Search

Abstract Background The γ-aminobutyric acid (GABA) hypothesis posits a role of GABA deficiency in the central nervous system in the pathogenesis and progression of essential tremor (ET). However, the specific causative factor for GABA deficiency is not clear. The gut microbiota in mammals has recently been considered as a significant source of GABA. Furthermore, the GABA-based signals originating from the intestine can be transmitted to the brain through the “enteric nervous system–vagus nerve–brain” axis. However, the plausible contribution of gut microbiota to ET seems inspiring but remains obscure. Methods Fecal samples from patients with ET and healthy controls were examined by metagenomic sequencing to compare the composition of gut microbiota and the expression of genes involved in GABA biosynthesis. The impact of gut microbiota on ET was explored through transplantation of fecal microbiota from patients with ET into the murine ET model. Lactic acid bacteria producing high amounts of GABA were identified through whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry. Subsequently, mice were treated with the high-GABA-producing strain Lactobacillus plantarum L5. Tremor severity, behavioral tests, pro-inflammatory cytokines, GABA concentration, and gut microbiota composition were examined in these mice. Results The gut microbiota of patients with ET demonstrated an impaired GABA-producing capacity and a reduced fecal GABA concentration. Transplantation of the gut microbiota from patients with ET induced an extension of tremor duration and impaired mobility in the murine model of ET. L5 exhibited an augmented GABA-producing capacity, with the De Man-Rogosa-Sharpe culture broth containing 262 mg/l of GABA. In addition, administration of L5 significantly decreased the tremor severity and enhanced the movement capability and grasping ability of ET mice. In vivo mechanistic experiments indicated that L5 reshaped the gut microbial composition, supplemented the mucosa-associated microbiota with GABA-producing capacity, increased the GABA concentrations in the cerebellum, and diminished inflammation in the central nervous system. Conclusions These findings highlight that deficiency of GABA-producing gut microbes plays an essential role in the pathogenesis of ET and that L5 is a promising candidate for treating ET.

Abstract The “death cap”, Amanita phalloides, is the world’s most poisonous mushroom, responsible for 90% of mushroom-related fatalities. The most fatal component of the death cap is α-amanitin. Despite its lethal effect, the exact mechanisms of how α-amanitin poisons humans remain unclear, leading to no specific antidote available for treatment. Here we show that STT3B is required for α-amanitin toxicity and its inhibitor, indocyanine green (ICG), can be used as a specific antidote. By combining a genome-wide CRISPR screen with an in silico drug screening and in vivo functional validation, we discover that N-glycan biosynthesis pathway and its key component, STT3B, play a crucial role in α-amanitin toxicity and that ICG is a STT3B inhibitor. Furthermore, we demonstrate that ICG is effective in blocking the toxic effect of α-amanitin in cells, liver organoids, and male mice, resulting in an overall increase in animal survival. Together, by combining a genome-wide CRISPR screen for α-amanitin toxicity with an in silico drug screen and functional validation in vivo, our study highlights ICG as a STT3B inhibitor against the mushroom toxin.

Background and objectiveEssential tremor (ET) lacks effective treatments because its underlying mechanism is largely unknown, but may involve gut microbiota via the microbiome-gut-brain axis. We explored the effects of gut microbiota on ET in mice.MethodsSpecific pathogen-free C57BL/6J mice were gavaged with stools from ET patients or matched healthy individuals. After 3 weeks of gavaging, behavioral tests were performed on all mice. Next, each mouse was injected with harmaline to induce tremors. The tremor duration was recorded; the tremor score was estimated every 30 min. Behavioral tests were repeated after modeling. Intestinal tissues and fecal samples of the mice were examined using histology and 16Sr DNA sequencing, respectively.ResultsCompared with mice receiving microbiota from healthy controls, mice receiving fecal suspensions from ET patients showed worse performance in the pre-modeling behavioral tests. After modeling, ET-group mice showed significantly greater tremor scores, longer tremor duration, and worse motor performance. They also had significantly lower body weight and lower fecal pellet count. Pathological scoring revealed more severe intestinal lesions in ET-group mice. The 16S rDNA sequencing data revealed significant differences in microbiota indices, and a correlation between these indices and tremors in mice. Functional predictions indicated that the abundance of GABA-related enzymes was altered in ET-group mice.ConclusionMice transplanted with gut microbiota from ET patients showed worse performance in behavioral tests. After modeling, ET-group mice presented longer tremor duration, higher tremor score, and worse motor performance. This study provides evidence for gut microbiota dysbiosis that may affect the pathogenesis of ET.

Abstract Anti‐obesity medications act by suppressing energy intake (EI), promoting energy expenditure (EE), or both. Metformin (Met) and mirabegron (Mir) cause weight loss by targeting EI and EE, respectively. However, anti‐obesity effects during concurrent use of both have yet to be explored. In this study, we investigated the anti‐obesity effects, metabolic benefits, and underlying mechanisms of Met/Mir combination therapy in two clinically relevant contexts: the prevention model and the treatment model. In the prevention model, Met/Mir caused further 12% and 14% reductions in body weight (BW) gain induced by a high‐fat diet compared to Met or Mir alone, respectively. In the treatment model, Met/Mir additively promoted 17% BW loss in diet‐induced obese mice, which was 13% and 6% greater than Met and Mir alone, respectively. Additionally, Met/Mir improved glucose tolerance and insulin sensitivity. These benefits of Met/Mir were associated with increased EE, activated brown adipose tissue thermogenesis, and white adipose tissue browning. Significantly, Met/Mir did not cause cardiovascular dysfunction in either model. Together, the combination of Met and Mir could be a promising approach for the prevention and treatment of obesity by targeting both EI and EE simultaneously.

Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. However, the majority of them have not been functionally validated. SEC16B has been identified in multiple obesity GWASs but its physiological role in energy homeostasis remains unknown. Here, we use Drosophila to determine the physiological functions of dSec16 in energy metabolism. Our results showed that global RNAi of dSec16 increased food intake and triglyceride (TAG) levels. Furthermore, this TAG increase was observed in flies with a specific RNAi of dSec16 in insulin-like peptide producing cells (IPCs) with an alteration of endocrine peptides. Together, our study demonstrates that dSec16 acting in IPCs controls energy balance and advances the molecular understanding of obesity.

The dataset presents the raw data collected through an online survey of senior high school students and their parents from 24 provinces, municipalities and autonomous regions (96 cities) of China. We conducted the online survey using electronic self-administered questionnaires designed as student-version and parent-version during 26th February and 4th March of 2020. The questionnaires were designed using the online survey tool Sojump (Shanghai Information Co.), and released through WeChat platform (Tencent Corp) following principals-head teachers-students/parents approach. All the students and the parents were asked to answer the questions voluntarily and anonymously after reading informed consent at the fore page of the questionnaires. The information collected from students included: 1) demographic characteristics, including sex, date of birth, name of high school, academic year, and self-evaluated performance level; 2) educational levels and occupations of parents; 3) degree preferences, including the willingness to learn medicine (prior and post COVID-19 outbreak), preferred medical career (clinician, public health practitioner, pharmacist, nurse or others), and main motivations for selecting or unselecting medical study; 4) infection of COVID-19 in acquaintances; 5) health literacy level on infectious diseases assessed using the Infectious Disease-specific Health Literacy Scale (IDSHL), and 6) anxiety level evaluated using the Chinese version of the Generalized Anxiety Disorder Screener (GAD-7). Information collected from parents included sex of their children and name of high school attended by their children, as well as their own educational level, occupation, anxiety symptoms, attitude toward their children's studying medicine, and main reasons for supportive or unsupportive attitudes, which were similar to the main motivations or de-motivations for medical study listed in the student-version questionnaire. Date and time for completion of the questionnaire were auto-recorded by the Sojump system. The dataset was established at the early stage of pandemic of COVID-19, and is valuable for understanding the instant psychological impacts of the outbreak of an emerging fatal infectious disease on senior high school students and their patents, and can provide evidence for policymakers on mental health intervention and medical education in China. The data are provided with this article.