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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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- Elvsashagen, T, et al.
(författare)
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The genetic architecture of human brainstem structures and their involvement in common brain disorders
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4016-
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Tidskriftsartikel (refereegranskat)abstract
- Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.
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- Streubel, K., et al.
(författare)
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Novel technologies for 1.55-mu m vertical cavity lasers
- 2000
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Ingår i: Optical Engineering. - : SPIE-Intl Soc Optical Eng. - 0091-3286 .- 1560-2303. ; 39:2, s. 488-497
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Tidskriftsartikel (refereegranskat)abstract
- We report on three novel vertical-cavity laser (VCL) structures for 1.55-mu m operation. Two of the structures utilize an n-type GalnAsP/InP Bragg mirror combined with an Al(Ga)As/GaAs mirror using either wafer fusion or metamorphic epitaxial growth. The third employs two wafer-fused AlGaAs/GaAs mirrors, in which lateral current confinement is obtained by localized fusion of the p mirror. Ali three VCLs use strained GalnAsP quantum welts as active material and achieve continuous-wave (cw) operation at room temperature or above. The single fused VCL operates up to 17 and 101 degrees C in continuous-wave and pulsed mode, respectively. The monolithic VCL-structure with a metamorphic GaAs/AlAs n-type mirror uses a reverse-biased tunnel junction for current injection. This laser achieves record high output power (1 mW) at room temperature and operates cw up to 45 degrees C. The double fused VCLs with a 10x10-mu m(2) active area operate cw up to 30 degrees C with threshold current as low as 2.5 mA and series resistance of 30 Omega. The emission spectra exhibit a single lasing mode polarized with 30-dB extinction ratio and a spectral linewidth of 150 MHz.
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