Metabolism was once relegated to the supply of energy and biosynthetic precursors, but it has now become clear that it is a specific mediator of nearly all physiological processes. In the context of ...microbial pathogenesis, metabolism has expanded outside its canonical role in bacterial replication. Among human pathogens, this expansion has emerged perhaps nowhere more visibly than for Mycobacterium tuberculosis, the causative agent of tuberculosis. Unlike most pathogens, M. tuberculosis has evolved within humans, which are both host and reservoir. This makes unrestrained replication and perpetual quiescence equally incompatible strategies for survival as a species. In this Review, we summarize recent work that illustrates the diversity of metabolic functions that not only enable M. tuberculosis to establish and maintain a state of chronic infection within the host but also facilitate its survival in the face of drug pressure and, ultimately, completion of its life cycle.
The radiant heating and cooling (RHC) system has been gaining much popularity due to high thermal comfort, reduced energy consumption, quiet operation, space saving, and so on. For this reason, there ...have been numerous studies on the RHC system to evaluate the thermal performance of the system and to implement the system for practical applications. This study conducted a literature review on the basic and applied research in RHC systems for the built environment. The objective of this review is to find out the research trend of the RHC system, to discover main issues for the RHC system understanding, and to suggest further studies for the system development. In this study, a comprehensive review was conducted, in terms of thermal comfort, thermal analysis including heat transfer model, heating/cooling capacity, CFD analysis, energy simulation, system configuration and control strategies. The results showed that the RHC system has been continuously developed, modified and improved to achieve better thermal comfort and energy efficiency. Based on the review results, several topics for future studies were suggested, which are required to overcome the limitations of the RHC system for extending its application to various building types, climate, and so on.
•A comprehensive review was conducted for the radiant heating and cooling system.•Research topics were analyzed for the publications in Building and Environment.•The review dealt with researches on comfort, heat transfer, CFD, and control.•Based on the review, several topics are suggested for the future study.
Mycobacterium tuberculosis is a chronic, facultative intracellular pathogen that spends the majority of its decades-long life cycle in a non- or slowly replicating state. However, the bacterium ...remains poised to resume replicating so that it can transmit itself to a new host. Knowledge of the metabolic adaptations used to facilitate entry into and exit from nonreplicative states remains incomplete. Here, we apply ¹³C-based metabolomic profiling to characterize the activity of M. tuberculosis tricarboxylic acid cycle during adaptation to and recovery from hypoxia, a physiologically relevant condition associated with nonreplication. We show that, as M. tuberculosis adapts to hypoxia, it slows and remodels its tricarboxylic acid cycle to increase production of succinate, which is used to flexibly sustain membrane potential, ATP synthesis, and anaplerosis, in response to varying degrees of O ₂ limitation and the presence or absence of the alternate electron acceptor nitrate. This remodeling is mediated by the bifunctional enzyme isocitrate lyase acting in a noncanonical role distinct from fatty acid catabolism. Isocitrate lyase-dependent production of succinate affords M. tuberculosis with a unique and bioenergetically efficient metabolic means of entry into and exit from hypoxia-induced quiescence.
Mycobacterium tuberculosis (Mtb) is a persistent intracellular pathogen intrinsically tolerant to most antibiotics. However, the specific factors that mediate this tolerance remain incompletely ...defined. Here we apply metabolomic profiling to discover a common set of metabolic changes associated with the activities of three clinically used tuberculosis drugs, isoniazid, rifampicin and streptomycin. Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant. These results identify a previously undescribed role for Mtb's ICLs in antioxidant defense as a mechanism of antibiotic tolerance.
Few mutations attenuate Mycobacterium tuberculosis (Mtb) more profoundly than deletion of its isocitrate lyases (ICLs). However, the basis for this attenuation remains incompletely defined. Mtb’s ...ICLs are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids. Here, we report that Mtb’s ICLs are essential for survival on both acetate and propionate because of its methylisocitrate lyase (MCL) activity. Lack of MCL activity converts Mtb’s methylcitrate cycle into a “dead end” pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH. Activation of an alternative vitamin B ₁₂-dependent pathway of propionate metabolism led to selective corrections of TCA cycle activity, membrane potential, and intrabacterial pH that specifically restored survival, but not growth, of ICL-deficient Mtb metabolizing acetate or propionate. These results thus resolve the biochemical basis of essentiality for Mtb’s ICLs and survival on fatty acids.
Radiant heating and cooling (RHC) systems are being increasingly applied not only in residential but also in non-residential buildings such as commercial buildings, education facilities, and even ...large scale buildings such as airport terminals. Furthermore, with the combined ventilation system used to handle latent load, the radiant cooling system has proven applicable in hot and humid climates. It is well known that the RHC system has advantages of low draught risk, quiet operation, low energy consumption, and ability for design integration with building elements. These merits have motivated numerous studies on RHC systems in terms of comfort, heat transfer analysis, energy simulation, control strategy, system configurations and so on. Many studies have demonstrated that the RHC system is a good solution to improve indoor environmental quality while reducing building energy consumption for heating and cooling. On the other hand, the RHC system has limitations such as complicated control of Thermally Activated Building System (TABS), acoustical issues, higher capital cost and cooling load than conventional air systems, and so on. For now, the required mitigation of these limitations and the need to extend the applicability of the RHC system are providing the continuous impetus for research on RHC systems. This paper summarizes the important issues involved in the research on RHC system, whereby ten questions and answers concerning the RHC system are discussed, which will help researchers to conduct relevant studies.
•The paper addresses ten essential questions on radiant heating and cooling systems.•Advantages and limitations of the radiant heating and cooling system are discussed.•Previous studies on the evaluation of system performance are revisited.•Current issues on controls for reducing energy and condensation risk are raised.•The authors suggest future research topics on the radiant heating and cooling systems.
Two recent studies in PNAS and Nat Chem Biol highlight the power of modern mass‐spectrometry techniques for enzyme discovery applied to microbiology. In so doing, they have uncovered new potential ...targets for the treatment of tuberculosis.
Mycobacterium tuberculosis (Mtb) is thought to preferentially rely on fatty acid metabolism to both establish and maintain chronic infections. Its metabolic network, however, allows efficient ...co-catabolism of multiple carbon substrates. To gain insight into the importance of carbohydrate substrates for Mtb pathogenesis we evaluated the role of glucose phosphorylation, the first reaction in glycolysis. We discovered that Mtb expresses two functional glucokinases. Mtb required the polyphosphate glucokinase PPGK for normal growth on glucose, while its second glucokinase GLKA was dispensable. (13)C-based metabolomic profiling revealed that both enzymes are capable of incorporating glucose into Mtb's central carbon metabolism, with PPGK serving as dominant glucokinase in wild type (wt) Mtb. When both glucokinase genes, ppgK and glkA, were deleted from its genome, Mtb was unable to use external glucose as substrate for growth or metabolism. Characterization of the glucokinase mutants in mouse infections demonstrated that glucose phosphorylation is dispensable for establishing infection in mice. Surprisingly, however, the glucokinase double mutant failed to persist normally in lungs, which suggests that Mtb has access to glucose in vivo and relies on glucose phosphorylation to survive during chronic mouse infections.
Metabolic adaptation to the host niche is a defining feature of the pathogenicity of Mycobacterium tuberculosis (Mtb). In vitro, Mtb is able to grow on a variety of carbon sources, but mounting ...evidence has implicated fatty acids as the major source of carbon and energy for Mtb during infection. When bacterial metabolism is primarily fueled by fatty acids, biosynthesis of sugars from intermediates of the tricarboxylic acid cycle is essential for growth. The role of gluconeogenesis in the pathogenesis of Mtb however remains unaddressed. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the first committed step of gluconeogenesis. We applied genetic analyses and ¹³C carbon tracing to confirm that PEPCK is essential for growth of Mtb on fatty acids and catalyzes carbon flow from tricarboxylic acid cycle-derived metabolites to gluconeogenic intermediates. We further show that PEPCK is required for growth of Mtb in isolated bone marrow-derived murine macrophages and in mice. Importantly, Mtb lacking PEPCK not only failed to replicate in mouse lungs but also failed to survive, and PEPCK depletion during the chronic phase of infection resulted in mycobacterial clearance. Mtb thus relies on gluconeogenesis throughout the infection. PEPCK depletion also attenuated Mtb in IFNγ-deficient mice, suggesting that this enzyme represents an attractive target for chemotherapy.
Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated with obesity and with an increased risk of colorectal cancer. Whether HFCS contributes directly to ...tumorigenesis is unclear. We investigated the effects of daily oral administration of HFCS in adenomatous polyposis coli (APC) mutant mice, which are predisposed to develop intestinal tumors. The HFCS-treated mice showed a substantial increase in tumor size and tumor grade in the absence of obesity and metabolic syndrome. HFCS increased the concentrations of fructose and glucose in the intestinal lumen and serum, respectively, and the tumors transported both sugars. Within the tumors, fructose was converted to fructose-1-phosphate, leading to activation of glycolysis and increased synthesis of fatty acids that support tumor growth. These mouse studies support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.
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