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- Helbig, K. L., et al.
(författare)
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De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
- 2018
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 666-678
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Tidskriftsartikel (refereegranskat)abstract
- Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha(1)-subunit of the voltage-gated Ca(V)2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca(V)2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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- Arnesen, H., et al.
(författare)
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Microbial experience through housing in a farmyard-type environment alters intestinal barrier properties in mouse colons
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- To close the gap between ultra-hygienic research mouse models and the much more environmentally exposed conditions of humans, we have established a system where laboratory mice are raised under a full set of environmental factors present in a naturalistic, farmyard-type habitat-a process we have called feralization. In previous studies we have shown that feralized (Fer) mice were protected against colorectal cancer when compared to conventionally reared laboratory mice (Lab). However, the protective mechanisms remain to be elucidated. Disruption of the protective intestinal barrier is an acknowledged player in colorectal carcinogenesis, and in the current study we assessed colonic mucosal barrier properties in healthy, feralized C57BL/6JRj male mice. While we found no effect of feralization on mucus layer properties, higher expression of genes encoding the mucus components Fcgbp and Clca1 still suggested mucus enforcement due to feralization. Genes encoding other proteins known to be involved in bacterial defense (Itln1, Ang1, Retnlb) and inflammatory mechanisms (Zbp1, Gsdmc2) were also higher expressed in feralized mice, further suggesting that the Fer mice have an altered intestinal mucosal barrier. These findings demonstrate that microbial experience conferred by housing in a farmyard-type environment alters the intestinal barrier properties in mice possibly leading to a more robust protection against disease. Future studies to unravel regulatory roles of feralization on intestinal barrier should aim to conduct proteomic analyses and in vivo performance of the feralized mice intestinal barrier.
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- Schätzle, M, et al.
(författare)
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The influence of margins of restorations of the periodontal tissues over 26 years
- 2001
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Ingår i: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 28:1, s. 57-64
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The purpose of this investigation was to examine the long-term relationship between dental restorations and periodontal health.MATERIAL AND METHODS: The data derived from a 26-year longitudinal study of a group of Scandinavian middle-class males characterized by good to moderate oral hygiene and regular dental check-ups. At each of 7 examinations between 1969 and 1995, the mesial and buccal surfaces were scored for dental, restorative and periodontal parameters. The mesial sites of premolars and molars of 160 participants were observed during 26 years (1969-1995). A control group with 615 sound surfaces or filling margins located more than 1 mm from the gingival margin in all 7 surveys was compared with a test cohort with 98 surfaces which were sound or had filling margins located more than 1 mm from the gingival margin at baseline (1969) and had a subgingival filling margin 2 years after (1971).RESULTS AND CONCLUSIONS: The study confirmed the long held concept that restorations placed below the gingival margin are detrimental to gingival and periodontal health. In addition, this study suggests that the increased loss of attachment found in teeth with subgingival restorations started slowly and could be detected clinically 1 to 3 years after the fabrication and placement of the restorations. A subsequent "burn-out" effect was suggested.
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- Paolini, Lucia, et al.
(författare)
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Large-scale production of extracellular vesicles: Report on the “massivEVs” ISEV workshop
- 2022
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Ingår i: Journal of Extracellular Biology. - : Wiley. - 2768-2811. ; 1:10
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) large-scale production is a crucial point for the translation of EVs from discovery to application of EV-based products. In October 2021, the International Society for Extracellular Vesicles (ISEV), along with support by the FET-OPEN projects, “The Extracellular Vesicle Foundry” (evFOUNDRY) and “Extracellular vesicles from a natural source for tailor-made nanomaterials” (VES4US), organized a workshop entitled “massivEVs” to discuss the potential challenges for translation of EV-based products. This report gives an overview of the topics discussed during “massivEVs”, the most important points raised, and the points of consensus reached after discussion among academia and industry representatives. Overall, the review of the existing EV manufacturing, upscaling challenges and directions for their resolution highlighted in the workshop painted an optimistic future for the expanding EV field.
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