congenital hypothyroidism (cH) is the most common neonatal endocrine disorder with a genetic origin. The purpose of the present study was to analyze the mutation spectrum of cH patients in china. a targeted next-generation sequencing panel covering all exons of 29 cH-related causative genes was used in 43 Han chinese patients with cH [11 dysgenesis and 32 glands in situ (GiS)]. The functional impact and pathogenicity of detected variants were analyzed using a comprehensive bioinformatics approach and co-segregation studies. a total of 47 rare non-polymorphic variants in 9 target genes associated with thyroid hormone synthesis (DUOX2, DUOXA2, TPO, TG, SLC26A4 and SLC5A5), thyroid stimulating hormone resistance (TSHR) and central hypothyroidism (PROP1 and TRHR) were identified in 31 patients (31/43, 72%). of these variants, 8 were novel, including 3 in DUOX2, 2 in TPO, 3 in TSHR and 1 in SLC5A5. Variants were mostly affected by DUOX2, TG, TPO and TSHR. approximately 44% of the patients (19/43) carried DUOX2 variants. The mutation detection rates in patients with GiS were higher compared with patients with dysgenesis [25/32 (78%) vs. 6/11 (54%)]. oligogenic mutations were detected in 25.6% of the total cases and 35% of the mutated cases. Genetic basis was ascertained in 13 patients, reaching a diagnosis detection rate of 30%. in conclusion, genetic defects in dyshormonogenesis, mainly in DUOX2, were the main genetic cause of cH in the chinese population. oligogenicity is highly involved in cH pathogenesis and may thus be an important factor in common phenotypic variability observed in patients with cH.

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Cerebral glycogen is principally localized in astrocytes rather than in neurons. Glycogen metabolism has been implicated in higher brain functions, including learning and memory, yet the distribution patterns of glycogen in different types of astrocytes have not been fully described. Here, we applied a method based on the incorporation of 2-NBDG, a d-glucose fluorescent derivative that can trace glycogen, to investigate glycogen's distribution in the brain. We identified two types of astrocytes, namely, 2-NBDG I (glycogen-deficient) and 2-NBDG II (glycogen-rich) cells. Whole-cell patch-clamp and fluorescence-activated cell sorting (FACS) were used to separate 2-NBDG II astrocytes from 2-NBDG I astrocytes. The expression levels of glycogen metabolic enzymes were analyzed in 2-NBDG I and 2-NBDG II astrocytes. We found unique glycogen metabolic patterns between 2-NBDG I and 2-NBDG II astrocytes. We also observed that 2-NBDG II astrocytes were mainly identified as fibrous astrocytes but not protoplasmic astrocytes. Our data reveal cell type-dependent glycogen distribution and metabolism patterns, suggesting diverse functions of these different astrocytes.

Brain edema is a grave complication of brain ischemia and is the main cause of herniation and death. Although astrocytic swelling is the main contributor to cytotoxic edema, the molecular mechanism involved in this process remains elusive. N-myc downstream-regulated gene 2 (NDRG2), a well-studied tumor suppressor gene, is mainly expressed in astrocytes in mammalian brains. Here, we found that NDRG2 deficiency leads to worsened cerebral edema, imbalanced Na + transfer, and astrocyte swelling after ischemia. We also found that NDRG2 deletion in astrocytes dramatically changed the expression and distribution of aquaporin-4 and Na +-K +-ATPase β1, which are strongly associated with cell polarity, in the ischemic brain. Brain edema and astrocyte swelling were significantly alleviated by rescuing the expression of astrocytic Na +-K +-ATPase β1 in NDRG2-knockout mouse brains. In addition, the upregulation of astrocytic NDRG2 by lentiviral constructs notably attenuated brain edema, astrocytic swelling, and blood-brain barrier destruction. Our results indicate a particular role of NDRG2 in maintaining astrocytic polarization to facilitate Na + and water transfer balance and to protect the brain from ischemic edema. These findings provide insight into NDRG2 as a therapeutic target in cerebral edema. Hang Guo, Anqi Yin, and Yulong Ma contributed equally to this study.

General anesthesia severely affects the metabolites in the brain. Glycogen, principally stored in astrocytes and providing the short-term delivery of substrates to neurons, has been implicated as an affected molecule. However, whether glycogen plays a pivotal role in modulating anesthesia–arousal remains unclear. Here, we demonstrated that isoflurane-anesthetized mice exhibited dynamic changes in the glycogen levels in various brain regions. Glycogen synthase (GS) and glycogen phosphorylase (GP), key enzymes of glycogen metabolism, showed increased activity after isoflurane exposure. Upon blocking glycogenolysis with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), a GP antagonist, we found a prolonged time of emergence from anesthesia and an enhanced δ frequency in the EEG (electroencephalogram). In addition, augmented expression of glycogenolysis genes in glycogen phosphorylase, brain (Pygb) knock-in (PygbH11/H11) mice resulted in delayed induction of anesthesia, a shortened emergence time, and a lower ratio of EEG-δ. Our findings revealed a role of brain glycogen in regulating anesthesia–arousal, providing a potential target for modulating anesthesia.