N-acetylneuraminic acid (NeuAc), which has been widely used as a nutraceutical and pharmaceutical intermediate, plays an important role in improving brain development and cognition while enhancing immunity. Bacillus subtilis, generally regarded as a food-safe microorganism, is suitable for developing as a chassis cell for efficient NeuAc synthesis. However, accumulated intermediates can lead to metabolic bottlenecks for NeuAc synthesis. To eliminate the accumulated byproduct N-acetylglucosamine (GlcNAc), the UDP-GlcNAc epimerase pathway without GlcNAc production was first reconstructed and optimized in B. subtilis, resulting in the NeuAc titer increase of 5.9 g/L with GlcNAc elimination. In addition, to reduce another accumulated byproduct N-acetylmannosamine (ManNAc), the directed evolution of N-acetylneuraminic acid synthase and the enhancement of phosphoenolpyruvate supply was implemented. Using this strategy, ManNAc decreased by 46.3%, and the NeuAc titer increased by 54.9%, reaching 7.9 g/L. Finally, the maximum titer of NeuAc in a 3-L fermenter reached 21.8 g/L with a productivity of 0.34 g/L/h.

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Study objectivesTo characterize sleep disturbances and sleep patterns in children with Tic disorder (TD), and explore their association with TD severity and types.MethodsA case-control study was conducted in 271 children with TD recruited from a clinical setting and 271 non-TD children recruited from a primary school, matched by age (mean = 8.47 years, SD = 1.53 years) and gender (15.1% female). The Children's Sleep Habits Questionnaire (CSHQ) was used to assess sleep patterns and sleep disturbances. The TD types and severity were assessed with the Yale Global Tic Severity Scale (YGTSS).ResultsThe TD children scored higher on CSHQ total score than non-TD group (t = 29.50, p < 0.001) and demonstrated severer global sleep disturbance. Compared to non-TD children, TD children presented with increased risks for global sleep disturbance (aOR: 1.95; 95% CI = 1.20–3.06), and most specific sleep disturbances, including bedtime resistance (aOR: 3.15; 95% CI = 1.96–5.06), sleep onset delay (aOR: 3.43; 95% CI = 1.58–7.46), sleep anxiety (aOR: 2.83; 95%CI = 1.83–4.38), parasomnias (aOR: 3.68; 95% CI = 2.02–6.62), night waking (aOR: 9.29; 95% CI = 2.64–32.65), sleep disordered breathing (aOR: 1.72; 95% CI = 1.03-2.90) and daytime sleepiness (aOR: 1.72; 95% CI = 1.09–2.74). Children with mild and moderate tics, Provisional Tic Disorder (PTD), Chronic Tic Disorder (CTD) and Tourette Syndrome (TS) presented with more global and more specific sleep disturbances. In addition, combined ADHD, etc.ConclusionChildren with TD are major risks for increased sleep disturbances, especially for those with severe and chronic symptoms. Furthermore, comorbid ADHD increases risk in certain areas of sleep. These findings highlight the importance to consider sleep outcomes in the assessment and treatment for children with TD.