| 1. |
- Langefeld, Carl D., et al.
(författare)
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Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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| 2. |
- Kottyan, Leah C., et al.
(författare)
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The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:2, s. 582-596
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Tidskriftsartikel (refereegranskat)abstract
- Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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| 3. |
- Glavaski-Joksimovic, A., et al.
(författare)
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Morphological differentiation of tau–green fluorescent protein embryonic stem cells into neurons after co-culture with auditory brain stem slices
- 2009
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Ingår i: Neuroscience. - : Elsevier. - 0306-4522 .- 1873-7544. ; 162:2, s. 472-481
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Tidskriftsartikel (refereegranskat)abstract
- Most types of congenital and acquired hearing loss are caused by loss of sensory hair cells in the inner ear and their respective afferent neurons. Replacement of spiral ganglion neurons (SGN) would therefore be one prioritized step in an attempt to restore sensory neuronal hearing loss. To initiate an SGN repair paradigm we previously transplanted embryonic neuronal tissue and stem cells (SC) into the inner ear in vivo. The results illustrated good survival of the implant. One such repair, however, would not have any clinical significance unless central connections from the implanted SIGN could be established. For the purpose of evaluating the effects of cell transplantation on cochlear nucleus (CN) neurons we have established organotypic brain stem (BS) cultures containing the CN. At present we have used in vitro techniques to study the survival and differentiation of tau-green fluorescent protein (GFP) mouse embryonic stem cells (MESC) as a mono- or co-culture with BS slices. For the co-culture, 300 mu m thick auditory BS slices encompassing the CN were prepared from postnatal Sprague-Dawley rats. The slices were propagated using the membrane interface method and the CN neurons labeled with Dil. After 5 +/- 2 days in culture a tau-GFP MESC suspension was deposited next to CN in the BS slice. Following deposition the MESC migrated towards the CN. One and two weeks after transplantation the co-cultures were fixed and immunostained with antibodies raised against neuroprogenitor, neuronal, glial and synaptic vesicle protein markers. Our experiments with the tau-GFP MESC and auditory BS co-cultures show a significant MESC survival but also differentiation into neuronal cells. The findings illustrate the significance of SC and auditory BS co-cultures regarding survival, migration, neuronal differentiation and connections.
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| 4. |
- Hu, Zhengqing, et al.
(författare)
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Functional Evaluation of a Cell Replacement Therapy in the Inner Ear
- 2009
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Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 30:4, s. 551-558
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Tidskriftsartikel (refereegranskat)abstract
- HYPOTHESIS:Cell replacement therapy in the inner ear will contribute to the functional recovery of hearing loss.BACKGROUND:Cell replacement therapy is a potentially powerful approach to replace degenerated or severely damaged spiral ganglion neurons. This study aimed at stimulating the neurite outgrowth of the implanted neurons and enhancing the potential therapeutic of inner ear cell implants.METHODS:Chronic electrical stimulation (CES) and exogenous neurotrophic growth factor (NGF) were applied to 46 guinea pigs transplanted with embryonic dorsal root ganglion (DRG) neurons 4 days postdeafening. The animals were evaluated with the electrically evoked auditory brainstem responses (EABRs) at experimental Days 7, 11, 17, 24, and 31. The animals were euthanized at Day 31, and the inner ears were dissected for immunohistochemistry investigation.RESULTS:Implanted DRG cells, identified by enhanced green fluorescent protein fluorescence and a neuronal marker, were found close to Rosenthal canal in the adult inner ear for up to 4 weeks after transplantation. Extensive neurite projections clearly, greater than in nontreated animals, were observed to penetrate the bony modiolus and reach the spiral ganglion region in animals supplied with CES and/or NGF. There was, however, no significant difference in the thresholds of EABRs between DRG-transplanted animals supplied with CES and/or NGF and DRG-transplanted animals without CES or NGF supplement.CONCLUSION:The results suggest that CES and/or NGF can stimulate neurite outgrowth from implanted neurons, although based on EABR measurement, these interventions did not induce functional connections to the central auditory pathway. Additional time or novel approaches may enhance functional responsiveness of implanted cells in the adult cochlea
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| 5. |
- Regala, C., et al.
(författare)
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Xenografted fetal dorsal root ganglion, embryonic stem cell and adult neural stem cell survival following implantation into the adult vestibulocochlear nerve
- 2005
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Ingår i: Experimental Neurology. - : Elsevier. - 0014-4886 .- 1090-2430. ; 193:2, s. 326-333
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Tidskriftsartikel (refereegranskat)abstract
- Sensorineural hearing loss is a disabling condition. In the post-embryonic and adult mammalian inner ear, the regeneration of auditory hair cells, spiral ganglion neurons or their axons does not occur naturally. This decrease in excitable neurons limits the success of auditory rehabilitation.Allografts and xenografts have shown promise in the treatment of a variety of neurological diseases. Fetal dorsal root ganglion (DRG) neurons can extend functional connections in the rat spinal cord. Embryonic stem cells (ES cells) and adult neural stem cells (ANSC) have the potential to differentiate into neurons.We have implanted embryonic days (E) 13–16 fetal mouse DRGs from transgenic mouse lines that express Enhanced Green Fluorescent Protein (EGFP) or lacZ reporter genes, EGFP-expressing ES cells or lacZ-expressing ANSC into the injured vestibulocochlear nerve of adult rats and guinea pigs. Survival of the implants was assessed 2 to 4 weeks postoperatively. For further evaluation of the differentiation of the implanted ES-cells, we double labeled with the mouse-specific neuronal antibody Thy 1.2.The rats implanted with EGFP- or lacZ-expressing DRGs showed labeled DRGs after sacrifice. In addition, EGFP-positive nerve fibers were seen growing within the proximal nerve. The results from the EGFP ES cells and lacZ ANSC revealed reporter-expressing cells at the site of injection in the vestibulocochlear nerve of the host rats and guinea pigs but also within the brain stem. Thy 1.2 profiles were seen among the EGFP ES cells within the 8th cranial nerve.The findings of this study indicate that the vestibulocochlear nerve of adult rats and guinea pigs will support xenotransplants of embryonic DRG, ES cells and ANSC. This may have future clinical applicability in recreating a neuronal conduit following neuronal injury between the inner ear and the central nervous system (CNS).
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| 6. |
- Al-Chalabi, Ammar, et al.
(författare)
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July 2017 ENCALS statement on edaravone
- 2017
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : TAYLOR & FRANCIS LTD. - 2167-8421 .- 2167-9223. ; 18:7-8, s. 471-474
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Tidskriftsartikel (refereegranskat)abstract
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| 7. |
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| 8. |
- Herlenius, E., et al.
(författare)
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Functional stem cell integration assessed by organotypic slice cultures
- 2012
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Ingår i: Current Protocols in Stem Cell Biology. - : John Wiley & Sons. - 1941-7322 .- 1938-8969. ; 1:SUPPL.23
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Tidskriftsartikel (refereegranskat)abstract
- Re-formation or preservation of functional, electrically active neural networks has been proffered as one of the goals of stem cell-mediated neural therapeutics. A primary issue for a cell therapy approach is the formation of functional contacts between the implanted cells and the host tissue. Therefore, it is of fundamental interest to establish protocols that allow us to delineate a detailed time course of grafted stem cell survival, migration, differentiation, integration, and functional interaction with the host. One option for in vitro studies is to examine the integration of exogenous stem cells into an existing active neuronal network in ex vivo organotypic cultures. Organotypic cultures leave the structural integrity essentially intact while still allowing the microenvironment to be carefully controlled. This allows detailed studies over time of cellular responses and cellcell interactions, which are not readily performed in vivo. This unit describes procedures for using organotypic slice cultures as ex vivo model systems for studying neural stem cell and embryonic stem cell engraftment and communication with CNS host tissue.
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| 9. |
- Hu, Z., et al.
(författare)
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NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear
- 2005
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Ingår i: Neurobiology of Disease. - : Elsevier. - 0969-9961 .- 1095-953X. ; 18:1, s. 184-192
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal tissue transplantation is a potential way to replace degenerated spiral ganglion neurons (SGNs) since these cells cannot regenerate in adult mammals. To investigate whether nerve growth factor (NGF) can stimulate neurite outgrowth from implanted neurons, mouse embryonic dorsal root ganglion (DRG) cells expressing enhanced green fluorescent protein (EGFP) were transplanted into the scala tympani of adult rats with a supplement of NGF or artificial perilymph. DRG neurons were observed in the cochlea for up to 6 weeks postoperatively. A significant difference was identified in the number of DRG neurons between the NGF and non-NGF groups. In the NGF group, extensive neurite projections from DRGs were found penetrating the osseous modiolus towards the spiral ganglion. These results suggest the possibility that embryonic neuronal implants may become integrated within the adult auditory nervous system. In combination with a cochlear prosthesis, a neuronal implantation strategy may provide a possibility for further treatment of profoundly deaf patients.
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