Systematic metabolic pathway modification to boost L-ornithine supply for bacitracin production in Bacillus licheniformis DW2.

Bacitracin is a cyclic dodecyl peptide antibiotic that is an effective bacteriocide against Gram-positive and some Gram-negative bacteria. Bacitracin has been widely used as an antibacterial feed additive for livestock since it is not absorbed easily by the intestine and is easily excreted. Precursor availability has been proven to be one of the core factors for bacitracin production by many previous studies. In this study, we focused on enhancing the supply of the precursor amino acid L-ornithine to enhance bacitracin production by Bacillus licheniformis DW2 through systematic metabolic pathway modification. Several genes encoding rate-limiting enzymes for L-ornithine biosynthesis were episomally overexpressed, including argB, rocF, ppnk1, and ppnk2. The results showed that the overexpression of ppnK1 was the most effective for both L-ornithine and bacitracin biosynthesis. Secondly, the competitive branch pathways for L-ornithine biosynthesis were blocked, and the repressor was also deleted to boost L-ornithine biosynthesis. The results suggested that the deletion of genes proB and proJ to prevent proline biosynthesis and the disruption of the gene encoding the arginine repressor ArgR could enhance the intracellular concentration of L-ornithine by 49% and 2.1 times respectively, and the bacitracin production also increased accordingly by 6.6% and 11.9% respectively. Finally, several most effective efforts were combined to construct the optimal strain DW2ΔproBΔproJΔargR::ppnk1. In the optimal strain, the NADPH availability was improved and the expression levels of several essential genes for L-ornithine biosynthesis were upregulated, resulting in the enhancement of both L-ornithine and bacitracin production by 71.4% and 16.5% respectively. The final bacitracin production titer was 950 U/mL, which reached the level for industrial production.

The effects of long-term high-altitude exposure on cognition: A meta-analysis.

Long-term high altitudes (HA) exposure's impact on cognition has yielded inconsistent findings in previous research. To address this, we conducted a meta-analysis of 49 studies (6191 individuals) to comprehensively evaluate this effect. Moderating factors such as cognitive task type, altitude (1500-2500 m, 2500-4000 m, and above 4000 m), residential type (chronic and lifelong), adaptation level and demographic factors were analyzed. Cognitive tasks were classified into eight categories: perceptual processes, psychomotor function, long-term memory, working memory, inhibitory control, problem-solving, language, and others. Results revealed a moderate negative effect of HA on cognitive performance (g = -.40, SE =.18, 95% CI = -.76 to -.05). Psychomotor function and long-term memory notably experience the most pronounced decline, while working memory and language skills show moderate decreases due to HA exposure. However, perceptual processes, inhibitory control, and problem-solving abilities remain unaffected. Moreover, residing at altitudes above 4000 m and being a HA immigrant are associated with significant cognitive impairment. In summary, our findings indicate a selective adaptation of cognitive performance to HA conditions.