Background: Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric condition that may be related to an imbalance of neural transmitters. The gut microbiota is the largest ecosystem in the human body, and the brain-gut axis theory proposes that the gut microbiome can affect brain function in multiple ways. The purpose of this study was to explore the gut microbiota in children with ADHD and assess the possible role of the gut microbiota in disease pathogenesis to open new avenues for ADHD treatment.Methods: A case-control design was used. We enrolled 17 children aged 6-12 years with ADHD who were treated in the Pediatric Outpatient Department of the First Medical Center of the Chinese PLA General Hospital from January to June, 2019. Seventeen children aged 6-12 years were selected as the healthy control (HC) group. Fecal samples of cases and controls were analyzed by shotgun metagenomics sequencing. Alpha diversity and the differences in the relative abundances of bacteria were compared between the two groups. Functional annotations were performed for the microbiota genes and metabolic pathways were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results:There was no significant difference in the alpha diversity of gut microbiota between the ADHD and HC groups. Compared with HCs, Faecalibacterium and Veillonellaceae were significantly reduced in children with ADHD (P < 0.05), Odoribacter and Enterococcus were significantly increased [linear discriminant analysis (LDA) > 2]. At the species level, Faecalibacterium prausnitzii, Lachnospiraceae bacterium, and Ruminococcus gnavus were significantly reduced in the ADHD group (P < 0.05), while Bacteroides caccae, Odoribacter splanchnicus, Paraprevotella xylaniphila, and Veillonella parvula were increased (P < 0.05). Metabolic pathway analysis revealed significant between-group differences in the metabolic pathways of neurotransmitters (e.g., serotonin and dopamine) (P < 0.05). Frontiers in Neuroscience | www.frontiersin.org 1 February 2020 | Volume 14 | Article 127 Wan et al. Gut Microbiota Role in ADHDConclusion: Composition differences of gut microbiota in subjects with ADHD may contribute to brain-gut axis alterations and affect neurotransmitter levels, which could contribute to ADHD symptoms.

Linker histone H1.2 (H1.2), encoded by HIST1H1C (H1C), is a major H1 variant in somatic cells. Among five histone H1 somatic variants, upregulated H1.2 was found in human hepatocellular carcinoma (HCC) samples and in a diethylnitrosamine (DEN)‐induced HCC mouse model. In vitro, H1.2 overexpression accelerated proliferation of HCC cell lines, whereas H1.2 knockdown (KD) had the opposite effect. In vivo, H1.2 insufficiency or deficiency (H1c KD or H1c KO) alleviated inflammatory response and HCC development in DEN‐treated mice. Mechanistically, H1.2 regulated the activation of signal transducer and activator of transcription 3 (STAT3), which in turn positively regulated H1.2 expression by binding to its promoter. Moreover, upregulation of the H1.2/STAT3 axis was observed in human HCC samples, and was confirmed in mouse models of methionine‐choline‐deficient diet induced nonalcoholic steatohepatitis or lipopolysaccharide induced acute inflammatory liver injury. Disrupting this feed‐forward loop by KD of STAT3 or treatment with STAT3 inhibitors rescued H1.2 overexpression‐induced proliferation. Moreover, STAT3 inhibitor treatment‐ameliorated H1.2 overexpression promoted xenograft tumor growth. Therefore, H1.2 plays a novel role in inflammatory response by regulating STAT3 activation in HCC, thus, blockade of the H1.2/STAT3 loop is a potential strategy against HCC.

Background: Infantile spasm (IS) is one of the most common catastrophic epilepsy syndromes in infancy characterized by epileptic spasm. While adrenocorticotropic hormone (ACTH) is the first-line treatment for IS, it is evident that the seizures associated with IS exhibit a clear circadian rhythm; however, the precise mechanisms underlying such seizures remain unclear. Melatonin is an important amine hormone and is regulated by circadian rhythm. Circadian proteins, especially Aryl Hydrocarbon Receptor Nuclear Trasnslocator-like Protein (ARNTL or BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), and their target proteins Period Circadian Regulator 1 (PER1), Period Circadian Regulator 2 (PER2), Cryptochrome 1 (CRY1), and Cryptochrome 2 (CRY2), play key roles in circadian rhythm. This study explored the relationships between melatonin, genes associated with circadian rhythm, and epileptic spasm. Materials and Methods: Eighteen female rats were mated with nine male rats and 16 became pregnant. Twelve pregnant rats were subjected to prenatal stress by forced swimming in cold water from the day of conception. Rat pups produced by stressed mothers received an intraperitoneal injection of N-methyl-D-aspartate (NMDA) on the 13th day after birth and were divided into four groups: NMDA (15 mg/kg), NMDA+ACTH (20 IU/kg), NMDA+melatonin (55 mg/kg), and NMDA+ACTH+melatonin (n = 36/group). Offspring from four dams that were not subjected to prenatal stress were used as controls. We then recorded latency and the frequency of flexion seizures. All offspring were sacrificed on the 14th day after birth and CLOCK, BMAL1, PER1, PER2, CRY1, and CRY2 expression was analyzed by western blotting, immunohistochemistry, and immunofluorescence. Results: NMDA induced spasm-like symptoms in rats. ACTH and melatonin significantly increased seizure latency and significantly reduced the frequency of seizures (P < 0.05). CLOCK, BMAL1, PER1, PER2, CRY1, and CRY2 expression was significantly lower in the NMDA group than the controls (P < 0.05). ACTH significantly increased the expression of CLOCK, BAML1, PER1, and CRY1 (P < 0.05) and melatonin significantly increased the expression of CLOCK, BMAL1, PER1, PER2, CRY1, and CRY2 (P < 0.05) compared with those of the NMDA group. There were no significant differences in the expression of BMAL1, CRY2, PER1, and PER2 when compared between the NMDA+ACTH+melatonin and control groups (P > 0.05). Wan et al. Circadian and Infantile Spasm Conclusion: ACTH and melatonin significantly increased the expression of circadian genes and improved NMDA-induced seizures. The anticonvulsant effects of ACTH and melatonin are likely to involve regulation of the expression of these genes.

Scope DNA methylation contributes to obesity, but the role of the DNA demethylase ten‐eleven translocation protein 1 (Tet1) in obesity remains unclear. Vitamin C is a cofactor for the Tet family of proteins, but whether vitamin C can be used to treat obesity via Tet1 awaits clarification. Methods and Results Tet1+/+ and Tet1+/− mice are fed a high fat diet (HFD). Higher weight gain and more severe hepatic steatosis, accompanied by reduced 5‐hydromethylcytosine (5hmC) levels, are found in the white adipose tissue and liver of Tet1+/− mice. Accumulated lipids are observed in palmitic acid or oleic acid treated primary hepatocytes derived from Tet1+/− mice, which are rescued by Tet1 overexpression or vitamin C treatment. Bisulfite sequencing reveals higher DNA methylation levels on lipolysis related genes in the liver of Tet1+/− mice. Notably, oral intake of vitamin C normalizes DNA methylation levels, promotes lipolysis, and decreases obesity in HFD‐fed Tet1+/− mice. Conclusions The results reveal a novel function of Tet1 in obesity and provide a new mechanism for the beneficial role of vitamin C in metabolic diseases through enhanced Tet1 activity.

The phenotype of nitrogen permease regulator-like 2 (NPRL2) gene-related epilepsy clinically manifests as a range of epilepsy syndromes, including familial focal epilepsy with variable foci (FFEVF), sleep-related hypermotor epilepsy (SHE), temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and infantile spasms (IS). The association between phenotype and genotype of NPRL2 variants has not been widely explored. This study aimed to explore the phenotype and genotype spectrum of NPRL2-related epilepsy. Here, we presented two clinical cases with NPRL2-related epilepsy, and discussed the characteristics, diagnosis, and treatment processes in the context of existing literature. Two novel NPRL2 likely pathogenic variants were identified by next-generation sequencing, including one splicing mutation (c.933-1G&gt;A), and one frameshift mutation (c.257delG). The results of literature review showed that there were a total of 20 patients with NPRL2-related epilepsy whose mutations were mostly missense and hereditary. These findings indicate that the possibility of NPRL2 gene mutations in focal epilepsy should be considered for patients with family history, and that patients carrying different NPRL2 variants have different clinical manifestations. Our study expanded the genotype spectrum of NPRL2 and suggested that the type of NPRL2 variants might provide important information for the prognosis evaluation.