Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy.

Somatic mosaicism in a fraction of brain cells causes neurodevelopmental disorders, including childhood intractable epilepsy. However, the threshold for somatic mosaicism leading to brain dysfunction is unknown. In this study, we induced various mosaic burdens in focal cortical dysplasia type II (FCD II) mice, featuring mTOR somatic mosaicism and spontaneous behavioral seizures. The mosaic burdens ranged from approximately 1,000 to 40,000 neurons expressing the mTOR mutant in the somatosensory (SSC) or medial prefrontal (PFC) cortex. Surprisingly, approximately 8,000 to 9,000 neurons expressing the MTOR mutant, which are extrapolated to constitute 0.08-0.09% of total cells or roughly 0.04% of variant allele frequency (VAF) in the mouse hemicortex, were sufficient to trigger epileptic seizures. The mutational burden was correlated with seizure frequency and onset, with a higher tendency for electrographic inter-ictal spikes and beta- and gamma-frequency oscillations in FCD II mice exceeding the threshold. Moreover, mutation-negative FCD II patients in deep sequencing of their bulky brain tissues revealed somatic mosaicism of the mTOR pathway genes as low as 0.07% in resected brain tissues through ultra-deep targeted sequencing (up to 20 million reads). Thus, our study suggests that extremely low levels of somatic mosaicism can contribute to brain dysfunction.

Methylsulfonylmethane promotes melanogenesis via activation of JNK in Mel-Ab cells.

OBJECTIVE: Methylsulfonylmethane (MSM), which contains organic sulphur, has been used for a long time as a medicinal ingredient because of its benefits to human health. MSM is reported to be protective against certain skin disorders, but it is unknown whether it affects melanin synthesis. Therefore, in our current research, we examined the possibility of MSM controlling the production of melanin in Mel-Ab melanocytes. METHODS: In Mel-Ab cells, melanin contents and tyrosinase activities were assessed and quantified. The expression of microphthalmia-associated transcription factor (MITF) and tyrosinase was evaluated using western blot analysis, while MSM-induced signalling pathways were investigated. RESULTS: The MSM treatment significantly resulted in a dose-dependent increase in melanin production. Furthermore, MSM elevated melanin-related proteins, including MITF and tyrosinase. However, the rate-limiting enzyme of melanin production, tyrosinase, was not directly influenced by it. Therefore, we investigated potential melanogenesis-related signalling pathways that may have been triggered by MSM. Our findings showed that MSM did not influence the signalling pathways associated with glycogen synthase kinase 3ß, cAMP response-element binding protein, extracellular signal-regulated kinase, or p38 mitogen-activated protein kinase. However, MSM phosphorylated c-Jun N-terminal kinases/stress-activated protein kinase (JNK/SAPK), which is known to induce melanogenesis. SP600125, a specific JNK inhibitor, inhibited MSM-induced melanogenesis. CONCLUSION: Taken together, our study indicates that MSM induces melanin synthesis and may serve as a therapeutic option for hypopigmentary skin disorders such as vitiligo.

Successful repigmentation of hypopigmented scars with micropunch grafting with a skin-seeding technique.

Hypopigmented scars are challenging to treat, and the focus for successful treatment is to cause pigment cells to produce more melanin. In this study, we evaluated the repigmentation effects of 0.4 mm motorized-micropunch grafting with skin-seeding for hypopigmented scars. Twenty-one patients with hypopigmented scars on the face and neck that had been resistant to conventional treatment and who had finally undergone micropunch grafting with a skin-seeding technique (SST) were retrospectively reviewed. Repigmentation outcomes were evaluated with global assessment by a physician using a 4-point repigmentation scale. Adverse events were noted. The subjects were followed for a 2-year follow-up period post grafting. All 21 subjects exhibited excellent to complete repigmentation of more than 75% of the hypopigmented scars. More than 90% repigmentation was observed in 17 patients. The mean duration for repigmentation that the subjects were satisfied with was 5.5 months. No adverse effects or recurrence instances were observed. Motorized micropunch grafting is an effective and promising alternative treatment for repigmentation of hypopigmented scars.

The Effects of a Gate Bias Condition on 1.2 kV SiC MOSFETs during Irradiating Gamma-Radiation.

We investigated the effects of gate bias regarding the degradation of electrical characteristics during gamma irradiation. Moreover, we observed the punch through failure of 1.2 kV rated commercial Silicon Carbide (SiC) Metal Oxide Semiconductor Field Effect Transistors (MOSFETs) due to the influence of gate bias. In addition, the threshold voltage (VT) and on-resistance (Ron) of the SiC MOSFETs decreased significantly by the influence of gate bias during gamma irradiation. We extracted the concentration of carriers and fixed charge (QF) in oxide using N-type SiC MOS capacitors and Transmission Line Measurement (TLM) patterns to analyze the effects of gamma irradiation. The Total Ionizing Dose (TID) effect caused by high-energy gamma-ray irradiation resulted in an increase in the concentration of holes and QF in both SiC and oxide. To analyze the phenomenon for increment of hole concentration in the device under gate bias, we extracted the subthreshold swing of SiC MOSFETs and verified the origin of TID effects accelerated by the gate bias. The QF and doping concentration of p-well values extracted from the experiments were used in TCAD simulations (version 2022.03) of the planar SiC MOSFET. As a result of analyzing the energy band diagram at the channel region of 1.2 kV SiC MOSFETs, it was verified that punch-through can occur in 1.2 kV SiC MOSFETs when the gate bias is applied, as the TID effect is accelerated by the gate bias.

Comprehensive multiomics analysis reveals distinct differences between pediatric choroid plexus papilloma and carcinoma.

Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level.