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Choline metabolite trimethylamine N-oxide (TMAO) has been recognized as a risk factor of gestational diabetes mellitus (GDM), but its exact role in GDM has not been reported. In this study, we focused on the placenta development to reveal the role of TMAO in GDM. We found that the TMAO levels in peripheral and cord plasma were increased in women with GDM and that TMAO levels were positively correlated with newborn weight and placental thickness. Neutrophil extracellular traps (NETs) in the peripheral and cord plasma and the myeloperoxidase expression in the placenta of women with GDM also increased. NETs could inhibit the proliferation, migration, invasion, and angiogenesis of HTR-8/Svneo cells. However, TMAO not only could inhibit the formation of NETs but also could enhance the biological function of HTR-8/Svneo cells. With induction of GDM in NETs-deficient PAD4-/- and wild-type mice, the placental weight of PAD4-/- mice increased significantly. TMAO feeding also inhibited the formation of NETs and further increased the weight of the placenta and fetuses, and this increase did not affect the placental structure. Our data indicate that higher TMAO levels and the formation of abnormal NETs were associated with GDM. TMAO not only could promote the development of the placenta and fetuses but also could inhibit the formation of NETs. [ABSTRACT FROM AUTHOR]

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain-predominantly in the cerebral cortex-and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known. In this study, we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed a favourable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database (gnomAD). Computational modelling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiological recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results indicate that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favourable outcome under anti-epileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition. [ABSTRACT FROM AUTHOR]