| 1. |
- Thoma, B, et al.
(författare)
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An international, interprofessional investigation of the self-reported podcast listening habits of emergency clinicians: A METRIQ Study
- 2020
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Ingår i: CJEM. - : Springer Science and Business Media LLC. - 1481-8043 .- 1481-8035. ; 22:1, s. 112-117
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesPodcasts are increasingly being used for medical education. A deeper understanding of usage patterns would inform both producers and researchers of medical podcasts. We aimed to determine how and why podcasts are used by emergency medicine and critical care clinicians.MethodsAn international interprofessional sample (medical students, residents, physicians, nurses, physician assistants, and paramedics) was recruited through direct contact and a multimodal social media (Twitter and Facebook) campaign. Each participant completed a survey outlining how and why they utilize medical podcasts. Recruitment materials included an infographic and study website.Results390 participants from 33 countries and 4 professions (medicine, nursing, paramedicine, physician assistant) completed the survey. Participants most frequently listened to medical podcasts to review new literature (75.8%), learn core material (75.1%), and refresh memory (71.8%). The majority (62.6%) were aware of the ability to listen at increased speeds, but most (76.9%) listened at 1.0 x (normal) speed. All but 25 (6.4%) participants concurrently performed other tasks while listening. Driving (72.3%), exercising (39.7%), and completing chores (39.2%) were the most common. A minority of participants used active learning techniques such as pausing, rewinding, and replaying segments of the podcast. Very few listened to podcasts multiple times.ConclusionsAn international cohort of emergency clinicians use medical podcasts predominantly for learning. Their listening habits (rarely employing active learning strategies and frequently performing concurrent tasks) may not support this goal. Further exploration of the impact of these activities on learning from podcasts is warranted.
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| 2. |
- Bastard, P, et al.
(författare)
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Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs
- 2022
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Ingår i: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 78:7490, s. eabp8966-
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Tidskriftsartikel (refereegranskat)abstract
- Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.
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| 3. |
- Geach, J.E., et al.
(författare)
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The SCUBA-2 Cosmology Legacy Survey: 850 μm maps, catalogues and number counts
- 2017
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 465:2, s. 1789-1806
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Tidskriftsartikel (refereegranskat)abstract
- We present a catalogue of similar to 3000 submillimetre sources detected (>= 3.5 sigma) at 850 mu m over similar to 5 deg(2) surveyed as part of the James Clerk Maxwell Telescope (JCMT) SCUBA-2 Cosmology Legacy Survey (S2CLS). This is the largest survey of its kind at 850 mu m, increasing the sample size of 850 mu m selected submillimetre galaxies by an order of magnitude. The wide 850 mu m survey component of S2CLS covers the extragalactic fields: UKIDSS-UDS, COSMOS, Akari-NEP, Extended Groth Strip, Lockman Hole North, SSA22 and GOODS-North. The average 1s depth of S2CLS is 1.2 mJy beam(-1), approaching the SCUBA-2 850 mu m confusion limit, which we determine to be sigma(c) approximate to 0.8 mJy beam(-1). We measure the 850 mu m number counts, reducing the Poisson errors on the differential counts to approximately 4 per cent at S-850 approximate to 3 mJy. With several independent fields, we investigate field-to-field variance, finding that the number counts on 0.5 degrees-1 degrees scales are generally within 50 per cent of the S2CLS mean for S-850 > 3 mJy, with scatter consistent with the Poisson and estimated cosmic variance uncertainties, although there is a marginal (2 sigma) density enhancement in GOODS-North. The observed counts are in reasonable agreement with recent phenomenological and semi-analytic models, although determining the shape of the faint-end slope (S-850 < 3 mJy) remains a key test. The large solid angle of S2CLS allows us to measure the bright-end counts: at S-850 > 10 mJy there are approximately 10 sources per square degree, and we detect the distinctive up-turn in the number counts indicative of the detection of local sources of 850 mu m emission
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| 4. |
- Geach, J.E., et al.
(författare)
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The SCUBA-2 Cosmology Legacy Survey: blank-field number counts of 450-mu m-selected galaxies and their contribution to the cosmic infrared background
- 2013
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 432:1, s. 53-61
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Tidskriftsartikel (refereegranskat)abstract
- The first deep blank-field 450 mu m map (1 sigma approximate to 1.3 mJy) from the Submillimetre Common-User Bolometer Array-2 SCUBA-2 Cosmology Legacy Survey (S2CLS), conducted with the James Clerk Maxwell Telescope (JCMT) is presented. Our map covers 140 arcmin(2) of the Cosmological Evolution Survey field, in the footprint of the Hubble Space Telescope (HST) Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey. Using 60 submillimetre galaxies detected at >= 3.75s, we evaluate the number counts of 450-mu m-selected galaxies with flux densities S-450 > 5 mJy. The 8 arcsec JCMT beam and high sensitivity of SCUBA-2 now make it possible to directly resolve a larger fraction of the cosmic infrared background (CIB, peaking at. similar to 200 mu m) into the individual galaxies responsible for its emission than has previously been possible at this wavelength. At S450 > 5 mJy, we resolve (7.4 +/- 0.7) x 10(-2) MJy sr(-1) of the CIB at 450 mu m (equivalent to 16 +/- 7 per cent of the absolute brightness measured by the Cosmic Background Explorer at this wavelength) into point sources. A further similar to 40 per cent of the CIB can be recovered through a statistical stack of 24 mu m emitters in this field, indicating that the majority (approximate to 60 per cent) of the CIB at 450 mu m is emitted by galaxies with S450 > 2 mJy. The average redshift of 450 mu m emitters identified with an optical/near-infrared counterpart is estimated to be = 1.3, implying that the galaxies in the sample are in the ultraluminous class (LIR approximate to 1.1 x 1012 L approximate to). If the galaxies contributing to the statistical stack lie at similar redshifts, then the majority of the CIB at 450 mu m is emitted by galaxies in the luminous infrared galaxy (LIRG) class with LIR > 3.6 x 1011 L-circle dot.
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| 5. |
- Hodge, J. A., et al.
(författare)
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An ALMA Survey of Submillimeter Galaxies in the Extended Chandra Deep Field South: Source Catalog and Multiplicity
- 2013
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Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 768:1
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Tidskriftsartikel (refereegranskat)abstract
- We present an Atacama Large Millimeter/submillimeter Array (ALMA) Cycle 0 survey of 126 submillimeter sources from the LABOCA ECDFS Submillimeter Survey (LESS). Our 870 mu m survey with ALMA (ALESS) has produced maps similar to 3x deeper and with a beam area similar to 200x smaller than the original LESS observations, doubling the current number of interferometrically-observed submillimeter sources. The high resolution of these maps allows us to resolve sources that were previously blended and accurately identify the origin of the submillimeter emission. We discuss the creation of the ALESS submillimeter galaxy (SMG) catalog, including the main sample of 99 SMGs and a supplementary sample of 32 SMGs. We find that at least 35% (possibly up to 50%) of the detected LABOCA sources have been resolved into multiple SMGs, and that the average number of SMGs per LESS source increases with LESS flux density. Using the (now precisely known) SMG positions, we empirically test the theoretical expectation for the uncertainty in the single-dish source positions. We also compare our catalog to the previously predicted radio/mid-infrared counterparts, finding that 45% of the ALESS SMGs were missed by this method. Our similar to 1 ''.6 resolution allows us to measure a size of similar to 9 kpc x 5 kpc for the rest-frame similar to 300 mu m emission region in one resolved SMG, implying a star formation rate surface density of 80 M-circle dot yr(-1) kpc(-2), and we constrain the emission regions in the remaining SMGs to be
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| 6. |
- Karim, A., et al.
(författare)
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An ALMA survey of submillimetre galaxies in the Extended Chandra Deep Field South: high-resolution 870 mu m source counts
- 2013
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 432:1, s. 2-9
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Tidskriftsartikel (refereegranskat)abstract
- We report the first counts of faint submillimetre galaxies (SMGs) in the 870-mu m band derived from arcsecond-resolution observations with the Atacama Large Millimeter Array (ALMA). We have used ALMA to map a sample of 122 870-mu m-selected submillimetre sources drawn from the 0 degrees.5x0 degrees.5 the Large Apex BOlometer CAmera (LABOCA) Extended Chandra Deep Field South submillimetre survey (LESS). These ALMA maps have an average depth of sigma 870(mu m) similar to 0.4 mJy, some approximately three times deeper than the original LABOCA survey and critically the angular resolution is more than an order of magnitude higher, FWHM of similar to 1.5 arcsec compared to similar to 19 arcsec for the LABOCA discovery map. This combination of sensitivity and resolution allows us to precisely pinpoint the SMGs contributing to the submillimetre sources from the LABOCA map, free from the effects of confusion. We show that our ALMA-derived SMG counts broadly agree with the submillimetre source counts from previous, lower resolution single-dish surveys, demonstrating that the bulk of the submillimetre sources are not caused by blending of unresolved SMGs. The difficulty which well-constrained theoretical models have in reproducing the high surface densities of SMGs, thus remains. However, our observations do show that all of the very brightest sources in the LESS sample, S-870 (mu m) greater than or similar to 12 mJy, comprise emission from multiple, fainter SMGs, each with 870-mu m fluxes of less than or similar to 9 mJy. This implies a natural limit to the star formation rate in SMGs of less than or similar to 10(3) M-circle dot yr(-1), which in turn suggests that the space densities of z > 1 galaxies with gas masses in excess of similar to 5 x 10(10) M-circle dot is
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| 7. |
- Simpson, J. M., et al.
(författare)
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AN ALMA SURVEY OF SUBMILLIMETER GALAXIES IN THE EXTENDED CHANDRA DEEP FIELD SOUTH: THE REDSHIFT DISTRIBUTION AND EVOLUTION OF SUBMILLIMETER GALAXIES
- 2014
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 788:2
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Tidskriftsartikel (refereegranskat)abstract
- We present the first photometric redshift distribution for a large sample of 870 mu m submillimeter galaxies (SMGs) with robust identifications based on observations with ALMA. In our analysis we consider 96 SMGs in the Extended Chandra Deep Field South, 77 of which have 4-19 band photometry. We model the SEDs for these 77 SMGs, deriving a median photometric redshift of z(phot) = 2.3 +/- 0.1. The remaining 19 SMGs have insufficient photometry to derive photometric redshifts, but a stacking analysis of Herschel observations confirms they are not spurious. Assuming that these SMGs have an absolute H-band magnitude distribution comparable to that of a complete sample of z similar to 1-2 SMGs, we demonstrate that they lie at slightly higher redshifts, raising the median redshift for SMGs to zphot = 2.5 +/- 0.2. Critically we show that the proportion of galaxies undergoing an SMG-like phase at z >= 3 is at most 35% +/- 5% of the total population. We derive a median stellar mass of M star = (8 +/- 1) x 10(10) M circle dot, although there are systematic uncertainties of up to 5 x for individual sources. Assuming that the star formation activity in SMGs has a timescale of similar to 100 Myr, we show that their descendants at z similar to 0 would have a space density and MH distribution that are in good agreement with those of local ellipticals. In addition, the inferred mass-weighted ages of the local ellipticals broadly agree with the look-back times of the SMG events. Taken together, these results are consistent with a simple model that identifies SMGs as events that form most of the stars seen in the majority of luminous elliptical galaxies at the present day.
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| 8. |
- Swinbank, A. M., et al.
(författare)
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An ALMA survey of sub-millimetre Galaxies in the Extended Chandra Deep Field South: the far-infrared properties of SMGs
- 2014
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 438:2, s. 1267-1287
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Tidskriftsartikel (refereegranskat)abstract
- We exploit Atacama Large Millimeter Array (ALMA) 870 mu m observations of sub-millimetre sources in the Extended Chandra Deep Field South to investigate the far-infrared properties of high-redshift sub-millimetre galaxies (SMGs). Using the precisely located 870 mu m ALMA positions of 99 SMGs, together with 24 mu m and radio imaging, we deblend the Herschel/SPIRE imaging to extract their far-infrared fluxes and colours. The median redshifts for ALMA LESS (ALESS) SMGs which are detected in at least two SPIRE bands increases with wavelength of the peak in their spectral energy distributions (SEDs), with z = 2.3 +/- 0.2, 2.5 +/- 0.3 and 3.5 +/- 0.5 for the 250, 350 and 500 mu m peakers, respectively. 34 ALESS SMGs do not have a >3 sigma counterpart at 250, 350 or 500 mu m. These galaxies have a median photometric redshift derived from the rest-frame UV-mid-infrared SEDs of z = 3.3 +/- 0.5, which is higher than the full ALESS SMG sample; z = 2.5 +/- 0.2. We estimate the far-infrared luminosities and characteristic dust temperature of each SMG, deriving L-IR = (3.0 +/- 0.3) x 10(12) L-circle dot (SFR = 300 +/- 30 M-circle dot yr(-1)) and T-d = 32 +/- 1 K. The characteristic dust temperature of these high-redshift SMGs is Delta T-d = 3-5K lower than comparably luminous galaxies at z = 0, reflecting the more extended star formation in these systems. We show that the contribution of S-870 mu m >= 1 mJy SMGs to the cosmic star formation budget is 20 per cent of the total over the redshift range z similar to 1-4. Adopting an appropriate gas-to-dust ratio, we estimate a typical molecular mass of the ALESS SMGs of M-H2 = (4.2 +/- 0.4) x 10(10) M-circle dot. Finally, we show that SMGs with S-870 mu m > 1 mJy (L-IR greater than or similar to 10(12) L-circle dot) contain similar to 10 per cent of the z similar to 2 volume-averaged H-2 mass density.
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| 9. |
- Coppin, K. E. K., et al.
(författare)
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Herschel-PACS observations of [O I]63 μm towards submillimetre galaxies at z~1
- 2012
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 427:1, s. 520-532
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Tidskriftsartikel (refereegranskat)abstract
- We present Herschel-PACS spectroscopy of the [O I]63 μm far-infrared cooling line from a sample of six unlensed and spectroscopically confirmed 870 μm selected submillimetre (submm) galaxies (SMGs) at 1.1
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| 10. |
- Swinbank, A. M., et al.
(författare)
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An ALMA survey of submillimetre galaxies in the Extended Chandra Deep Field-South: detection of C II at z=4.4
- 2012
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 427:2, s. 1066-1074
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Tidskriftsartikel (refereegranskat)abstract
- We present Atacama Large Millimeter Array (ALMA) 870-mu m (345-GHz) observations of two submillimetre galaxies (SMGs) drawn from an ALMA study of the 126 submillimetre sources from the LABOCA Extended Chandra Deep Field-South Survey (LESS). The ALMA data identify the counterparts to these previously unidentified submillimetre sources and serendipitously detect bright emission lines in their spectra which we show are most likely to be [CII] 157.74 mu m emission yielding redshifts of z = 4.42 and 4.44. This blind detection rate within the 7.5-GHz bandpass of ALMA is consistent with the previously derived photometric redshift distribution of SMGs and suggests a modest, but not dominant (less than or similar to 25 per cent), tail of 870-mu m selected SMGs at z greater than or similar to 4. We find that the ratio of L-[CII]/L-FIR in these SMGs is much higher than seen for similarly far-infrared-luminous galaxies at z similar to 0, which is attributed to the more extended gas reservoirs in these high-redshift ultraluminous infrared galaxies (ULIRGs). Indeed, in one system we show that the [C II] emission shows hints of extended emission on greater than or similar to 3 kpc scales. Finally, we use the volume probed by our ALMA survey to show that the bright end of the [CII] luminosity function evolves strongly between z = 0 and similar to 4.4, reflecting the increased interstellar medium cooling in galaxies as a result of their higher star formation rates. These observations demonstrate that even with short integrations, ALMA is able to detect the dominant fine-structure cooling lines from high-redshift ULIRGs, measure their energetics and spatially resolved properties and trace their evolution with redshift.
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| 11. |
- Wardlow, J. L., et al.
(författare)
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The LABOCA survey of the Extended Chandra Deep Field-South: a photometric redshift survey of submillimetre galaxies
- 2011
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 415:2, s. 1479-1508
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Tidskriftsartikel (refereegranskat)abstract
- We derive photometric redshifts from 17-band optical to mid-infrared photometry of 78 robust radio, 24-mu m and Spitzer IRAC counterparts to 72 of the 126 submillimetre galaxies (SMGs) selected at 870 mu m by LABOCA observations in the Extended Chandra Deep Field-South (ECDF-S). We test the photometric redshifts of the SMGs against the extensive archival spectroscopy in the ECDF-S. The median photometric redshift of identified SMGs is z = 2.2 +/- 0.1, the standard deviation is sigma(z) = 0.9 and we identify 11 (similar to 15 per cent) high-redshift (z >= 3) SMGs. A statistical analysis of sources in the error circles of unidentified SMGs identifies a population of possible counterparts with a redshift distribution peaking at z = 2.5 +/- 0.2, which likely comprises similar to 60 per cent of the unidentified SMGs. This confirms that the bulk of the undetected SMGs are coeval with those detected in the radio/mid-infrared. We conclude that at most similar to 15 per cent of all the SMGs are below the flux limits of our IRAC observations and thus may lie at z greater than or similar to 3 and hence at most similar to 30 per cent of all SMGs have z greater than or similar to 3. We estimate that the full S(870 mu m) > 4mJy SMG population has a median redshift of 2.5 +/- 0.5. In contrast to previous suggestions, we find no significant correlation between submillimetre flux and redshift. The median stellar mass of the SMGs derived from spectral energy distribution fitting is (9.1 +/- 0.5) x 10(10)M(circle dot) although we caution that the uncertainty in the star formation histories results in a factor of similar to 5 uncertainty in these stellarmasses. Using a single temperature modified blackbody fit with beta = 1.5, the median characteristic dust temperature of SMGs is 37.4 +/- 1.4K. The infrared luminosity function shows that SMGs at z = 2-3 typically have higher far-infrared luminosities and luminosity density than those at z = 1-2. This is mirrored in the evolution of the star formation rate density (SFRD) for SMGs which peaks at z similar to 2. The maximum contribution of bright SMGs to the global SFRD (similar to 5 per cent for SMGs with S(870 mu m) greater than or similar to 4mJy or similar to 50 per cent extrapolated to SMGs with S(870 mu m) > 1mJy) also occurs at z similar to 2.
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| 12. |
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| 13. |
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| 14. |
- Andersson, H.O., et al.
(författare)
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Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
- 2003
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.
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| 15. |
- Anttila, V., et al.
(författare)
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Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
- 2023
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Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0016. ; 31:3, s. 866-874
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%–50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool. © 2022
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| 16. |
- Danielson, Mattias, et al.
(författare)
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Neuroinflammatory markers associate with cognitive decline after major surgery: Findings of an explorative study
- 2020
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 87:3, s. 370-382
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Tidskriftsartikel (refereegranskat)abstract
- Objective Long-term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long-term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long-term cognitive decline defined as a composite cognitive z score of >= 1.0 compared to patients without long-term cognitive decline at 3 months postsurgery. Methods Serum and CSF biomarkers of inflammation and blood-brain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5 days and 3 months postoperatively. Results Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48-hour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with long-term cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with long-term cognitive decline at 3 months. Patients both with and patients without long-term cognitive decline showed early transient increases of the astroglial biomarkers S-100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio). Interpretation Surgery rapidly triggers a temporal neuroinflammatory response closely associated with long-term cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort.
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| 17. |
- Gan, Li-Ming, 1969, et al.
(författare)
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Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4-24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis.
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| 18. |
- Kesters, D., et al.
(författare)
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Structural basis of ligand recognition in 5-HT3 receptors
- 2013
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 14:1, s. 49-56
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Tidskriftsartikel (refereegranskat)abstract
- The 5-HT 3 receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT 3 receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation-π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT 3 receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT 3 receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT 3 receptor.
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| 19. |
- Polyakov,, et al.
(författare)
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Borealization of the Arctic Ocean in Response to Anomalous Advection From Sub-Arctic Seas
- 2020
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- An important yet still not well documented aspect of recent changes in the Arctic Ocean is associated with the advection of anomalous sub-Arctic Atlantic- and Pacific-origin waters and biota into the polar basins, a process which we refer to as borealization. Using a 37-year archive of observations (1981-2017) we demonstrate dramatically contrasting regional responses to atlantification (that part of borealization related to progression of anomalies from the Atlantic sector of sub-Arctic seas into the Arctic Ocean) and pacification (the counterpart of atlantification associated with influx of anomalous Pacific waters). Particularly, we show strong salinification of the upper Eurasian Basin since 2000, with attendant reductions in stratification, and potentially altered nutrient fluxes and primary production. These changes are closely related to upstream conditions. In contrast, pacification is strongly manifested in the Amerasian Basin by the anomalous influx of Pacific waters, creating conditions favorable for increased heat and freshwater content in the Beaufort Gyre halocline and expansion of Pacific species into the Arctic interior. Here, changes in the upper (overlying) layers are driven by local Arctic atmospheric processes resulting in stronger wind/ice/ocean coupling, increased convergence within the Beaufort Gyre, a thickening of the fresh surface layer, and a deepening of the nutricline and deep chlorophyll maximum. Thus, a divergent (Eurasian Basin) gyre responds altogether differently than does a convergent (Amerasian Basin) gyre to climate forcing. Available geochemical data indicate a general decrease in nutrient concentrations Arctic-wide, except in the northern portions of the Makarov and Amundsen Basins and northern Chukchi Sea and Canada Basin. Thus, changes in the circulation pathways of specific water masses, as well as the utilization of nutrients in upstream regions, may control the availability of nutrients in the Arctic Ocean. Model-based evaluation of the trajectory of the Arctic climate system into the future suggests that Arctic borealization will continue under scenarios of global warming. Results from this synthesis further our understanding of the Arctic Ocean's complex and sometimes non-intuitive Arctic response to climate forcing by identifying new feedbacks in the atmosphere-ice-ocean system in which borealization plays a key role.
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| 22. |
- Alarabi, A A, et al.
(författare)
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Complement activation during tryptophan immunoadsorption treatment.
- 1993
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Ingår i: Artificial Organs. - 0160-564X .- 1525-1594. ; 17:9, s. 782-786
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies against human lymphocyte antigens (HLA) are frequently seen among patients undergoing repeated renal transplantations. Graft survival can be improved by eliminating these antibodies by plasmapheresis before transplantation. In this study, we have tried a new extracorporeal procedure to remove the anti-HLA antibodies. An immunoadsorption column (IM-TR) with a matrix of polyvinyl alcohol (PVA) gel conjugated with a hydrophobic amino acid tryptophan was utilized. Previous results have shown that repeated IM-TR treatments are at least equally effective as plasmapheresis in reducing levels of specific immunoglobulins in treated patients. In this study, 7 HLA-immunized patients were treated before renal transplantation. Each patient was subjected to a total of 12 treatment sessions divided into 3 sessions per week. After each treatment session, the reduction of the immunoglobulins was less than what has been reported for plasmapheresis. This suggests that mechanisms other than immunoglobulin depletion are involved in the reduction of the total immunoglobulin levels. The IM-TR treatment resulted in a strong complement activation triggered by the alternative pathway. Since the adsorbed plasma was returned to the patient, exceedingly high levels of the activation fragment C3d (C3dg) were found in plasma during and after the treatment. We conclude that the extensive generation of C3dg may be one of the factors that plays a role in the reduction of the antibody levels since the C3dg fragment has been shown to down-regulate the immune response.
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- Anscombe, Elizabeth, et al.
(författare)
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Identification and Characterization of an Irreversible Inhibitor of CDK2
- 2015
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Ingår i: Chemistry and Biology. - : Elsevier BV. - 1074-5521 .- 1879-1301. ; 22:9, s. 1159-1164
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Tidskriftsartikel (refereegranskat)abstract
- Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclo-hexylmethoxy)-9H-purin-2-yl) amino) benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl) phenyl)-9H- purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.
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