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- Massaro, Giulia, et al.
(författare)
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Fetal gene therapy for neurodegenerative disease of infants
- 2018
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 24:9, s. 1317-1323
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Tidskriftsartikel (refereegranskat)abstract
- For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood–brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains.
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- Cervin, Jakob, et al.
(författare)
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GM1 ganglioside-independent intoxication by Cholera toxin
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors via its B subunit (CTB). We have recently shown that in addition to the previously described binding partner ganglioside GM1, CTB binds to fucosylated proteins. Using flow cytometric analysis of primary human jejunal epithelial cells and granulocytes, we now show that CTB binding correlates with expression of the fucosylated Lewis X (LeX) glycan. This binding is competitively blocked by fucosylated oligosaccharides and fucose-binding lectins. CTB binds the LeX glycan in vitro when this moiety is linked to proteins but not to ceramides, and this binding can be blocked by mAb to LeX. Inhibition of glycosphingolipid synthesis or sialylation in GM1-deficient C6 rat glioma cells results in sensitization to CT-mediated intoxication. Finally, CT gavage produces an intact diarrheal response in knockout mice lacking GM1 even after additional reduction of glycosphingolipids. Hence our results show that CT can induce toxicity in the absence of GM1 and support a role for host glycoproteins in CT intoxication. These findings open up new avenues for therapies to block CT action and for design of detoxified enterotoxin-based adjuvants.
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- Valente, André, et al.
(författare)
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A compilation of global bio-optical in situ data for ocean-colour satellite applications - version two
- 2019
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Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3508 .- 1866-3516. ; 11:3, s. 1037-1068
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Tidskriftsartikel (refereegranskat)abstract
- A global compilation of in situ data is useful to evaluate the quality of ocean-colour satellite data records. Here we describe the data compiled for the validation of the ocean-colour products from the ESA Ocean Colour Climate Change Initiative (OC-CCI). The data were acquired from several sources (including, inter alia, MOBY, BOUSSOLE, AERONET-OC, SeaBASS, NOMAD, MERMAID, AMT, ICES, HOT and GeP&CO) and span the period from 1997 to 2018. Observations of the following variables were compiled: spectral remote-sensing reflectances, concentrations of chlorophyll a, spectral inherent optical properties, spectral diffuse attenuation coefficients and total suspended matter. The data were from multi-project archives acquired via open internet services or from individual projects, acquired directly from data providers. Methodologies were implemented for homogenization, quality control and merging of all data. No changes were made to the original data, other than averaging of observations that were close in time and space, elimination of some points after quality control and conversion to a standard format. The final result is a merged table designed for validation of satellite-derived ocean-colour products and available in text format. Metadata of each in situ measurement (original source, cruise or experiment, principal investigator) was propagated throughout the work and made available in the final table. By making the metadata available, provenance is better documented, and it is also possible to analyse each set of data separately. This paper also describes the changes that were made to the compilation in relation to the previous version (Valente et al., 2016). The compiled data are available at https://doi.org/10.1594/PANGAEA.898188 (Valente et al., 2019).
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- Groopman, Emily E., et al.
(författare)
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Diagnostic Utility of Exome Sequencing for Kidney Disease
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 380:2, s. 142-151
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.METHODS We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.RESULTS In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.CONCLUSIONS Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases.
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- Quintana, C., et al.
(författare)
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High Speed Electro-Absorption Modulator for Long Range Retroreflective Free Space Optics
- 2017
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Ingår i: IEEE Photonics Technology Letters. - 1041-1135 .- 1941-0174. ; 29:9, s. 707-710
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Tidskriftsartikel (refereegranskat)abstract
- In this letter, we present the design and implementation of a pixelated electro-absorption modulator-based modulating retroreflector (MRR) for high-speed optical wireless communications. The modulator is based on a multiple quantum well structure embedded in an asymmetric Fabry-Perot cavity. This MRR was used in an outdoor link, operating at 150 Mb/s with a bit error rate (BER) of 1.22 × 10-6 at a range of 200 m. The system was also tested in laboratory-controlled conditions achieving a data rate of 200 Mb/s with a BER of 2 × 10-4. To the best of our knowledge, this is the fastest retroreflective free-space optics demonstration in both the indoor and outdoor environments.
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