Skip to main content

MSTPublications: April 2021

Posted by on Friday, April 30, 2021 in New Publications .

Cytochrome bd promotes Escherichia coli biofilm antibiotic tolerance by regulating accumulation of noxious chemicals.
Beebout CJ, Sominsky LA, Eberly AR, Van Horn GT, Hadjifrangiskou M.
NPJ Biofilms Microbiomes. 2021 Apr 16;7(1):35. doi: 10.1038/s41522-021-00210-x.

Nutrient gradients in biofilms cause bacteria to organize into metabolically versatile communities capable of withstanding threats from external agents including bacteriophages, phagocytes, and antibiotics. We previously determined that oxygen availability spatially organizes respiration in uropathogenic Escherichia coli biofilms, and that the high-affinity respiratory quinol oxidase cytochrome bd is necessary for extracellular matrix production and biofilm development. In this study we investigate the physiologic consequences of cytochrome bd deficiency in biofilms and determine that loss of cytochrome bd induces a biofilm-specific increase in expression of general diffusion porins, leading to elevated outer membrane permeability. In addition, loss of cytochrome bd impedes the proton mediated efflux of noxious chemicals by diminishing respiratory flux. As a result, loss of cytochrome bd enhances cellular accumulation of noxious chemicals and increases biofilm susceptibility to antibiotics. These results identify an undescribed link between E. coli biofilm respiration and stress tolerance, while suggesting the possibility of inhibiting cytochrome bd as an antibiofilm therapeutic approach.


 Cell-programmed nutrient partitioning in the tumour microenvironment.
Reinfeld BI*, Madden MZ*, Wolf MM, Chytil A, Bader JE, Patterson AR, Sugiura A, Cohen AS, Ali A, Do BT, Muir A, Lewis CA, Hongo RA, Young KL, Brown RE, Todd VM, Huffstater T, Abraham A, O’Neil RT, Wilson MH, Xin F, Tantawy MN, Merryman WD, Johnson RW, Williams CS, Mason EF, Mason FM, Beckermann KE, Vander Heiden MG, Manning HC, Rathmell JC, Rathmell WK.
Nature. 2021 Apr 7. doi: 10.1038/s41586-021-03442-1. Online ahead of print.

Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.

Brad and Matt’s publication was featured in the VUMC Reporter!


A Phenotypic Comparison of Loudness and Pain Hyperacusis: Symptoms, Comorbidity, and Associated Features in a Multinational Patient Registry.
Williams ZJ, Suzman E, Woynaroski TG.
Am J Audiol. 2021 Apr 20:1-18. doi: 10.1044/2021_AJA-20-00209. Online ahead of print.

Purpose Hyperacusis is a complex and poorly understood auditory disorder characterized by decreased tolerance to sound at levels that would not trouble most individuals. Recently, it has been suggested that individuals who experience otalgia in response to everyday sounds (termed pain hyperacusis) may differ clinically from those whose primary symptom is the perception of everyday sounds as excessively loud (termed loudness hyperacusis). Despite this theoretical distinction, there have been no empirical studies directly comparing these two populations of hyperacusis patients. Method Using data from a multinational patient registry (the Coordination of Rare Diseases at Sanford Registry), we examined self-reported demographics, symptoms, comorbidity, and response to treatment in a sample of 243 adults with hyperacusis, 152 of whom were classified as having pain hyperacusis based on reported symptoms. Bayesian statistical tests were used to investigate both the presence and absence of group differences between patients with loudness and pain hyperacusis. Results Individuals with pain hyperacusis presented with a more severe clinical phenotype, reporting a higher frequency of temporary symptom exacerbations (i.e., “setbacks”), less perceived symptom improvement over time, more severe comorbid headache disorders, and reduced benefit from sound therapy. However, the two hypothesized hyperacusis subtypes exhibited more similarities than differences, with the majority of symptoms and comorbidities being equally prevalent across groups. Multiple comorbidities were commonly observed, including tinnitus, primary headache disorders, psychiatric disorders, and functional somatic syndromes. Intolerance of sensory stimuli in other modalities was also frequently reported. Conclusion Although this study provides little evidence that loudness and pain hyperacusis are pathophysiologically distinct conditions, our findings indicate that a pain-predominant phenotype may be a meaningful prognostic marker in patients with hyperacusis.


Assessing general and autism-relevant quality of life in autistic adults: A psychometric investigation using item response theory.
Williams ZJ, Gotham KO.
Autism Res. 2021 Apr 19. doi: 10.1002/aur.2519. Online ahead of print.

Although many interventions and services for autistic people have the ultimate goal of improving quality of life (QoL), there is relatively little research on how best to assess this construct in the autistic population, and existing scales designed for non-autistic individuals may not assess all meaningful facets of QoL in the autistic population. To address this need, the autism spectrum QoL form (ASQoL) was recently developed as a measure of the autism-relevant quality of life. However, the psychometrics of the ASQoL have not been examined beyond the authors’ initial validation study, and important properties such as measurement invariance/differential item functioning (DIF) have not yet been tested. Using data from 700 autistic adults recruited from the Simons Foundation’s SPARK cohort, the current study sought to perform a comprehensive independent psychometric evaluation of the ASQoL using item response theory, comparing its performance to a newly-proposed brief measure of general QoL (the WHOQOL-4). Our models revealed substantial DIF by sex and gender in the ASQoL, which caused ASQoL scores to grossly underestimate the self-reported QoL of autistic women. Based on a comparison of latent variable means, we demonstrated that observed sex/gender differences in manifest ASQoL scores were the result of statistical artifacts, a claim that was further supported by the lack of significant group differences on the sex/gender-invariant WHOQOL-4. Our findings indicate that the ASQoL composite score is psychometrically problematic in its current form, and substantial revisions may be necessary before valid and meaningful inferences can be made regarding autism-relevant aspects of QoL. LAY SUMMARY: Quality of life (QoL) is an extremely important outcome for autistic people, but many of the tools that are used to measure it does not take into account how QoL may be different for autistic people. Using data from 700 autistic adults, we examined the measurement properties of the autism spectrum quality of life form (ASQoL), a new measure of QoL designed specifically for autistic people. Our results indicate that the ASQoL shows a pronounced sex/gender bias, which causes it to underestimate QoL in autistic women. This bias needs to be eliminated before the ASQoL can be successfully used to measure QoL in the autistic population.

Bifunctional Nitrone-Conjugated Secondary Metabolite Targeting the Ribosome.
Limbrick EM, Graf M, Derewacz DK, Nguyen F, Spraggins JM, Wieland M, Ynigez-Gutierrez AE, Reisman BJ, Zinshteyn B, McCulloch KM, Iverson TM, Green R, Wilson DN, Bachmann BO.
J Am Chem Soc. 2020 Oct 28;142(43):18369-18377. doi: 10.1021/jacs.0c04675. Epub 2020 Oct 19.

Hypertension: Do Inflammation and Immunity Hold the Key to Solving this Epidemic?
Madhur MS, Elijovich F, Alexander MR, Pitzer A, Ishimwe J, Van Beusecum JP, Patrick DM, Smart CD, Kleyman TR, Kingery J, Peck RN, Laffer CL, Kirabo A.
Circ Res. 2021 Apr 2;128(7):908-933. doi: 10.1161/CIRCRESAHA.121.318052. Epub 2021 Apr 1.

Sex Differences in Adaptive Immunity in Chronic Lung Disease
Chowdhury NU, Gandhi VD, Newcomb DC.
(2021) Sex Differences in Adaptive Immunity in Chronic Lung Disease. In: Silveyra P., Tigno X.T. (eds) Sex-Based Differences in Lung Physiology. Physiology in Health and Disease. Springer, Cham.

The Complex Integration of T-cell Metabolism and Immunotherapy.
Madden MZ, Rathmell JC.
Cancer Discov. 2021 Apr 1. doi: 10.1158/2159-8290.CD-20-0569. Online ahead of print.

Patch-clamp and multi-electrode array electrophysiological analysis in acute mouse brain slices.
Manz KM, Siemann JK, McMahon DG, Grueter BA.
STAR Protoc. 2021 Apr 5;2(2):100442. doi: 10.1016/j.xpro.2021.100442. eCollection 2021 Jun 18.

The Human Islet: Mini-organ with Mega-impact.
Walker JT, Saunders DC, Brissova M, Powers AC.
Endocr Rev. 2021 Apr 12:bnab010. doi: 10.1210/endrev/bnab010. Online ahead of print.

A guide to interrogating immunometabolism.
Voss K, Hong HS, Bader JE, Sugiura A, Lyssiotis CA, Rathmell JC.
Nat Rev Immunol. 2021 Apr 15. doi: 10.1038/s41577-021-00529-8. Online ahead of print.