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- Hirsch, S. D., et al.
(författare)
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The role of CDHR3 in susceptibility to otitis media
- 2021
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Ingår i: Journal of Molecular Medicine. - : Springer Nature. - 0946-2716 .- 1432-1440. ; 99:11, s. 1571-1583
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. Key messages: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.
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| 3. |
- Samoc, Marek, et al.
(författare)
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Nonlinear absorption and nonlinear refraction: Maximizing the merit factors
- 2012
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 0277-786X .- 1996-756X. - 9780819489012 ; 8258, s. Art. no. 82580V-
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Konferensbidrag (refereegranskat)abstract
- Both nonlinear absorption and nonlinear refraction are effects that are potentially useful for a plethora of applications in photonics, nanophotonics and biophotonics. Despite substantial attention given to these phenomena by researchers studying the merits of disparate systems such as organic materials, hybrid materials, metal-containing molecules and nanostructures, it is virtually impossible to compare the results obtained on different materials when varying parameters of the light beams and different techniques are employed. We have attempted to address the problem by studying the properties of various systems in a systematic way, within a wide range of wavelengths, and including the regions of onephoton, two-photon and three-photon absorption. The objects of our studies have been typical nonlinear chromophores, such as π-conjugated molecules, oligomers and polymers, organometallics and coordination complexes containing transition metals, organometallic dendrimers, small metal-containing clusters, and nanoparticles of various kinds, including semiconductor quantum dots, plasmonic particles and rare-earth doped nanocrystals. We discuss herein procedures to quantify the nonlinear response of all of these systems, by defining and comparing the merit factors relevant for various applications.
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| 4. |
- Bootpetch, TC, et al.
(författare)
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Multi-omic studies on missense PLG variants in families with otitis media
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 15035-
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Tidskriftsartikel (refereegranskat)abstract
- Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.
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| 5. |
- Frank, DN, et al.
(författare)
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Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants
- 2021
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Ingår i: Journal of medical genetics. - : BMJ. - 1468-6244 .- 0022-2593. ; 58:7, s. 442-452
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Tidskriftsartikel (refereegranskat)abstract
- Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility.MethodsWe performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues.ResultsA large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma.ConclusionSPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.
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| 6. |
- Szeremeta, Janis, et al.
(författare)
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Low mRNA expression and activity of monoacylglycerol lipase in human SH-SY5Y neuroblastoma cells
- 2019
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Ingår i: Prostaglandins & other lipid mediators. - : Elsevier. - 1098-8823 .- 2212-196X. ; 142, s. 59-67
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Tidskriftsartikel (refereegranskat)abstract
- Relatively little is known about the endocannabinoid system in human neuroblastoma cell lines. In the present study, we have investigated the expression of the genes coding for the enzymes involved in the synthesis and catabolism of endocannabinoids in the SH-SY5Y cell line. The expression of MGLL, the gene coding for the 2-arachidonoylglycerol hydrolytic enzyme monoacylglycerol lipase (MAGL), was found to be 85 and 340 fold lower than the expression levels for the genes coding for alpha/beta-hydrolase domain containing 6 and 12 (ABHD6, ABHD12), which are alternative hydrolytic enzymes for this endocannabinoid. In comparison, mRNA levels of MGLL were 1.5 fold higher than ABHD6 and 2 fold lower than the levels of ABHD12 in DU-145 human prostate cells. In functional assays, the hydrolysis of the 2-arachidonoylglycerol homologue 2-oleoylglycerol by intact SH-SY5Y cells was partially inhibited by the ABHD6 inhibitor WWL70, but not by the MAGL inhibitor JZL184, whereas the reverse was true in DU-145 cells. The combination of JZL184 + WWL70 did, however produce a significantly greater inhibition of 2-OG hydrolysis than seen with WWL70 alone in the SH-SY5Y cells. The low MGLL expression in the SH-SY5Y cells was not due to epigenetic silencing, since levels were not affected by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine and/or the histone acetylase inhibitor trichostatin A. The low MGLL expression in SH-SY5Y cells should be taken into account when using these cells in experiments investigating the involvement of the endocannabinoid system in models of physiological and pathological processes.
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