| 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. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- 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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| 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. |
- Jonsson, Frida, et al.
(författare)
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Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)
- 2015
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 36:4, s. 463-473
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Tidskriftsartikel (refereegranskat)abstract
- Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.
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| 12. |
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| 13. |
- 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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| 14. |
- 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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| 15. |
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| 16. |
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| 17. |
- El-Habta, Roine, 1988-
(författare)
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Cell therapy for denervated tissue
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Peripheral nerve injury results in denervation of tendons and muscles. The biology of denervated muscle has been well studied but little is known about the associated tendons. Denervation of muscle leads to atrophy which includes muscle fiber shrinkage and cell death, a process that is influenced by the lack of acetylcholine (ACh) signaling to the muscle cells. Recovery of long-term denervated muscle function is often poor. This thesis describes how a cell therapy approach using adipose tissue-derived stromal vascular fraction (SVF) may be used to protect and regenerate denervated muscle. Previous studies have shown how adipose tissue-dervied stem cells (ASCs), commonly expanded from the SVF, have pro-regenerative effects on the injured peripheral nervous system, and how ASCs differentiated towards a “Schwann cell-like phenotype” (dASCs) reduce muscle atrophy. In this thesis work, we studied the possible mechanisms underlying the regenerative potential of both SVF and culture expanded dASCs.Hypotheses: We hypothesized that: 1) denervated tendon displays morphological and biochemical properties that resemble the chronic degenerative tendon condition known as tendinosis; 2) denervated muscle up-regulates expression of muscarinic acetylcholine (ACh) receptors and apoptosis-associated signaling mechanisms; 3) dASCs enhance the proliferation of myoblasts in vitro through secretion of ACh; 4) SVF influences the proliferation, differentiation, and survival of myoblasts in vitro via secretion of growth factors; and 5) SVF can preserve denervated muscle tissue. To test our hypotheses, two model systems were used: an in vitro model based on indirect co-culture, and an in vivo rat sciatic nerve transection model.Results: Denervated tendon displayed morphological changes similar to tendinosis, including hypercellularity, disfigurement of cells, and disorganized collagen architecture, along with an increased expression of type I and type III collagen. In addition, levels of neurokinin 1 receptor (NK-1R) were upregulated in the tendon cells. In denervated muscle, there was an increased expression of muscarinic ACh receptors, as well as of genes associated with apoptosis, such as caspases, cytokines (e.g., tumor necrosis factor-alpha; TNF-a), and death domain receptors. We subsequently used TNF-aas an inducer of apoptosis in an in vitrorat primary myoblast culture model. TNF-aactivated/cleaved caspase 7 and increased poly ADP-ribose polymerase (PARP) levels. Moreover, Annexin V and TUNEL were increased after TNF-atreatment. Indirect co-culture with SVF significantly reduced all these measures of apoptosis. Proliferation studies showed that both dASCs and SVF enhanced growth of myoblasts in vitro. With dASCs, the effect was partially explained by secretion of ACh, and for SVF by released growth factors, such as hepatocyte growth factor (HGF). In both cases, the signal was mediated via phosphorylation of ERK1/2 (MAPK). HGF also had an inhibitory effect on the differentiation of myoblasts into myotubes. Finally, the protective effects of SVF were confirmed in vivo: injections of SVF into denervated muscle significantly increased the mean fiber area and diameter, as well as reduced the expression of apoptotic genes and TUNEL reactivity.Conclusions: Denervated tendons undergo severe degenerative changes similar to tendinosis. Furthermore, SVF has the ability to reduce muscle atrophy in vivo. Using in vitro systems, we showed that this might occur through secretion of growth factors which activate MAPK signaling and anti-apoptotic pathways. In conclusion, SVF offers a promising approach for future clinical application in the treatment of denervated muscle.
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| 18. |
- FitzGerald, Edward A., et al.
(författare)
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Multiplexed experimental strategies for fragment library screening using SPR biosensors
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Surface plasmon resonance biosensor technology (SPR) is ideally suited for fragment-based lead discovery. However, generally suitable experimental procedures or detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are lacking. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. By adopting a multiplexed strategy, the range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded. We here illustrate innovative strategies using five challenging targets and variants thereof. Two libraries of 90 and 1056 fragments were screened using two different flow-based SPR biosensor systems, allowing different experimental approaches. Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted.Competing Interest StatementAnna Moberg, Maria T. Lindgren and Claes Holmgren work for Cytiva, which produce Biacore systems.
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| 19. |
- FitzGerald, Edward, et al.
(författare)
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Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors
- 2024
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Ingår i: SLAS Discovery. - : Elsevier. - 2472-5560 .- 2472-5552. ; :1, s. 40-51
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Tidskriftsartikel (refereegranskat)abstract
- Surface plasmon resonance (SPR) biosensor methods are ideally suited for fragment-based lead discovery. However, generally applicable experimental procedures and detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are not available. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. The range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded by adopting multiplexed strategies, using multiple complementary surfaces or experimental conditions. Here we illustrate principles and multiplexed approaches for using flow-based SPR biosensor systems for screening fragment libraries of different sizes (90 and 1056 compounds) against a selection of challenging targets. It shows strategies for the identification of fragments interacting with 1) large and structurally dynamic targets, represented by acetyl choline binding protein (AChBP), a Cys-loop receptor ligand gated ion channel homologue, 2) targets in multi protein complexes, represented by lysine demethylase 1 and a corepressor (LSD1/CoREST), 3) structurally variable or unstable targets, represented by farnesyl pyrophosphate synthase (FPPS), 4) targets containing intrinsically disordered regions, represented by protein tyrosine phosphatase 1B (PTP1B), and 5) aggregation-prone proteins, represented by an engineered form of human tau (tau K18M). Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted. The study shows that the challenges for addressing these types of targets is not identification of potentially useful fragments per se, but establishing methods for their validation and evolution into leads.
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| 20. |
- 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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| 21. |
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| 22. |
- 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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| 23. |
- Luttens, Andreas, et al.
(författare)
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Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses
- 2022
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 144:7, s. 2905-2920
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Tidskriftsartikel (refereegranskat)abstract
- Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.
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| 24. |
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| 25. |
- Rikard, S. Michaela, et al.
(författare)
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Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601)
- 2021
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Ingår i: Cellular and Molecular Bioengineering. - : Springer. - 1865-5025 .- 1865-5033. ; 14:4, s. 321-338
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Pharmacologic approaches for promoting angiogenesis have been utilized to accelerate healing of chronic wounds in diabetic patients with varying degrees of success. We hypothesize that the distribution of proangiogenic drugs in the wound area critically impacts the rate of closure of diabetic wounds. To evaluate this hypothesis, we developed a mathematical model that predicts how spatial distribution of VEGF-A produced by delivery of a modified mRNA (AZD8601) accelerates diabetic wound healing. Methods We modified a previously published model of cutaneous wound healing based on coupled partial differential equations that describe the density of sprouting capillary tips, chemoattractant concentration, and density of blood vessels in a circular wound. Key model parameters identified by a sensitivity analysis were fit to data obtained from an in vivo wound healing study performed in the dorsum of diabetic mice, and a pharmacokinetic model was used to simulate mRNA and VEGF-A distribution following injections with AZD8601. Due to the limited availability of data regarding the spatial distribution of AZD8601 in the wound bed, we performed simulations with perturbations to the location of injections and diffusion coefficient of mRNA to understand the impact of these spatial parameters on wound healing. Results When simulating injections delivered at the wound border, the model predicted that injections delivered on day 0 were more effective in accelerating wound healing than injections delivered at later time points. When the location of the injection was varied throughout the wound space, the model predicted that healing could be accelerated by delivering injections a distance of 1-2 mm inside the wound bed when compared to injections delivered on the same day at the wound border. Perturbations to the diffusivity of mRNA predicted that restricting diffusion of mRNA delayed wound healing by creating an accumulation of VEGF-A at the wound border. Alternatively, a high mRNA diffusivity had no effect on wound healing compared to a simulation with vehicle injection due to the rapid loss of mRNA at the wound border to surrounding tissue. Conclusions These findings highlight the critical need to consider the location of drug delivery and diffusivity of the drug, parameters not typically explored in pre-clinical experiments, when designing and testing drugs for treating diabetic wounds.
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| 26. |
- Westergren, Helena, 1977, et al.
(författare)
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Insulin resistance, endothelial function, angiogenic factors and clinical outcome in non-diabetic patients with chest pain without myocardial perfusion defects
- 2016
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Ingår i: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 15:36
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with angina-like symptoms without myocardial perfusion scintigram (MPS)-verified abnormality may still be at risk for cardiovascular events. We hypothesized that insulin resistance could play a role in this population even without diagnosed diabetes. We further explored physiological and blood biomarkers, as well as global gene expression patterns that could be closely related to impaired glucose homeostasis to deepen our mechanistic understanding. Methods: A total of 365 non-diabetic patients with suspected myocardial ischemia referred to MPS were enrolled and followed up regarding event-free survival with a median time of 5.1 years. All patients underwent endothelial function assessment by reactive hyperemic index (RHI) using EndoPAT and extensive biomarker analysis. Whole blood global gene expression pathway analysis was performed in a subset of patients. Results: Homeostasis model assessment of insulin resistance (HOMA-IR) added independent prognostic value in patients without myocardial perfusion defects. In a multivariable analysis, HOMA-IR was inversely associated with low RHI. Furthermore, elevated HOMA-IR was associated with decreased levels of vascular endothelial growth factor D, stem cell factor and endocan as well as to increased level of interleukin-6. Global gene expression pathway analysis of whole blood cells showed that high HOMA-IR and impaired endothelial function were associated with upregulated pro-inflammatory pathways and down-regulated eukaryotic initiation factor-2 pathway. Conclusions: Insulin resistance measured by HOMA-IR is associated with endothelial dysfunction and confers independent prognostic information in non-diabetic patients with chest pain without myocardial perfusion defects. Increased systemic pro-inflammatory state and decreased levels of pro-angiogenic vascular growth factors may be important underlying molecular mechanisms.
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| 27. |
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| 28. |
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| 29. |
- 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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| 30. |
- Backman, Ludvig J, 1983-, et al.
(författare)
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Akt-mediated anti-apoptotic effects of substance P in Anti-Fas-induced apoptosis of human tenocytes
- 2013
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Ingår i: Journal of Cellular and Molecular Medicine (Print). - : Wiley-Blackwell. - 1582-1838 .- 1582-4934. ; 17:6, s. 723-733
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Tidskriftsartikel (refereegranskat)abstract
- Substance P (SP) and its receptor, the neurokinin-1 receptor (NK-1 R), are expressed by human tenocytes, and they are both up-regulated incases of tendinosis, a condition associated with excessive apoptosis. It is known that SP can phosphorylate/activate the protein kinase Akt,which has anti-apoptotic effects. This mechanism has not been studied for tenocytes. The aims of this study were to investigate if Anti-Fastreatment is a good apoptosis model for human tenocytes in vitro, if SP protects from Anti-Fas-induced apoptosis, and by which mechanismsSP mediates an anti-apoptotic response. Anti-Fas treatment resulted in a time- and dose-dependent release of lactate dehydrogenase (LDH), i.e.induction of cell death, and SP dose-dependently reduced the Anti-Fas-induced cell death through a NK-1 R specific pathway. The same trendwas seen for the TUNEL assay, i.e. SP reduced Anti-Fas-induced apoptosis via NK-1 R. In addition, it was shown that SP reduces Anti-Fas-induced decrease in cell viability as shown with crystal violet assay. Protein analysis using Western blot confirmed that Anti-Fas inducescleavage/activation of caspase-3 and cleavage of PARP; both of which were inhibited by SP via NK-1 R. Finally, SP treatment resulted in phosphorylation/activation of Akt as shown with Western blot, and it was confirmed that the anti-apoptotic effect of SP was, at least partly, inducedthrough the Akt-dependent pathway. In conclusion, we show that SP reduces Anti-Fas-induced apoptosis in human tenocytes and that this antiapoptoticeffect of SP is mediated through NK-1 R and Akt-specific pathways.
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| 31. |
- Backman, Ludvig J, et al.
(författare)
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Alpha-2 adrenergic stimulation triggers Achilles tenocyte hypercellularity : comparison between two model systems
- 2013
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : John Wiley & Sons. - 0905-7188 .- 1600-0838. ; 23:6, s. 687-696
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Tidskriftsartikel (refereegranskat)abstract
- The histopathology of tendons with painful tendinopathy is often tendinosis, a fibrosis-like condition of unclear pathogenesis characterized by tissue changes including hypercellularity. The primary tendon cells (tenocytes) have been shown to express adrenoreceptors (mainly alpha-2A) as well as markers of catecholamine production, particularly in tendinosis. It is known that adrenergic stimulation can induce proliferation in other cells. The present study investigated the effects of an exogenously administered alpha-2 adrenergic agonist in an established in vivo Achilles tendinosis model (rabbit) and also in an in vitro human tendon cell culture model. The catecholamine producing enzyme tyrosine hydroxylase and the alpha-2A-adrenoreceptor (α(2A) AR) were expressed by tenocytes, and alpha-2 adrenergic stimulation had a proliferative effect on these cells, in both models. The proliferation was inhibited by administration of an α(2A) AR antagonist, and the in vitro model further showed that the proliferative alpha-2A effect was mediated via a mitogenic cell signaling pathway involving phosphorylation of extracellular-signal-regulated kinases 1 and 2. The results indicate that catecholamines produced by tenocytes in tendinosis might contribute to the proliferative nature of the pathology through stimulation of the α(2A) AR, pointing to a novel target for future therapies. The study furthermore shows that animal models are not necessarily required for all aspects of this research.
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| 32. |
- Backman, Ludvig J, et al.
(författare)
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Low range of ankle dorsiflexion predisposes for patellar tendinopathy in junior elite basketball players : a 1-year prospective study
- 2011
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Ingår i: American Journal of Sports Medicine. - : SAGE Publications. - 0363-5465 .- 1552-3365. ; 39:12, s. 2626-2633
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patellar tendinopathy (PT) is one of the most common reasons for sport-induced pain of the knee. Low ankle dorsiflexion range might predispose for PT because of load-bearing compensation in the patellar tendon. PURPOSE: The purpose of this 1-year prospective study was to analyze if a low ankle dorsiflexion range increases the risk of developing PT for basketball players. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Ninety junior elite basketball players were examined for different characteristics and potential risk factors for PT, including ankle dorsiflexion range in the dominant and nondominant leg. Data were collected over a 1-year period and follow-up, including reexamination, was made at the end of the year. RESULTS: Seventy-five players met the inclusion criteria. At the follow-up, 12 players (16.0%) had developed unilateral PT. These players were found to have had a significantly lower mean ankle dorsiflexion range at baseline than the healthy players, with a mean difference of -4.7° (P = .038) for the dominant limb and -5.1° (P = .024) for the nondominant limb. Complementary statistical analysis showed that players with dorsiflexion range less than 36.5° had a risk of 18.5% to 29.4% of developing PT within a year, as compared with 1.8% to 2.1% for players with dorsiflexion range greater than 36.5°. Limbs with a history of 2 or more ankle sprains had a slightly less mean ankle dorsiflexion range compared to those with 0 or 1 sprain (mean difference, -1.5° to -2.5°), although this was only statistically significant for nondominant legs. CONCLUSION: This study clearly shows that low ankle dorsiflexion range is a risk factor for developing PT in basketball players. In the studied material, an ankle dorsiflexion range of 36.5° was found to be the most appropriate cutoff point for prognostic screening. This might be useful information in identifying at-risk individuals in basketball teams and enabling preventive actions. A history of ankle sprains might contribute to reduced ankle dorsiflexion range.
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| 33. |
- Backman, Ludvig J., et al.
(författare)
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Substance P reduces TNF-α-induced apoptosis in human tenocytes through NK-1 receptor stimulation
- 2014
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 48:19, s. 1414-1420
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: It has been hypothesised that an upregulation of the neuropeptide substance P (SP) and its preferred receptor, the neurokinin-1 receptor (NK-1 R), is a causative factor in inducing tenocyte hypercellularity, a characteristic of tendinosis, through both proliferative and antiapoptotic stimuli. We have demonstrated earlier that SP stimulates proliferation of human tenocytes in culture.AIM: The aim of this study was to investigate whether SP can mediate an antiapoptotic effect in tumour necrosis factor-α (TNF-α)-induced apoptosis of human tenocytes in vitro.RESULTS: A majority (approximately 75%) of tenocytes in culture were immunopositive for TNF Receptor-1 and TNF Receptor-2. Exposure of the cells to TNF-α significantly decreased cell viability, as shown with crystal violet staining. TNF-α furthermore significantly increased the amount of caspase-10 and caspase-3 mRNA, as well as both BID and cleaved-poly ADP ribosome polymerase (c-PARP) protein. Incubation of SP together with TNF-α resulted in a decreased amount of BID and c-PARP, and in a reduced lactate dehydrogenase release, as compared to incubation with TNF-α alone. The SP effect was blocked with a NK-1 R inhibitor.DISCUSSION: This study shows that SP, through stimulation of the NK-1 R, has the ability to reduce TNF-α-induced apoptosis of human tenocytes. Considering that SP has previously been shown to stimulate tenocyte proliferation, the study confirms SP as a potent regulator of cell-turnover in tendon tissue, capable of stimulating hypercellularity through different mechanisms. This gives further support for the theory that the upregulated amount of SP seen in tendinosis could contribute to hypercellularity.
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| 34. |
- Beshara, Soheir, et al.
(författare)
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Assessment of erythropoiesis following renal transplantation
- 1997
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Ingår i: European Journal of Haematology. - 0902-4441 .- 1600-0609. ; 58:3, s. 167-173
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Tidskriftsartikel (refereegranskat)abstract
- Ten patients, who received cadaveric kidneys, were followed for 24 wk with serial measurements of serum erythropoietin (S-Epo), transferrin receptor (S-TfR) and iron variables. The mean pretransplant creatinine clearance was 8.2 (range 0-22) ml/min and the mean haemoglobin (Hb) level was 99 +/- 18.6 (range 66-124) g/l. Nine patients demonstrated a gradual increase in S-Epo levels, which reached a peak, and was accompanied by a parallel increase in S-TfR levels with a median lag period of 3 wk between both peaks. Hb correction followed the S-TfR peak after a second lag period (median 7 wk). Elevated S-Epo and S-TfR did not result in correction of anaemia in 1 patient due to impaired graft function. Within 4 months, S-Epo levels reached the normal range while TfR levels were higher than normal. Follow-up of iron status demonstrated the development of iron deficiency in 5 patients, which was corrected spontaneously. Improvement in erythropoiesis after renal transplantation seems to occur by means of expansion of the erythroid marrow, as detected by increasing S-TfR levels, subsequent to a S-Epo peak. This expansion precedes Hb normalization. A nonuraemic environment is probably a prerequisite for the correction of anaemia but not for the increase in S-Epo or S-TfR levels. Iron deficiency may occur after transplantation due to an increase in iron utilization.
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| 35. |
- Beverborg, Niels Grote, et al.
(författare)
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Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy
- 2021
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Ingår i: Nature Communications. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 2041-1723.
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca2+ handling is a key feature of HF pathophysiology. Restoring the Ca2+ regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp−/−), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF.
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| 36. |
- Borbely, Gabor, 1981-, et al.
(författare)
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The role of neurokinin A in corneal wound repair
- 2015
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Ingår i: Investigative Ophthalmology and Visual Science. - Rockville, MD, USA : Assoc Research Vision Ophthalmology Inc. - 0146-0404 .- 1552-5783. ; 56:7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 37. |
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| 38. |
- Chen, Jialin, et al.
(författare)
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Ascorbic Acid Promotes the Stemness of Corneal Epithelial Stem/Progenitor Cells and Accelerates Epithelial Wound Healing in the Cornea
- 2017
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Ingår i: Stem Cells Translational Medicine. - : WILEY. - 2157-6564 .- 2157-6580. ; 6:5, s. 1356-1365
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Tidskriftsartikel (refereegranskat)abstract
- High concentration of ascorbic acid (vitamin C) has been found in corneal epithelium of various species. However, the specific functions and mechanisms of ascorbic acid in the repair of corneal epithelium are not clear. In this study, it was found that ascorbic acid accelerates corneal epithelial wound healing in vivo in mouse. In addition, ascorbic acid enhanced the stemness of cultured mouse corneal epithelial stem/progenitor cells (TKE2) in vitro, as shown by elevated clone formation ability and increased expression of stemness markers (especially p63 and SOX2). The contribution of ascorbic acid on the stemness enhancement was not dependent on the promotion of Akt phosphorylation, as concluded by using Akt inhibitor, nor was the stemness found to be dependent on the regulation of oxidative stress, as seen by the use of two other antioxidants (GMEE and NAC). However, ascorbic acid was found to promote extracellular matrix (ECM) production, and by using two collagen synthesis inhibitors (AzC and CIS), the increased expression of p63 and SOX2 by ascorbic acid was decreased by around 50%, showing that the increased stemness by ascorbic acid can be attributed to its regulation of ECM components. Moreover, the expression of p63 and SOX2 was elevated when TKE2 cells were cultured on collagen I coated plates, a situation that mimics the in vivo situation as collagen I is the main component in the corneal stroma. This study shows direct therapeutic benefits of ascorbic acid on corneal epithelial wound healing and provides new insights into the mechanisms involved.
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| 39. |
- Chen, Jialin, et al.
(författare)
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Ciliary Neurotrophic Factor Promotes the Migration of Corneal Epithelial Stem/progenitor Cells by Up-regulation of MMPs through the Phosphorylation of Akt
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- The migration of limbal epithelial stem cells is important for the homeostasis and regeneration of corneal epithelium. Ciliary neurotrophic factor (CNTF) has been found to promote corneal epithelial wound healing by activating corneal epithelial stem/progenitor cells. However, the possible effect of CNTF on the migration of corneal epithelial stem/progenitor cells is not clear. This study found the expression of CNTF in mouse corneal epithelial stem/progenitor cells (TKE2) to be up-regulated after injury, on both gene and protein level. CNTF promoted migration of TKE2 in a dose-dependent manner and the peak was seen at 10 ng/ml. The phosphorylation level of Akt (p-Akt), and the expression of MMP3 and MMP14, were up-regulated after CNTF treatment both in vitro and in vivo. Akt and MMP3 inhibitor treatment delayed the migration effect by CNTF. Finally, a decreased expression of MMP3 and MMP14 was observed when Akt inhibitor was applied both in vitro and in vivo. This study provides new insights into the role of CNTF on the migration of corneal epithelial stem/progenitor cells and its inherent mechanism of Up-regulation of matrix metalloproteinases through the Akt signalling pathway.
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| 40. |
- Chen, Jialin, et al.
(författare)
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Mechanical stress potentiates the differentiation of periodontal ligament stem cells into keratocytes
- 2018
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Ingår i: British Journal of Ophthalmology. - : BMJ Publishing Group Ltd. - 0007-1161 .- 1468-2079. ; 102:4, s. 562-569
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Tidskriftsartikel (refereegranskat)abstract
- Aims To explore the role of corneal-shaped static mechanical strain on the differentiation of human periodontal ligament stem cells (PDLSCs) into keratocytes and the possible synergistic effects of mechanics and inducing medium. Methods PDLSCs were exposed to 3% static dome-shaped mechanical strain in a Flexcell Tension System for 3 days and 7 days. Keratocyte phenotype was determined by gene expression of keratocyte markers. Keratocyte differentiation (inducing) medium was introduced in the Flexcell system, either continuously or intermittently combined with mechanical stimulation. The synergistic effects of mechanics and inducing medium on keratocyte differentiation was evaluated by gene and protein expression of keratocyte markers. Finally, a multilamellar cell sheet was assembled by seeding PDLSCs on a collagen membrane and inducing keratocyte differentiation. The transparency of the cell sheet was assessed, and typical markers of native human corneal stroma were evaluated by immunofluorescence staining. Results Dome-shaped mechanical stimulation promoted PDLSCs to differentiate into keratocytes, as shown by the upregulation of ALDH3A1, CD34, LUM, COL I and COL V. The expression of integrins were also upregulated after mechanical stimulation, including integrin alpha 1, alpha 2, beta 1 and non-muscle myosin II B. A synergistic effect of mechanics and inducing medium was found on keratocyte differentiation. The cell sheets were assembled under the treatment of mechanics and inducing medium simultaneously. The cell sheets were transparent, multilamellar and expressed typical markers of corneal stroma. Conclusion Dome-shaped mechanical stimulation promotes differentiation of PDLSCs into keratocytes and has synergistic effects with inducing medium. Multilamellar cell sheets that resemble native human corneal stroma show potential for future clinical applications.
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| 41. |
- Chen, Jialin, et al.
(författare)
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Regulation of Keratocyte Phenotype and Cell Behavior by Substrate Stiffness
- 2020
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Ingår i: ACS Biomaterials Science & Engineering. - : American Chemical Society (ACS). - 2373-9878. ; 6:9, s. 5162-5171
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Tidskriftsartikel (refereegranskat)abstract
- Corneal tissue engineering is an alternative way to solve the problem of lack of corneal donor tissue in corneal transplantation. Keratocytes with a normal phenotype and function in tissue-engineered cornea would be critical for corneal regeneration. Although the role of extracellular/substrate material stiffness is well-known for the regulation of the cell phenotype and cell behavior in many different cell types, its effects in keratocyte culture have not yet been thoroughly studied. This project studied the effect of substrate stiffness on the keratocyte phenotype marker expression and typical cell behavior (cell adhesion, proliferation, and migration), and the possible mechanisms involved. Human primary keratocytes were cultured on tissue culture plastic (TCP, similar to 10(6) kPa) or on plates with the stiffness equivalent of physiological human corneal stroma (25 kPa) or vitreous body (1 kPa). The expression of keratocyte phenotype markers, cell adhesion, proliferation, and migration were compared. The results showed that the stiffness of the substrate material regulates the phenotype marker expression and cell behavior of cultured keratocytes. Physiological corneal stiffness (25 kPa) superiorly preserved the cell phenotype when compared to the TCP and 1 kPa group. Keratocytes had a larger cell area when cultured on 25 kPa plates as compared to on TCP. Treatment of cells with NSC 23766 (Rac1 inhibitor) mimicked the response in the cell phenotype and behavior seen in the transition from soft materials to stiff materials, including the cytoskeletal structure, expression of keratocyte phenotype markers, and cell behavior. In conclusion, this study shows that substrate stiffness regulates the cell phenotype marker expression and cell behavior of keratocytes by Rac1-mediated cytoskeletal reorganization. This knowledge contributes to the development of corneal tissue engineering.
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| 42. |
- Chen, Jialin, et al.
(författare)
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Substance P and patterned silk biomaterial stimulate periodontal ligament stem cells to form corneal stroma in a bioengineered three-dimensional model
- 2017
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Ingår i: Stem Cell Research & Therapy. - : BIOMED CENTRAL LTD. - 1757-6512. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to generate a bioengineered multi-lamellar human corneal stroma tissue in vitro by differentiating periodontal ligament stem cells (PDLSCs) towards keratocytes on an aligned silk membrane.Methods: Human PDLSCs were isolated and identified. The neuropeptide substance P (SP) was added in keratocyte differentiation medium (KDM) to evaluate its effect on keratocyte differentiation of PDLSCs. PDLSCs were then seeded on patterned silk membrane and cultured with KDM and SP. Cell alignment was evaluated and the expression of extracellular matrix (ECM) components of corneal stroma was detected. Finally, multi-lamellar tissue was constructed in vitro by PDLSCs seeded on patterned silk membranes, which were stacked orthogonally and stimulated by KDM supplemented with SP for 18 days. Sections were prepared and subsequently stained with hematoxylin and eosin or antibodies for immunofluorescence observation of human corneal stroma-related proteins.Results: SP promoted the expression of corneal stroma-related collagens (collagen types I, III, V, and VI) during the differentiation induced by KDM. Patterned silk membrane guided cell alignment of PDLSCs, and important ECM components of the corneal stroma were shown to be deposited by the cells. The constructed multi-lamellar tissue was found to support cells growing between every two layers and expressing the main type of collagens (collagen types I and V) and proteoglycans (lumican and keratocan) of normal human corneal stroma.Conclusions: Multi-lamellar human corneal stroma-like tissue can be constructed successfully in vitro by PDLSCs seeded on orthogonally aligned, multi-layered silk membranes with SP supplementation, which shows potential for future corneal tissue engineering.
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- Danielson, J, et al.
(författare)
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Vital exhaustion in relation to lipid profile in healthy women
- 2001
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Ingår i: Psychosomatic Medicine. - Karolinska Inst, Div Prevent Med, Stockholm, Sweden. : LIPPINCOTT WILLIAMS & WILKINS. - 0033-3174 .- 1534-7796. ; 63:1, s. 106-107
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 47. |
- Danielson, Magnus, et al.
(författare)
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Analysis of Communication Network Challenges for Synchrophasor-Based Wide-Area Applications
- 2013
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Ingår i: Proceedings of IREP Symposium. - : IEEE conference proceedings. - 9781479901999
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Konferensbidrag (refereegranskat)abstract
- Wide-area synchrophasor applications inherently depend on the underlying IT and communications infrastructure supporting them. In particular, closed loop control systems for power grid oscillation damping is problematic, as it is a complex mixture of power grid monitoring, communication network properties and overall system stability issues. This article offers a holistic analysis of these fields, proposing a combined requirement on the full system: to keep system delays down to maintain stability. Simulation results to support the analysis findings, also showing how observability of power oscillations is important in combination with system delays related to feedback signals, and finally laying out experimentation plans to be performed in the lab on a complex power-grid model with real PMUs, communication network and controllers interacting with the SmarTS Lab real-time hardware-in-the-loop simulator platform.
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| 48. |
- Danielson, M., et al.
(författare)
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Clinicians' attitudes toward standardized assessment and diagnosis within child and adolescent psychiatry
- 2019
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Ingår i: Child and Adolescent Psychiatry and Mental Health. - : Springer Science and Business Media LLC. - 1753-2000. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a strong call for clinically useful standardized assessment tools in everyday child and adolescent psychiatric practice. The attitudes of clinicians have been raised as a key-facilitating factor when implementing new methods. An explorative study was conducted aimed to investigate the clinicians' attitudes regarding standardized assessments and usefulness of diagnoses in treatment planning.Methods: 411 mental health service personnel working with outpatient and inpatient assessment and treatment within the specialist child and adolescent mental health services, Stockholm County Council were asked to participate in the study, of which 345 (84%) agreed answer a questionnaire. The questionnaire included questions regarding Attitudes toward Standardized Assessment and Utility of Diagnosis. Descriptive analyses were performed and four subscales were compared with information from a similar study in US using the same instruments. The demographic and professional characteristics (age, working years, gender, education, profession, management position, involvement in assessment, level of service) in terms of prediction of attitudes were studied by univariate and multivariate linear regressions.Results: Overall, the clinicians had quite positive attitudes and were more positive compared to a similar study conducted in the US earlier. There were differences in attitudes due to several characteristics but the only characteristic predicting all subscales was type of profession (counselor, nurse, psychiatrist, psychologist, other), with counselors being less positive than other groups.Conclusion: The overall positive attitudes toward standard assessment are of importance in the development of evidence-based practice and our study implies that clinicians in general value and are willing to use standardized assessment. Nevertheless, there are specific issues such as adequate training and available translated assessment instrument that need to be addressed. When implementing new methods in practice, there are general as well as specific resistances that need to be overcome. Studies in different cultural settings are of importance to further extend the knowledge of what is general and what is specific barriers.
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| 49. |
- 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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