Mycobacterium tuberculosis WhiB3 Maintains Redox Homeostasis by Regulating Virulence Lipid Anabolism to Modulate Macrophage Response

The metabolic events associated with maintaining redox homeostasis in Mycobacterium tuberculosis (Mtb) during infection are poorly understood. Here, we discovered a novel redox switching mechanism by which Mtb WhiB3 under defined oxidizing and reducing conditions differentially modulates the assimilation of propionate into the complex virulence polyketides polyacyltrehaloses (PAT), sulfolipids (SL-1), phthiocerol dimycocerosates (PDIM), and the storage lipid triacylglycerol (TAG) that is under control of the DosR/S/T dormancy system. We developed an in vivo radio-labeling technique and demonstrated for the first time the lipid profile changes of Mtb residing in macrophages, and identified WhiB3 as a physiological regulator of virulence lipid anabolism. Importantly, MtbΔwhiB3 shows enhanced growth on medium containing toxic levels of propionate, thereby implicating WhiB3 in detoxifying excess propionate. Strikingly, the accumulation of reducing equivalents in MtbΔwhiB3 isolated from macrophages suggests that WhiB3 maintains intracellular redox homeostasis upon infection, and that intrabacterial lipid anabolism functions as a reductant sink. MtbΔwhiB3 infected macrophages produce higher levels of pro- and anti-inflammatory cytokines, indicating that WhiB3-mediated regulation of lipids is required for controlling the innate immune response. Lastly, WhiB3 binds to pks2 and pks3 promoter DNA independent of the presence or redox state of its [4Fe-4S] cluster. Interestingly, reduction of the apo-WhiB3 Cys thiols abolished DNA binding, whereas oxidation stimulated DNA binding. These results confirmed that WhiB3 DNA binding is reversibly regulated by a thiol-disulfide redox switch. These results introduce a new paradigmatic mechanism that describes how WhiB3 facilitates metabolic switching to fatty acids by regulating Mtb lipid anabolism in response to oxido-reductive stress associated with infection, for maintaining redox balance. The link between the WhiB3 virulence pathway and DosR/S/T signaling pathway conceptually advances our understanding of the metabolic adaptation and redox-based signaling events exploited by Mtb to maintain long-term persistence

Environmental and Social Disclosures and Firm Risk

ArticleWe examine the link between a firm’s environmental (E) and social (S) disclosures and measures of its risk including total, systematic, and idiosyncratic risk. While we do not find any link between a firm’s E and S disclosures and its systematic risk, we find a negative and significant association between these disclosures and a firm’s total and idiosyncratic risk. These are novel findings and are consistent with the predictions of the stakeholder theory and the resource based view of the firm suggesting that firms which make extensive and objective E and S disclosures promote corporate transparency that can help them build a positive reputation and trust with its stakeholders, which in turn can help mitigate the firm’s idiosyncratic/operational risk. These findings are important for all corporate stakeholders including managers, employees, and suppliers who have a significant economic interest in the survival and success of the firm

Phenytoin Pharmacokinetics After Intravenous Administration to Patients Receiving Enteral Tube-Feeding

Serial plasma samples were collected after administration of 13 intravenous dose of phenytoin to 11 patients with head injury; 5 to patients who had been receiving enteral feeds for less than 5 days (group 1), and 8 to patients who had been receiving enteral feeds for loner than 5 days (group 2). Average plasma phenytoin concentrations were higher in group 1 than in group 2 (0.003). The median intravenous study dose was the same (300 mg) in both groups (p=0.17). Group 2 received slightly higher doses expressed as mg/kg (median of 5.45 mg/kg compared to 4.29 mg/kg in group 1, p=0.21). Phenytoin was more rapidly eliminated following intravenous dosing patients receiving long-term enteral feeding. V-max was higher in group 2 than in group 1 (medians, 709 versus 394 mg/day) and K-m smaller (medians, 2.5 versus 3.9 mg/l), but volume of distribution was similar in both groups (p=0.88). The kinetic parameters of phenytoin in group 1 were similar to previously published population pharmacokinetic parameters. In order to maintain phenytoin concentrations adequate for seizure prophylaxis in patients receiving long-term enteral feeding it would be advisable to decrease the dosing interval as well as increasing the phenytoin dose when the drug is administered intravenously