The Regulation of Sulfur Metabolism in Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) has evolved into a highly successful human pathogen. It deftly subverts the bactericidal mechanisms of alveolar macrophages, ultimately inducing granuloma formation and establishing long-term residence in the host. These hallmarks of Mtb infection are facilitated by the metabolic adaptation of the pathogen to its surrounding environment and the biosynthesis of molecules that mediate its interactions with host immune cells. The sulfate assimilation pathway of Mtb produces a number of sulfur-containing metabolites with important contributions to pathogenesis and survival. This pathway is regulated by diverse environmental cues and regulatory proteins that mediate sulfur transactions in the cell. Here, we discuss the transcriptional and biochemical mechanisms of sulfur metabolism regulation in Mtb and potential small molecule regulators of the sulfate assimilation pathway that are collectively poised to aid this intracellular pathogen in its expert manipulation of the host. From this global analysis, we have identified a subset of sulfur-metabolizing enzymes that are sensitive to multiple regulatory cues and may be strong candidates for therapeutic intervention

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Stability in a denitrifying fluidized bed reactor

This study evaluates changes in the microbial community structure and function of a pilot-scale denitrifying fluidized bed reactor during periods of constant operating conditions and periods of perturbation. The perturbations consisted of a shutdown period without feed, two disturbances in which biofilms were mechanically sheared from carrier particles, and a twofold step increase in feed nitrate concentration. In the absence of perturbations, nitrate removal was stable and consistently greater than 99%. The structure and dynamics of the microbial community were studied using cloning and sequencing techniques and terminal restriction fragment length polymorphism (T-RFLP) of the SSU rRNA gene. Under unperturbed operating conditions, stable function was accompanied by high constancy and low variability of community structure with the majority of terminal restriction fragments (T-RFs) appearing throughout operation at consistent relative abundances. Several of the consistently present T-RFs correlated with clone sequences closely related to Acidovorax (98% similarity), Dechloromonas (99% similarity), and Zoogloea (98% similarity), genera recently identified by molecular analyses of similar systems. Significant changes in community structure and function were not observed after the shutdown period. In contrast, following the increase in loading rate and the mechanical disturbances, new T-RFs appeared. After both mechanical disturbances, function and community structure recovered. However, function was much more resilient than community structure. The similarity of response to the mechanical disturbances despite differences in community structure and operating conditions suggests that flexible community structure and potentially the activity of minor members under nonperturbation conditions promotes system recovery. © Springer Science+Business Media, Inc. 2006.http://deepblue.lib.umich.edu/bitstream/2027.42/191259/2/Microbial Ecology paper.pdfPublished versionDescription of Microbial Ecology paper.pdf : Accepted versio

Uranium (VI) reduction by denitrifying biomass

Groundwater near the S3 ponds at the US Department of Energy's Y-12 site in Oak Ridge, Tennessee, is contaminated by high levels of nitrate (up to 160 mM) and U(VI) (~0.3 mM). To minimize nitrate inhibition, the authors proposed extraction of contaminated groundwater, nitrate removal in a denitrifying fluidized bed bioreactor (FBR), and return of nitrate-free effluent to the aquifer to stimulate in situ microbial reduction of U(VI). In the presence of carbonate, U(VI) sorption to biomass was negligible, but in its absence, sorption was significant. Biomass reduced U(VI) to U(IV), exhibiting slow firstorder removal with respect to U(VI). Addition of electron donor increased rates. Addition of an inhibitor of sulfate reduction (molybdate) slowed the rate and inhibited sulfate reduction. Denitrifying β-Proteobacteria dominated clone libraries of SSU rRNA and dsrA gene sequences. Approximately 10% were low-G+C microorganisms that had 90% to 92% sequence identity with Sporomusa, Acetonema, and Propionispora. The dsrA sequences were dominated by a single clone with ~80% nucleotide identity to dsrA of Desulfovibrio vulgaris sub sp. oxamicus. The authors conclude that some members of this denitrifyng community reduce uranium, and that sulfate-reducing bacteria likely contribute to this capability. © 2005 Taylor and Francis Inc.http://deepblue.lib.umich.edu/bitstream/2027.42/191261/2/JA2-2005-PDF.pdfPublished versio

The mechanism of pentabromopseudilin inhibition of myosin motor activity

We have identified pentabromopseudilin (PBP) as a potent inhibitor of myosin-dependent processes such as isometric tension development and unloaded shortening velocity. PBP-induced reductions in the rate constants for ATP binding, ATP hydrolysis and ADP dissociation extend the time required per myosin ATPase cycle in the absence and presence of actin. Additionally, coupling between the actin and nucleotide binding sites is reduced in the presence of the inhibitor. The selectivity of PBP differs from that observed with other myosin inhibitors. To elucidate the binding mode of PBP, we crystallized the Dictyostelium myosin-2 motor domain in the presence of Mg2+-ADP–meta-vanadate and PBP. The electron density for PBP is unambiguous and shows PBP to bind at a previously unknown allosteric site near the tip of the 50-kDa domain, at a distance of 16 Å from the nucleotide binding site and 7.5 Å away from the blebbistatin binding pocket