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

Re-designing the pathway to surgery: better care and added value

Abstract The case for radical pathway re-design before surgery is in part driven by healthcare system pressures which are in turn the result of continuously rising demand in the face of tightly constrained resources. Such circumstances tend to drive revolutionary, rather than incremental, change. The current approach to preoperative assessment, that typically occurs in the weeks leading up to surgery, but is all too often only a few days before surgery, results in a lost opportunity for perioperative physicians to improve patient care. Re-engineering this process based on a patient-focused, pathway-driven vision of perioperative medicine offers a means of exploiting this opportunity. This review explores drivers for change, the opportunity offered by pathway re-design, and suggests a variety of strategies to add value in the preoperative pathway, each of which is facilitated by early engagement between perioperative physician and patient: collaborative decision-making, collaborative behavioural change, targeted comorbidity management as well as expectation management and psychological preparation for surgery including surgery schools

Muon flux measurements at the davis campus of the sanford underground research facility with the MAJORANA DEMONSTRATOR veto system

We report the first measurement of the total muon flux underground at the Davis Campus of the Sanford Underground Research Facility at the 4850 ft level. Measurements were performed using the MAJORANA DEMONSTRATOR muon veto system arranged in two different configurations. The measured total flux is (5.31±0.17)×10−9μ/s/cm2