is primarily caused by ocean-driven basal melting. Here we assess ocean variability below Thwaites Eastern Ice Shelf (TEIS) and reveal the importance of local ocean circulation and sea-ice. Measurements obtained from two sub-ice-shelf moorings, spanning January 2020 to March 2021, show warming of the ice-shelf cavity and an increase in meltwater fraction of the upper sub-ice layer. Combined with ocean modelling results, our observations suggest that meltwater from Pine Island Ice Shelf feeds into the TEIS cavity, adding to horizontal heat transport there. We propose that a weakening of the Pine Island Bay gyre caused by prolonged sea-ice cover from April 2020 to March 2021 allowed meltwater-enriched waters to enter the TEIS cavity, which increased the temperature of the upper layer. Our study highlights the sensitivity of ocean circulation beneath ice shelves to local atmosphere-sea-ice-ocean forcing in neighbouring open oceans.
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| 19. |
- Graham, Alastair G.C., et al.
(författare)
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Rapid retreat of Thwaites Glacier in the pre-satellite era
- 2022
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Ingår i: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 15, s. 706-713
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the recent history of Thwaites Glacier, and the processes controlling its ongoing retreat, is key to projecting Antarctic contributions to future sea-level rise. Of particular concern is how the glacier grounding zone might evolve over coming decades where it is stabilized by sea-floor bathymetric highs. Here we use geophysical data from an autonomous underwater vehicle deployed at the Thwaites Glacier ice front, to document the ocean-floor imprint of past retreat from a sea-bed promontory. We show patterns of back-stepping sedimentary ridges formed daily by a mechanism of tidal lifting and settling at the grounding line at a time when Thwaites Glacier was more advanced than it is today. Over a duration of 5.5 months, Thwaites grounding zone retreated at a rate of >2.1 km per year—twice the rate observed by satellite at the fastest retreating part of the grounding zone between 2011 and 2019. Our results suggest that sustained pulses of rapid retreat have occurred at Thwaites Glacier in the past two centuries. Similar rapid retreat pulses are likely to occur in the near future when the grounding zone migrates back off stabilizing high points on the sea floor.
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| 20. |
- Herlitz, Johan, et al.
(författare)
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Effects of metoprolol CR/XL on mortality and hospitalizations in patients with heart failure and history of hypertension.
- 2002
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Ingår i: Journal of Cardiac Failure. - : Churchill Livingstone. - 1071-9164 .- 1532-8414. ; 8:1, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We describe the effect of controlled-release/extended-release (CR/XL) metoprolol succinate once daily on mortality and hospitalizations among patients with a history of hypertension complicated by chronic systolic heart failure. METHODS AND RESULTS: We enrolled 3,991 patients with chronic heart failure of New York Heart Association functional class II-IV with an ejection fraction of < or = 0.40, stabilized with optimum standard therapy, in a double-blind randomized placebo-controlled study. A total of 1,747 patients (44%) had a history of hypertension; 871 were randomized to receive metoprolol CR/XL and 876 to receive placebo. Treatment with metoprolol CR/XL compared with placebo resulted in a significant reduction in total mortality (relative risk [RR], 0.61; 95% confidence interval [CI], 0.44-0.84; P =.0022), mainly because of reductions in sudden death (RR, 0.51; 95% CI, 0.33-0.79; P =.0022) and mortality from worsening heart failure (RR, 0.49; 95% CI, 0.25-0.99; P =.042). Total number of hospitalizations for worsening heart failure was reduced by 30% in the metoprolol CR/XL group compared with placebo (P =.015). Metoprolol CR/XL was well tolerated: 12% fewer patients withdrew from study medication (all-cause) compared with placebo (P =.048). CONCLUSIONS: A subgroup analysis of MERIT-HF shows that patients with heart failure and a history of hypertension received a similar benefit from metoprolol CR/XL treatment as all patients included in the total study.
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| 21. |
- Heslegrave, A. J., et al.
(författare)
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A Selected reaction monitoring protocol for the measurement of sTREM2 in cerebrospinal fluid
- 2018
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Ingår i: Biomarkers for Preclinical Alzheimer’s Disease. Perneczky R. (red.). - New York, NY : Springer. - 0893-2336. - 9781493976744 ; , s. 169-177
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Bokkapitel (refereegranskat)abstract
- Mass spectrometry plays an increasingly important role in the biomarker field with the advent of targeted proteomics. Tryptic peptides from a protein of interest can be used to create a targeted assay to interrogate cerebrospinal fluid (CSF) for biomarkers. Since heterozygous mutations in the TREM2 gene have been associated with an increased risk of Alzheimer’s disease, measuring this soluble protein in CSF has become a priority. This chapter demonstrates the development, optimization, and validation of a method to measure soluble TREM2 using a single reaction monitoring (SRM) targeted mass spectrometry assay. © 2018, Springer Science+Business Media, LLC.
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| 22. |
- Heywood, Wendy E, et al.
(författare)
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A High Throughput, Multiplexed and Targeted Proteomic CSF Assay to Quantify Neurodegenerative Biomarkers and Apolipoprotein E Isoforms Status.
- 2016
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Ingår i: Journal of visualized experiments : JoVE. - : MyJove Corporation. - 1940-087X. ; :116
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Tidskriftsartikel (refereegranskat)abstract
- Many neurodegenerative diseases arestill lacking effective treatments. Reliable biomarkers for identifying and classifying these diseases will be important in the development of future novel therapies. Oftenpotential new biomarkers do not make itinto the clinicdue to limitationsin their development andhigh costs.However,targeted proteomics using Multiple Reaction Monitoring Liquid Chromatography-tandem/Mass Spectrometry (MRM LC-MS/MS), specifically using triple quadrupole mass spectrometers, is one method that can be used to rapidly evaluate and validate biomarkersfor clinical translation into diagnostic laboratories. Traditionally, this platform has been used extensively for measurement of small moleculesin clinical laboratories, but it is the potential to analyze proteins, that makes it an attractive alternative to ELISA (Enzyme-Linked Immunosorbent Assay)-based methods. We describe here how targeted proteomics can be used to measure multiplexed markers of dementia, including the detection and quantitation of the known risk factor apolipoprotein E isoform 4 (ApoE4). In order to make the assay suitable for translation, it is designed to be rapid, simple, highly specific and cost effective. To achieve this, every step in the development of the assay must be optimized for the individual proteins and tissues they are analyzed in. This method describes a typical workflow including various tips and tricks to developing a targeted proteomics MRM LC-MS/MS for translation. The method development is optimized using custom synthesized versions of tryptic quantotypic peptides, which calibratethe MS for detection and then spiked into CSF to determine correct identification of the endogenous peptide in the chromatographic separation prior to analysis in the MS. To achieve absolute quantitation, stable isotope-labeled internal standard versions of the peptides with short amino acid sequence tags and containing a trypsin cleavage site, are included in the assay.
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| 23. |
- Heywood, W. E., et al.
(författare)
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Cerebrospinal fluid neurofilament light chain levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment
- 2022
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Ingår i: F1000Research. - : F1000 Research Ltd. - 2046-1402. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT. © 2022 Iwan K et al.
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| 24. |
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| 25. |
- Kleeman, Sam O, et al.
(författare)
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Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.
- 2023
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Ingår i: Cell genomics. - 2666-979X. ; 3:8
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Tidskriftsartikel (refereegranskat)abstract
- Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.
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| 26. |
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| 27. |
- Mallett, H. K. W., et al.
(författare)
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Variation in the Distribution and Properties of Circumpolar Deep Water in the Eastern Amundsen Sea, on Seasonal Timescales, Using Seal-Borne Tags
- 2018
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276. ; 45:10, s. 4982-4990
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Tidskriftsartikel (refereegranskat)abstract
- In the Amundsen Sea, warm saline Circumpolar Deep Water (CDW) crosses the continental shelf toward the vulnerable West Antarctic ice shelves, contributing to their basal melting. Due to lack of observations, little is known about the spatial and temporal variability of CDW, particularly seasonally. A new data set of 6,704 seal tag temperature and salinity profiles in the easternmost trough between February and December 2014 reveals a CDW layer on average 49dbar thicker in late winter (August to October) than in late summer (February to April), the reverse seasonality of that seen at moorings in the western trough. This layer contains more heat in winter, but on the 27.76 kg/m(3) density surface CDW is 0.32 degrees C warmer in summer than in winter, across the northeastern Amundsen Sea, which may indicate that wintertime shoaling offshelf changes CDW properties onshelf. In Pine Island Bay these seasonal changes on density surfaces are reduced, likely by gyre circulation. Plain Language Summary In the Amundsen Sea, Antarctica, warm salty water crosses the continental shelf from the deep open ocean, toward the vulnerable West Antarctic ice shelves, bringing heat to help melt them from underneath. Due to lack of observations, little is known about how this flow of warm water varies in space and time, particularly seasonally. Between February and December 2014, in a trough in the eastern Amundsen Sea, 6,704 profiles were collected by sensors attached to seals, measuring temperature and salinity as the seals return from dives up to 1,200m deep. These data showed that this warm (similar to 1 degrees C) deep layer is on average similar to 50m thicker in late winter (August to October) than in late summer (February to April), the reverse seasonality of that seen within a trough in the western Amundsen Sea. This warm layer contains more heat in winter but on a surface of constant density is 0.32 degrees C warmer in summer than in winter, across the northeastern Amundsen Sea. This may indicate that in winter the deep waters offshelf rise, allowing different water onto the continental shelf. In Pine Island Bay these seasonal changes on density surfaces are reduced, probably because here the water circulates and mixes.
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| 28. |
- Oelerich, Ria, et al.
(författare)
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Stirring across the Antarctic Circumpolar Current's southern boundary at the prime meridian, Weddell Sea
- 2023
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Ingår i: Ocean Science. - 1812-0784 .- 1812-0792. ; 19:5, s. 1465-1482
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Tidskriftsartikel (refereegranskat)abstract
- At the southern boundary of the Antarctic Circumpolar Current (ACC), relatively warm ACC waters encounter the colder waters surrounding Antarctica. Strong density gradients across the southern boundary indicate the presence of a frontal jet and are thought to modulate the southward heat transport across the front. In this study, the southern boundary in the Weddell Sea sector at the prime meridian is surveyed for the first time in high resolution over 2 months during an austral summer with underwater gliders occupying a transect across the front on five occasions. The five transects show that the frontal structure (i.e. hydrography, velocities and lateral density gradients) varies temporally. The results demonstrate significant, transient (a few weeks) variability of the southern boundary and its frontal jet in location, strength and width. A mesoscale cold-core eddy is identified to disrupt the southern boundary's frontal structure and strengthen lateral density gradients across the front. The front's barrier properties are assessed using mixing length scales and potential vorticity to establish the cross-frontal exchange of properties between the ACC and the Weddell Gyre. The results show that stronger lateral density gradients caused by the mesoscale eddy strengthen the barrier-like properties of the front through reduced mixing length scales and pronounced gradients of potential vorticity. In contrast, the barrier-like properties of the southern boundary are reduced when no mesoscale eddy is influencing the density gradients across the front. Using satellite altimetry, we further demonstrate that the barrier properties over the past decade have strengthened as a result of increased meridional gradients of absolute dynamic topography and increased frontal jet speeds in comparison to previous decades. Our results emphasise that locally and rapidly changing barrier properties of the southern boundary are important to quantify the cross-frontal exchange, which is particularly relevant in regions where the southern boundary is located near the Antarctic shelf break (e.g. in the West Antarctic sector).
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| 29. |
- 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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| 30. |
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| 31. |
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| 32. |
- Testor, Pierre, et al.
(författare)
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OceanGliders: A component of the integrated GOOS
- 2019
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 6
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Forskningsöversikt (refereegranskat)abstract
- The OceanGliders program started in 2016 to support active coordination and enhancement of global glider activity. OceanGliders contributes to the international efforts of the Global Ocean Observation System (GOOS) for Climate, Ocean Health and Operational Services. It brings together marine scientists and engineers operating gliders around the world: (1) to observe the long-term physical, biogeochemical, and biological ocean processes and phenomena that are relevant for societal applications; and, (2) to contribute to the GOOS through real-time and delayed mode data dissemination. The OceanGliders program is distributed across national and regional observing systems and significantly contributes to integrated, multi-scale and multi-platform sampling strategies. OceanGliders shares best practices, requirements, and scientific knowledge needed for glider operations, data collection and analysis. It also monitors global glider activity and supports the dissemination of glider data through regional and global databases, in real-time and delayed modes, facilitating data access to the wider community. OceanGliders currently supports national, regional and global initiatives to maintian and expand the capabilities and application of gliders to meet key global challenges such as improved measurement of ocean boundary currents, water transformation and storm forecast.
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| 33. |
- Webber, B. G. M., et al.
(författare)
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The Impact of Overturning and Horizontal Circulation in Pine Island Trough on Ice Shelf Melt in the Eastern Amundsen Sea
- 2019
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Ingår i: Journal of Physical Oceanography. - : American Meteorological Society. - 0022-3670 .- 1520-0485. ; 49:1, s. 63-83
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Tidskriftsartikel (refereegranskat)abstract
- The ice shelves around the Amundsen Sea are rapidly melting as a result of the circulation of relatively warm ocean water into their cavities. However, little is known about the processes that determine the variability of this circulation. Here we use an ocean circulation model to diagnose the relative importance of horizontal and vertical (overturning) circulation within Pine Island Trough, leading to Pine Island and Thwaites ice shelves. We show that melt rates and southward Circumpolar Deep Water (CDW) transports covary over large parts of the continental shelf at interannual to decadal time scales. The dominant external forcing mechanism for this variability is Ekman pumping and suction on the continental shelf and at the shelf break, in agreement with previous studies. At the continental shelf break, the southward transport of CDW and heat is predominantly barotropic. Farther south within Pine Island Trough, northward and southward barotropic heat transports largely cancel, and the majority of the net southward temperature transport is facilitated by baroclinic and overturning circulations. The overturning circulation is related to water mass transformation and buoyancy gain on the shelf that is primarily facilitated by freshwater input from basal melting.
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| 34. |
- Zheng, Y. X., et al.
(författare)
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Reversal of ocean gyres near ice shelves in the Amundsen Sea caused by the interaction of sea ice and wind
- 2022
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Ingår i: Cryosphere. - : Copernicus GmbH. - 1994-0416. ; 16:7, s. 3005-3019
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Tidskriftsartikel (refereegranskat)abstract
- Floating ice shelves buttress the Antarctic Ice Sheet, which is losing mass rapidly mainly due to ocean-driven melting and the associated disruption to glacial dynamics. The local ocean circulation near ice shelves is therefore important for the prediction of future ice mass loss and related sea-level rise as it determines the water mass exchange, heat transport under the ice shelf and resultant melting. However, the dynamics controlling the near-coastal circulation are not fully understood. A cyclonic (i.e. clockwise) gyre circulation (27 km radius) in front of the Pine Island Ice Shelf has previously been identified in both numerical models and velocity observations. Mooring data further revealed a potential reversal of this gyre during an abnormally cold period. Here we present ship-based observations from 2019 to the west of Thwaites Ice Shelf, revealing another gyre (13 km radius) for the first time in this habitually ice-covered region, rotating in the opposite (anticyclonic, anticlockwise) direction to the gyre near Pine Island Ice Shelf, despite similar wind forcing. We use an idealised configuration of MITgcm, with idealised forcing based on ERA5 climatological wind fields and a range of idealised sea ice conditions typical for the region, to reproduce key features of the observed gyres near Pine Island Ice Shelf and Thwaites Ice Shelf. The model driven solely by wind forcing in the presence of ice can reproduce the horizontal structure and direction of both gyres. We show that the modelled gyre direction depends upon the spatial difference in the ocean surface stress, which can be affected by the applied wind stress curl filed, the percentage of wind stress transferred through the ice, and the angle between the wind direction and the sea ice edge. The presence of ice, either it is fast ice/ice shelves blocking the effect of wind or mobile sea ice enhancing the effect of wind, has the potential to reverse the gyre direction relative to ice-free conditions.
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| 35. |
- Zheng, Y. X., et al.
(författare)
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Winter seal-based observations reveal glacial meltwater surfacing in the southeastern Amundsen Sea
- 2021
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Ingår i: Communications Earth & Environment. - : Springer Science and Business Media LLC. - 2662-4435. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Determining the injection of glacial meltwater into polar oceans is crucial for quantifying the climate system response to ice sheet mass loss. However, meltwater is poorly observed and its pathways poorly known, especially in winter. Here we present winter meltwater distribution near Pine Island Glacier using data collected by tagged seals, revealing a highly variable meltwater distribution with two meltwater-rich layers in the upper 250m and at around 450m, connected by scattered meltwater-rich columns. We show that the hydrographic signature of meltwater is clearest in winter, when its presence can be unambiguously mapped. We argue that the buoyant meltwater provides near-surface heat that helps to maintain polynyas close to ice shelves. The meltwater feedback onto polynyas and air-sea heat fluxes demonstrates that although the processes determining the distribution of meltwater are small-scale, they are important to represent in Earth system models. A highly variable meltwater distribution with interlinked layers and columns is found in the Amundsen Sea in winter, and it may sustain polynyas in the region, according to hydrographic data obtained by seals.
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