Six mutations in the salt-inducible kinase 1 (SIK1) have been identified in developmental and epileptic encephalopathy (DEE-30) patients, and two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. In a previous study, we generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing and found an increase in excitatory synaptic transmission and enhancement of neural excitability in neocortical neurons in SIK1-MT mice. NMDA was injected into SIK1-MT males to induce epileptic seizures in the mice. The severity of the NMDA-induced seizures was estimated by the latency and the number of tail flickering and hyperflexion. Activated brain regions were evaluated by immunohistochemistry against c-fos, Iba1, and GFAP. As another epilepsy model, pentylenetetrazol was injected into the adult SIK1 mutant mice. Seizure susceptibility induced by both NMDA and PTZ was enhanced in SIK1-MT mice. Brain regions including the thalamus and hypothalamus were strongly activated in NMDA-induced seizures. The epilepsy-associated mutation of SIK1 canceled the pharmacological effects of the ACTH treatment on NMDA-induced seizures. These results suggest that SIK1 may be involved in the neuropathological mechanisms of NMDA-induced spasms and the pharmacological mechanism of ACTH treatment.

Purpose: Microbial communities have emerged as crucial regulators in the initiation and progression of thyroid cancer. However, most studies focus on single microbial sources, and the interplay between microbes across different ecological niches and their impact on thyroid carcinogenesis are largely unknown. Patients and Methods: In this study, we collected tissue, oral, and fecal samples from 32 patients with benign thyroid nodules (BTN) and 32 patients with papillary thyroid carcinoma (PTC). The oral and fecal samples were subjected to 16S rRNA sequencing, while the tissue samples were analyzed using 5R 16S sequencing to comprehensively characterize the microbial communities. Results: Clustering analysis using the Dirichlet Multinomial Mixture model with Laplace approximation identified two distinct oral microbial community types (O_1 and O_2) and three fecal types (F_1, F_2, and F_3). Microbial diversity patterns in thyroid tissues mirrored those observed in oral and fecal samples, suggesting potential microbial translocation or systemic interactions. Inflammatory markers were significantly elevated in PTC patients relative to BTN controls. Notably, the genus Veillonella, a potential anti-tumor biomarker, was significantly reduced in PTC samples across niches. Conclusion: This study highlights the pivotal role of oral and intestinal microbiota in PTC development, emphasizing the interplay between microbial composition, inflammatory processes, and immune regulation in tumor progression. The discovery of Veillonella as a potential anti-tumor microbe, along with evidence of microbial translocation, opens new possibilities for targeted therapeutic strategies.