Metabolic adaptation of two in silico mutants of Mycobacterium tuberculosis during infection

ABSTRACT: Background: Up to date, Mycobacterium tuberculosis (Mtb) remains as the worst intracellular killer pathogen. To establish infection, inside the granuloma, Mtb reprograms its metabolism to support both growth and survival, keeping a balance between catabolism, anabolism and energy supply. Mtb knockouts with the faculty of being essential on a wide range of nutritional conditions are deemed as target candidates for tuberculosis (TB) treatment. Constraint-based genome-scale modeling is considered as a promising tool for evaluating genetic and nutritional perturbations on Mtb metabolic reprogramming. Nonetheless, few in silico assessments of the effect of nutritional conditions on Mtb’s vulnerability and metabolic adaptation have been carried out. Results: A genome-scale model (GEM) of Mtb, modified from the H37Rv iOSDD890, was used to explore the metabolic reprogramming of two Mtb knockout mutants (pfkA- and icl-mutants), lacking key enzymes of central carbon metabolism, while exposed to changing nutritional conditions (oxygen, and carbon and nitrogen sources). A combination of shadow pricing, sensitivity analysis, and flux distributions patterns allowed us to identify metabolic behaviors that are in agreement with phenotypes reported in the literature. During hypoxia, at high glucose consumption, the Mtb pfkA-mutant showed a detrimental growth effect derived from the accumulation of toxic sugar phosphate intermediates (glucose-6-phosphate and fructose-6-phosphate) along with an increment of carbon fluxes towards the reductive direction of the tricarboxylic acid cycle (TCA). Furthermore, metabolic reprogramming of the icl-mutant (icl1&icl2) showed the importance of the methylmalonyl pathway for the detoxification of propionyl-CoA, during growth at high fatty acid consumption rates and aerobic conditions. At elevated levels of fatty acid uptake and hypoxia, we found a drop in TCA cycle intermediate accumulation that might create redox imbalance. Finally, findings regarding Mtb-mutant metabolic adaptation associated with asparagine consumption and acetate, succinate and alanine production, were in agreement with literature reports. Conclusions: This study demonstrates the potential application of genome-scale modeling, flux balance analysis (FBA), phenotypic phase plane (PhPP) analysis and shadow pricing to generate valuable insights about Mtb metabolic reprogramming in the context of human granulomas

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Design for remanufacturing in China : a case study of electrical and electronic equipment

As global demand for consumer goods continues to rise, the problem of waste electrical and electronic equipment (or e-waste) increases. E-waste is of particular concern to the world’s governments and environmentalists alike, not just because of the sheer quantity that is being produced annually, but also because e-waste often contains both hazardous materials and scarce or valuable materials. Much research is now focused upon how this waste can be treated safely, economically, and in an environmentally sound manner. This paper presents the findings from a literature review and case study research conducted as a small part of the Globally Recoverable and Eco-friendly E-equipment Network with Distributed Information Service Management (GREENet) project. The GREENet project aims to share knowledge and expertise in e-waste treatment across Europe (in this case, the UK) and China. The focus of this particular study was upon ‘design for remanufacture’ and e-waste in China: as a remanufacturing industry begins to emerge, are Chinese original equipment manufacturers (OEMs) prepared to design more remanufacturable products and could electrical and electronic products become a part of this industry? Findings presented in this paper suggest that design for remanufacture could become more relevant to Chinese OEMs in the near future, as environmental legislation becomes increasingly stringent and a government remanufacturing pilot scheme expands. However, findings from case studies of Chinese e-waste recyclers would suggest that electrical and electronic products are not presently highly suited to the remanufacturing process

Carbon gold rush and carbon cowboys: a new chapter in green mythology?

Individual and collective efforts to mitigate climate change in the form of carbon offsetting and emissions trading schemes have recently become the focus of much media attention. In this paper we explore a subset of the UK national press coverage centered on such schemes. The articles, selected from general as well as specialized business and finance newspapers, make use of gold rush, Wild West and cowboy imagery which is rooted in deeply entrenched myths and metaphors and allows readers to make sense of very complex environmental, political, ethical, and financial issues associated with carbon mitigation. They make what appears complicated and unfamiliar, namely carbon trading and offsetting, seem less complex and more familiar. A critical discussion of this type of imagery is necessary in order to uncover and question tacit assumptions and connotations which are built into it and which might otherwise go unnoticed and unchallenged in environmental communication