Glutamate mediated metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis.

Metabolic networks in biological systems are interconnected, such that malfunctioning parts can be corrected by other parts within the network, a process termed adaptive metabolism. Unlike Bacillus Calmette-Guérin (BCG), Mycobacterium tuberculosis (Mtb) better manages its intracellular lifestyle by executing adaptive metabolism. Here, we used metabolomics and identified glutamate synthase (GltB/D) that converts glutamine to glutamate (Q → E) as a metabolic effort used to neutralize cytoplasmic pH that is acidified while consuming host propionate carbon through the methylcitrate cycle (MCC). Methylisocitrate lyase, the last step of the MCC, is intrinsically downregulated in BCG, leading to obstruction of carbon flux toward central carbon metabolism, accumulation of MCC intermediates, and interference with GltB/D mediated neutralizing activity against propionate toxicity. Indeed, vitamin B12 mediated bypass MCC and additional supplement of glutamate led to selectively correct the phenotypic attenuation in BCG and restore the adaptive capacity of BCG to the similar level of Mtb phenotype. Collectively, a defective crosstalk between MCC and Q → E contributes to attenuation of intracellular BCG. Furthermore, GltB/D inhibition enhances the level of propionate toxicity in Mtb. Thus, these findings revealed a new adaptive metabolism and propose GltB/D as a synergistic target to improve the antimicrobial outcomes of MCC inhibition in Mtb.

Impact of disability status on suicide risks in South Korea: Analysis of National Health Insurance cohort data from 2003 to 2013.

BACKGROUND: The elevated risk of suicide in people with disability has been suggested in the previous studies; however, the majority of study results have been limited to specific disability types, and there is a lack of research comparing the risk of suicide in people with disability in general. OBJECTIVES: To examine the hazard ratio of suicide according to the presence and the types of disability and identify patterns in the results. METHODS: In this study, we used National Health Insurance Service-National Sample Cohort data on 990,598 people, and performed analysis on the cause of death from 2003 through 2013. A Cox proportional hazard model was used to estimate the hazard ratio of suicide associated with disability and its types. RESULTS: The hazard ratio of suicide among people with disability was 1.9-folds higher compared to people without disability. The risk of suicide among different disability types was higher in mental disorder, renal failure, brain injury and physical disability. The hazard ratio of suicide in people with disability was not varied by income. The time to death by suicide for people with disability from the onset of their disability was 39.8 months on average. CONCLUSIONS: Our findings suggest that when the government plans suicide prevention policies, early and additional interventions specific to people with disability are needed. Disability due to mental disorder, renal failure should be given priority.