Comparison of clinical and neuroimaging features between NOTCH3 mutations and nongenetic spontaneous intracerebral haemorrhage.

BACKGROUND AND PURPOSE: The NOTCH3 mutation is a common cause of hereditary cerebral small vessel disease (CSVD) and may be a cause of spontaneous intracerebral haemorrhage (ICH). The aim was to investigate the clinical/imaging features for identifying the NOTCH3-mutation-related ICH. METHODS: The study was based on a cohort of 749 CSVD patients in Taiwan who received next-generation sequencing of CSVD genes including NOTCH3. Patients with a history of ICH (n = 206) were included for analysis. The CSVD neuroimaging markers were compared between the patients with NOTCH3 and those without known genetic mutations. RESULTS: After excluding patients with other causes of ICH (structural lesions, systemic/medication related or amyloid angiopathy) and those without neuroimaging, 45 NOTCH3 mutation patients and 109 nongenetic ICH patients were included. The NOTCH3 mutation patients were more likely to have thalamic haemorrhage, a family history of stroke and more severe CSVD neuroimaging markers. A five-point NOTCH3-ICH score was constructed and consisted of a history of stroke in siblings, thalamic haemorrhage, any deep nuclei lacunae, any hippocampal cerebral microbleed (CMB) and a thalamic CMB >5 (one point for each). A score ≥2 had a sensitivity of 88.9% and a specificity of 64.2% in identifying the NOTCH3 mutation. The NOTCH3 mutation patients had a higher risk of recurrent stroke (9.1 vs. 4.5 per 100 person-years, log-rank p = 0.03) during follow-up. CONCLUSION: The patients with NOTCH3-mutation-related ICH had a higher burden of CMBs in the hippocampus/thalamus and a higher recurrent stroke risk. The NOTCH3-ICH score may assist in identifying genetic causes of ICH.

Mechanism of a novel missense mutation, p.V174M, of the human connexin31 (GJB3) in causing nonsyndromic hearing loss.

Hearing loss is the most common sensory disorder, worldwide. In a recent study, we have identified a missense mutation, p.V174M, in the connexin 31 encoded by the GJB3 gene, in a patient with nonsyndromic hearing loss. However, the functional change in the CX31V174M mutant remains unknown. This study compared the intracellular distribution and assembly of the mutant CX31V174M with that of the wild-type (WT) CX31 in HeLa cells, and it examined the effect that the mutant protein had on those cells. A fluorescent localization assay of WT CX31 showed the typical punctuate pattern of a gap junction channel between the neighboring expression cells. Conversely, the p.V174M missense mutation resulted in the accumulation of the mutant protein in the lysosomes rather than in the cytoplasmic membrane. Moreover, dye transfer experiments have also demonstrated that the CX31V174M mutant did not form functional gap junction channels, probably due to the incorrect assembly or the altered properties of the CX31 channels. In addition, we found that CX31V174M-transfection can cause cell death by MTT assay. CX31V174M co-expressed with either CX31WT or CX26WT studies, suggested the impairment of the ability of CX26WT proteins to intracellular trafficking and targeting to the plasma membrane, but did not influence the trafficking of CX31WT. Based on these findings, we suggest that the CX31V174M mutant may have an effect on the formation and function of the gap junction, and CX31V174M has a trans-dominant negative effect on the function of wild types CX26. These results provide a novel molecular explanation for the role that GJB3 plays in hearing loss.

Revealing the Cooperative Relationship between Spin, Energy, and Polarization Parameters toward Developing High-Efficiency Exciplex Light-Emitting Diodes.

Experimental studies to reveal the cooperative relationship between spin, energy, and polarization through intermolecular charge-transfer dipoles to harvest nonradiative triplets into radiative singlets in exciplex light-emitting diodes are reported. Magneto-photoluminescence studies reveal that the triplet-to-singlet conversion in exciplexes involves an artificially generated spin-orbital coupling (SOC). The photoinduced electron parametric resonance measurements indicate that the intermolecular charge-transfer occurs with forming electric dipoles (D+• →A-• ), providing the ionic polarization to generate SOC in exciplexes. By having different singlet-triplet energy differences (ΔEST ) in 9,9'-diphenyl-9H,9'H-3,3'-bicarbazole (BCzPh):3',3'″,3'″″-(1,3,5-triazine-2,4,6-triyl)tris(([1,1'-biphenyl]-3-carbonitrile)) (CN-T2T) (ΔEST = 30 meV) and BCzPh:bis-4,6-(3,5-di-3-pyridylphenyl)-2-methyl-pyrimidine (B3PYMPM) (ΔEST = 130 meV) exciplexes, the SOC generated by the intermolecular charge-transfer states shows large and small values (reflected by different internal magnetic parameters: 274 vs 17 mT) with high and low external quantum efficiency maximum, EQEmax (21.05% vs 4.89%), respectively. To further explore the cooperative relationship of spin, energy, and polarization parameters, different photoluminescence wavelengths are selected to concurrently change SOC, ΔEST , and polarization while monitoring delayed fluorescence. When the electron clouds become more deformed at a longer emitting wavelength due to reduced dipole (D+• →A-• ) size, enhanced SOC, increased orbital polarization, and decreased ΔEST can simultaneously occur to cooperatively operate the triplet-to-singlet conversion.