| 1. |
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| 2. |
- Bestas, Burcu, et al.
(författare)
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Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 124:9, s. 4067-4081
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Tidskriftsartikel (refereegranskat)abstract
- X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
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| 3. |
- Dhawan, Suhail, et al.
(författare)
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The Zwicky Transient Facility Type Ia supernova survey : first data release and results
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 510:2, s. 2228-2241
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Tidskriftsartikel (refereegranskat)abstract
- Type Ia supernovae (SNe Ia) in the nearby Hubble flow are excellent distance indicators in cosmology. The Zwicky Transient Facility (ZTF) has observed a large sample of SNe from an untargeted, rolling survey, reaching 20.8, 20.6, and 20.3 mag in g r, and i band, respectively. With an FoV of 47 deg(2), ZTF discovered > 3000 SNe Ia in a little over 2.5 yr. Here, we report on the sample of 761 spectroscopically classified SNe Ia from the first year of operations (DR1). The sample has a median redshift (z) over bar = 0.057, nearly a factor of 2 higher than the current low-z sample. Our sample has a total of 934 spectra, of which 632 were obtained with the robotic SEDm on Palomar P60. We assess the potential for precision cosmology for a total of 305 SNe with redshifts from host galaxy spectra. The sample is already comparable in size to the entire combined literature low-z anchor sample. The median first detection is 13.5 d before maximum light, about 10 d earlier than the median in the literature. Furthermore, six SNe from our sample are at D-L < 80 Mpc, for which host galaxy distances can be obtained in the JAMES WEBB SPACE TELESCOPE era, such that we have calibrator and Hubble flow SNe observed with the same instrument. In the entire duration of ZTF-I, we have observed nearly 50 SNe for which we can obtain calibrator distances, key for per cent level distance scale measurements.
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| 4. |
- Goobar, Ariel, 1962-, et al.
(författare)
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Uncovering a population of gravitational lens galaxies with magnified standard candle SN Zwicky
- 2023
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Ingår i: Nature Astronomy. - 2397-3366. ; 7:9, s. 1098-1107
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Tidskriftsartikel (refereegranskat)abstract
- Detecting gravitationally lensed supernovae is among the biggest challenges in astronomy. It involves a combination of two very rare phenomena: catching the transient signal of a stellar explosion in a distant galaxy and observing it through a nearly perfectly aligned foreground galaxy that deflects light towards the observer. Here we describe how high-cadence optical observations with the Zwicky Transient Facility, with its unparalleled large field of view, led to the detection of a multiply imaged type Ia supernova, SN Zwicky, also known as SN 2022qmx. Magnified nearly 25-fold, the system was found thanks to the standard candle nature of type Ia supernovae. High-spatial-resolution imaging with the Keck telescope resolved four images of the supernova with very small angular separation, corresponding to an Einstein radius of only θE = 0.167″ and almost identical arrival times. The small θE and faintness of the lensing galaxy are very unusual, highlighting the importance of supernovae to fully characterize the properties of galaxy-scale gravitational lenses, including the impact of galaxy substructures.
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| 5. |
- Gupta, Dhanu, et al.
(författare)
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Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
- 2021
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Ingår i: Nature Biomedical Engineering. - Stockholm : Karolinska Institutet, Dept of Laboratory Medicine. - 2157-846X.
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.
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| 6. |
- Leloudas, Georgios, et al.
(författare)
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Supernova spectra below strong circumstellar interaction
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 574
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Tidskriftsartikel (refereegranskat)abstract
- We construct spectra of supernovae (SNe) interacting strongly with a circumstellar medium (CSM) by adding SN templates, a black-body continuum, and an emission-line spectrum. In a Monte Carlo simulation we vary a large number of parameters, such as the SN type, brightness and phase, the strength of the CSM interaction, the extinction, and the signal to noise ratio (S/N) of the observed spectrum. We generate more than 800 spectra, distribute them to ten different human classifiers, and study how the different simulation parameters affect the appearance of the spectra and their classification. The SNe IIn showing some structure over the continuum were characterized as SNe IInS to allow for a better quantification. We demonstrate that the flux ratio of the underlying SN to the continuum f(v) is the single most important parameter determining whether a spectrum can be classified correctly. Other parameters, such as extinction, S/N, and the width and strength of the emission lines, do not play a significant role. Thermonuclear SNe get progressively classified as Ia-CSM, IInS, and IIn as f(v) decreases. The transition between Ia-CSM and IInS occurs at f(v) similar to 0.2-0.3. It is therefore possible to determine that SNe Ia-CSM are found at the (un-extincted) magnitude range -19.5 > M > -21.6, in very good agreement with observations, and that the faintest SN IIn that can hide a SN Ia has M = -20.1. The literature sample of SNe Ia-CSM shows an association with 91T-like SNe Ia. Our experiment does not support that this association can be attributed to a luminosity bias (91T-like being brighter than normal events). We therefore conclude that this association has real physical origins and we propose that 91T-like explosions result from single degenerate progenitors that are responsible for the CSM. Despite the spectroscopic similarities between SNe Ibc and SNe Ia, the number of misclassifications between these types was very small in our simulation and mostly at low S/N. Combined with the SN luminosity function needed to reproduce the observed SN Ia-CSM luminosities, it is unlikely that SNe Ibc constitute an important contaminant within this sample. We show how Type II spectra transition to IIn and how the H alpha profiles vary with f(v). SNe IIn fainter than M = -17.2 are unable to mask SNe IIP brighter than M = -15. A more advanced simulation, including radiative transfer, shows that our simplified model is a good first order approximation. The spectra obtained are in good agreement with real data.
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| 7. |
- Muthukrishnan, Uma, 1984-, et al.
(författare)
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The exosome membrane localization of histones is independent of DNA and upregulated in response to stress
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Extracellular histones contribute to many acute and chronic diseases but also populate the secretomes of healthy cells and biofluids. However, a secretory pathway for histones has not been described. Here we report that core and linker histones localize to multivesicular bodies and are secreted via exosomes. Histones are tightly associated with the exosome membrane, with N-terminal domains exposed, in a DNA-independent manner. Furthermore, rapid upregulation of exosomal histones occurs following heat stress, accompanied by enhanced vesicle secretion and a shift towards a population of smaller vesicles. Proteomic analyses identified the downregulation of endosomal sorting complex required for transport (ESCRT) complex as a possible mechanism underlying increased histone secretion.We show for the first time that membrane-associated histones are actively secreted from intact cells via the multivesicular body/exosomal pathway. We demonstrate a novel pathway for extracellular histone release that may have a role in both health and disease.
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| 8. |
- Nordin, Joel Z
(författare)
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Purification and biodistribution of extracellular vesicles
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Extracellular vesicles (EVs) are nano-sized vesicles that contain bioactive lipids, RNAs and proteins, which can be transferred to recipient cells. EVs are important for physiological as well as pathological processes, such as coagulation and immune homeostasis, aiding cancer metastasis and spread of infectious diseases. Owing to their relatively small size the purification of EVs is a challenge, hence we have established and optimised workflows consisting of ultrafiltration with subsequent size exclusion liquid chromatography (UFLC)( Paper I) and bind-elute combined with size exclusion (BE-SEC) columns (Paper III) for EV purification. UF-LC allowed for purification of biophysically intact EVs with better yield and purity compared to ultracentrifugation (UC), which is the gold standard purification method in the field. The biodistribution of UF-LC EVs was different compared to vesicles isolated using UC, despite having highly similar protein composition according to proteomics analysis. We found that UF-LC vesicles accumulated less in lung, possibly owing to their higher integrity. Indeed, fluorescence correlation spectroscopy and transmission electron microscopy indicated that the high gravitational forces in UC lead to aggregation and disruption of the vesicles. The BE-SEC method is a similar method to UF-LC, however protein impurities less than 700 kDa in size are bound in the interior of the beads, thus improving simple size-based exclusion. The BE-SEC method is scalable, produces samples with better purity than UC, displaying yields exceeding 70% and demonstrates a good reproducibility between samples. Moreover, vesicles purified by BE-SEC display the same EV surface markers as UC purified EVs, and CD63-eGFP positive vesicles are taken up in recipient cells to the same extent. In summary, the BE-SEC method is a reproducible and fast alternative to UF-LC for large media volumes. Reliable purification methods are important for the implementation of therapeutically active EVs, however knowledge regarding their eventual organotropism and biodistribution is equally important. Thus, in article II we evaluated the biodistribution of EVs specifically labeled with a near-infrared dye. The main sites of accumulation of exogenously injected EVs were liver, spleen and lungs. Biodistribution profile of EVs depended strongly on injection route, and to certain extent, on EV cell type source, as dendritic cell derived EVs exhibited a more pronounced uptake in spleen compared to the other cell sources tested. We further showed that small alterations of EV surface proteins could significantly affect biodistribution as well, since EVs equipped with a brain targeting peptide on their surface increased the uptake of targeted EVs in brain. This study highlights that the biodistribution of EVs follows other nano-sized particles with uptake mainly in liver. Administration route, cell source and a targeting peptide influence the distribution, however the overall distribution is unaltered with the highest signal originating from liver. To summarise, this thesis has resulted in improvements of the EV field by systematically enhancing EV isolation workflows to achieve greater sample purity and at the same time preserving EV biophysical characteristics. Furthermore, it has laid groundwork for studying in vivo effects of exogenous vesicles. Both these aspects are particularly important for understanding EV biology more clearly and with increased detail.
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| 9. |
- Nordin, Joel Z., et al.
(författare)
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Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties
- 2015
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Ingår i: Nanomedicine. - : Elsevier BV. - 1549-9634 .- 1549-9642. ; 11:4, s. 879-883
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) are natural nanoparticles that mediate intercellular transfer of RNA and proteins and are of great medical interest; serving as novel biomarkers and potential therapeutic agents. However, there is little consensus on the most appropriate method to isolate high-yield and high-purity EVs from various biological fluids. Here, we describe a systematic comparison between two protocols for EV purification: ultrafiltration with subsequent liquid chromatography (UF-LC) and differential ultracentrifugation (UC). A significantly higher EV yield resulted from UF-LC as compared to UC, without affecting vesicle protein composition. Importantly, we provide novel evidence that, in contrast to UC-purified EVs, the biophysical properties of UF-LC-purified EVs are preserved, leading toadifferent in vivo biodistribution, with less accumulation in lungs. Finally, we show that UF-LC is scalable and adaptable for EV isolation from complex media types such as stem cell media, which is of huge significance for future clinical applications involving EVs.
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| 10. |
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| 11. |
- Sarlus, Zimer, 1984-, et al.
(författare)
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Character and tectonic setting of plutonic rocks in the Gällivare area, northern Norrbotten, Sweden
- 2019
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Ingår i: GFF. - : Taylor & Francis. - 1103-5897 .- 2000-0863. ; 141:1, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- Petrographical and lithogeochemical investigations in combination with mapping in the Gällivare area, northern Norrbotten, Sweden, have led to the identification of several igneous intrusive rock types. These include: (1) ultramafic-mafic complexes, (2) mafic-intermediate rocks, (3) dolerites and (4) felsic plutons. The ultramafic-mafic rocks include the ca. 1.88 Ga Dundret complex and ca. 1.80 Ga Vassaravaara complex. The Dundret complex has tholeiitic to calc-alkaline affinity, shows a primitive mineral content and was formed in an extensional tectonic setting. The Vassaravaara complex has a similar chemical signature as the Dundret complex. The mafic-intermediate plutons vary in composition from gabbro to diorite. The chemical signature of the dioritic rocks indicate formation in a volcanic arc setting. Dolerites occur as solitary dikes and have calc-alkaline affinity. The felsic plutons include granite and syenite of ca. 1.88, 1.80 and 1.78 Ga age. The felsic plutons have calc-alkaline to shoshonitic affinity and mostly show a metaluminous I-type character. Results indicate subduction at 1.90 Ga resulting in a volcanic arc system, and including extensional events generating back-arc environments leading to mafic, intermediate and felsic magmatism in the Gällivare area. Subduction at 1.80 Ga is suggested to have caused a similar process generating mafic and felsic magmatic rocks in the same area. A subsequent collision event finally generated 1.78 Ga granitic rocks.
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| 12. |
- Sarlus, Zimer, et al.
(författare)
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Geochemistry of Ultramafic-Mafic Units Related to Fe-, Cu-, and Au Deposits in the Gallivare Region, Northern Norrbotten, Sweden
- 2015
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Ingår i: Mineral Resources in a Sustainable World. - 9782855550664 ; , s. 1123-1126
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Konferensbidrag (refereegranskat)abstract
- Geochemical investigations were carried out in the Gallivare area as a part of a larger project aiming to understand the crustal architecture of the region in 3D. Major igneous suites such as the Dundret and Vassaravaara intrusions with additional smaller mafic intrusions have been identified as key localities and investigated. Results indicate two distinct rock units. The first suite is assigned to ultramafic-mafic layered intrusions with a calc-alkaline to a more tholeiitic composition belonging to the Dundret and Vassaravaara intrusions. The second suite is mainly of mafic to intermediate composition with a clear ophitic texture. This paper investigate the source and origin of the key rock suites, playing a major role on the evolution of the Gallivare region, a region which is characterized by porphyry Cu, IOCG, and Al0 deposits including some of Europe's top producing Fe and Cu-Au-Ag (-Mo) mines.
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| 13. |
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| 14. |
- Sarlus, Zmar, et al.
(författare)
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Timing of plutonism in the Gällivare area : mplications for Proterozoic crustal development in the northern Norrbotten ore district, Sweden
- 2018
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Ingår i: Geological Magazine. - : Cambridge University Press. - 0016-7568 .- 1469-5081. ; 155:6, s. 1351-1376
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Tidskriftsartikel (refereegranskat)abstract
- Zircon ion probe (secondary-ion mass spectrometry or SIMS) data from a set of intrusive rocks emplaced in the vicinity of major ore bodies, as well as from large igneous intrusions in the Gällivare area, gave the following results: (1) the Dundret ultramafic–mafic layered complex (1883±5 Ma), the Aitik granite (1883±5 Ma), the Nautanen diorite (1870±12 Ma), the Vassaravaara ultramafic–mafic layered complex (1798±4 Ma), the Aitik dolerite (1813±9 Ma), the Bergmästergruvan and Sikträsk syenites (1795±4 Ma and 1801±3 Ma, respectively) and the Naalojärvi granite (1782±5 Ma). These data broadly fall within the ranges 1.89–1.87 Ga (early Svecofennian) and 1.80–1.78 Ga (late Svecofennian), but geochronologically allow further subdivision into pulses at 1885–1880, 1875–1870, 1800 and 1780 Ma. During these events, large layered ultramafic–mafic and felsic plutonic rocks were generated with distinct overlap in time suggesting coeval felsic–mafic magmatism. Results also indicate the presence of inherited c. 1.87 Ga zircon crystals in the plutonic rocks at 1.78 Ga, supporting reworking of the previous crust. These data indicate the importance of mantle-derived mafic underplating in the process of crustal magma generation in the region. The c. 1.88 Ga event that generated ultramafic–mafic layered complexes is tentatively suggested to have played an important role in the formation of the Aitik Cu–Au porphyry system. The later event at c. 1.80 Ga, generating voluminous mafic–felsic units, is suggested to be coupled to the regional iron-oxide-copper-gold (IOCG) overprint.
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| 15. |
- Simonson, Oscar E., et al.
(författare)
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In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome
- 2015
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Ingår i: Stem Cells Translational Medicine. - : Oxford University Press (OUP). - 2157-6564 .- 2157-6580. ; 4:10, s. 1199-1213
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions. Both patients received 2 x 10(6) cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar-capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti-inflammatory capacity, including suppression of T-cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1199-1213
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| 16. |
- Sork, Helena, et al.
(författare)
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Heterogeneity and interplay of the extracellular vesicle small RNA transcriptome and proteome
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) mediate cell-to-cell communication by delivering or displaying macromolecules to their recipient cells. While certain broad-spectrum EV effects reflect their protein cargo composition, others have been attributed to individual EV-loaded molecules such as specific miRNAs. In this work, we have investigated the contents of vesicular cargo using small RNA sequencing of cells and EVs from HEK293T, RD4, C2C12, Neuro2a and C17.2. The majority of RNA content in EVs (49-96%) corresponded to rRNA-, coding-and tRNA fragments, corroborating with our proteomic analysis of HEK293T and C2C12 EVs which showed an enrichment of ribosome and translation-related proteins. On the other hand, the overall proportion of vesicular small RNA was relatively low and variable (2-39%) and mostly comprised of miRNAs and sequences mapping to piRNA loci. Importantly, this is one of the few studies, which systematically links vesicular RNA and protein cargo of vesicles. Our data is particularly useful for future work in unravelling the biological mechanisms underlying vesicular RNA and protein sorting and serves as an important guide in developing EVs as carriers for RNA therapeutics.
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| 17. |
- Sork, Helena, et al.
(författare)
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Lipid-based Transfection Reagents Exhibit Cryo-induced Increase in Transfection Efficiency
- 2016
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Ingår i: Molecular Therapy Nucleic Acids. - : Elsevier BV. - 2162-2531. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- The advantages of lipid-based transfection reagents have permitted their widespread use in molecular biology and gene therapy. This study outlines the effect of cryo-manipulation of a cationic lipid-based formulation, Lipofectamine 2000, which, after being frozen and thawed, showed orders of magnitude higher plasmid delivery efficiency throughout eight different cell lines, without compromising cell viability. Increased transfection efficiency with the freeze-thawed reagent was also seen with 2'-O-methyl phosphorothioate oligonucleotide delivery and in a splice-correction assay. Most importantly, a log-scale improvement in gene delivery using the freeze-thawed reagent was seen in vivo. Using three different methods, we detected considerable differences in the polydispersity of the different nucleic acid complexes as well as observed a clear difference in their surface spreading and sedimentation, with the freeze-thawed ones displaying substantially higher rate of dispersion and deposition on the glass surface. This hitherto overlooked elevated potency of the freeze-thawed reagent facilitates the targeting of hard-to-transfect cells, accomplishes higher transfection rates, and decreases the overall amount of reagent needed for delivery. Additionally, as we also saw a slight increase in plasmid delivery using other freeze-thawed transfection reagents, we postulate that freeze-thawing might prove to be useful for an even wider variety of transfection reagents.
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| 18. |
- Sork, Helena, et al.
(författare)
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Profiling of Extracellular Small RNAs Highlights a Strong Bias towards Non-Vesicular Secretion
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular environment consists of a plethora of molecules, including extracellular miRNA that can be secreted in association with extracellular vesicles (EVs) or soluble protein complexes (non-EVs). Yet, interest in therapeutic short RNA carriers lies mainly in EVs, the vehicles conveying the great majority of the biological activity. Here, by overexpressing miRNA and shRNA sequences in parent cells and using size exclusion liquid chromatography (SEC) to separate the secretome into EV and non-EV fractions, we saw that >98% of overexpressed miRNA was secreted within the non-EV fraction. Furthermore, small RNA sequencing studies of native miRNA transcripts revealed that although the abundance of miRNAs in EVs, non-EVs and parent cells correlated well (R-2 = 0.69-0.87), quantitatively an outstanding 96.2-99.9% of total miRNA was secreted in the non-EV fraction. Nevertheless, though EVs contained only a fraction of secreted miRNAs, these molecules were stable at 37 degrees C in a serum-containing environment, indicating that if sufficient miRNA loading is achieved, EVs can remain delivery-competent for a prolonged period of time. This study suggests that the passive endogenous EV loading strategy might be a relatively wasteful way of loading miRNA to EVs, and active miRNA loading approaches are needed for developing advanced EV miRNA therapies in the future.
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