A number of bacteria are known to differentiate into cells with distinct phenotypic traits during processes such as biofilm formation or the development of reproductive structures. These cell types, by virtue of their specialized functions, embody a division of labor. However, how bacteria build spatial patterns of differentiated cells is not well understood. Here, we examine the factors that drive spatial patterns in divisions of labor in colonies of Streptomyces coelicolor, a multicellular bacterium capable of synthesizing an array of antibiotics and forming complex reproductive structures (e.g., aerial hyphae and spores). Using fluorescent reporters, we demonstrate that the pathways for antibiotic biosynthesis and aerial hypha formation are activated in distinct waves of gene expression that radiate outwards in S. coelicolor colonies. We also show that the spatiotemporal separation of these cell types depends on a key activator in the developmental pathway, AdpA. Importantly, when we manipulated local gradients by growing competing microbes nearby, or through physical disruption, expression in these pathways could be decoupled and/or disordered, respectively. Finally, the normal spatial organization of these cell types was partially restored with the addition of a siderophore, a public good made by these organisms, to the growth medium. Together, these results indicate that spatial divisions of labor in S. coelicolor colonies are determined by a combination of physiological gradients and regulatory network architecture, key factors that also drive patterns of cellular differentiation in multicellular eukaryotic organisms. IMPORTANCE Streptomyces coelicolor is a multicellular bacterium that differentiates into specialized cell types and produces a diverse array of natural products. While much is known about the genetic networks that regulate development and antibiotic biosynthesis in S. coelicolor, what drives the spatial organization of these activities within a colony remains to be explored. By using time-lapse microscopy to monitor gene expression in developmental and antibiotic biosynthesis pathways, we found that expression in these pathways occurs in spatiotemporally separated waves. Normally, expression of the antibiotic biosynthesis pathway preceded expression in the developmental pathway; however, this order was compromised in a mutant lacking a key developmental regulator. Furthermore, when we disrupted the local gradients during S. coelicolor growth, we observed disordered patterns of gene expression within colonies. Together, these results indicate that spatial divisions of labor in S. coelicolor colonies are determined by a combination of regulatory network architecture and physiological gradients.
Some insects form symbioses in which actinomycetes provide defense against pathogens by making antimicrobials. The range of chemical strategies employed across these associations, and how these strategies relate to insect lifestyle, remains underexplored. We assessed subsocial passalid beetles of the species Odontotaenius disjunctus, and their frass (fecal material), which is an important food resource within their galleries, as a model insect/actinomycete system. Through chemical and phylogenetic analyses, we found that O. disjunctus frass collected across eastern North America harbored multiple lineages of Streptomyces and diverse antimicrobials. Metabolites detected in frass displayed synergistic and antagonistic inhibition of a fungal entomopathogen, Metarhizium anisopliae, and multiple streptomycete isolates inhibited this pathogen when co-cultivated directly in frass. These findings support a model in which the lifestyle of O. disjunctus accommodates multiple Streptomyces lineages in their frass, resulting in a rich repertoire of antimicrobials that likely insulates their galleries against pathogenic invasion.
<p> </p> <p>Objective: Fatty liver disease (FLD) is prevalent in diabetes, and both disproportionately affect vulnerable populations. The fibrosis-4 score (FIB-4) is recommended to screen for advanced liver fibrosis. Limited data have suggested that diabetes may impact FIB-4. Research Design and Methods: We evaluated FIB-4 accuracy for advanced fibrosis compared to liver biopsy in presence of diabetes and obesity. </p> <p>Results: Among 363 FLD patients receiving care in San Francisco’s safety-net from 8/2009-2/2020, characteristics were: median age 51yrs, 46% male, 59% Hispanic, 68% obese, 33% with diabetes and 31% had advanced fibrosis on histology. Overall, the c-statistic for FIB-4 was 0.79, but was worse in patients with diabetes, 0.68, than without, 0.85 (p=0.003). Accuracy also varied by weight, at 0.65, 0.85, 0.75, for normal-weight, overweight and obese, respectively, although not significantly (p=0.24). </p> <p>Conclusions: The findings highlight limitations of FIB-4 in screening for advanced liver fibrosis, particularly in individuals with diabetes.</p>
<p> </p> <p>Objective: Fatty liver disease (FLD) is prevalent in diabetes, and both disproportionately affect vulnerable populations. The fibrosis-4 score (FIB-4) is recommended to screen for advanced liver fibrosis. Limited data have suggested that diabetes may impact FIB-4. Research Design and Methods: We evaluated FIB-4 accuracy for advanced fibrosis compared to liver biopsy in presence of diabetes and obesity. </p> <p>Results: Among 363 FLD patients receiving care in San Francisco’s safety-net from 8/2009-2/2020, characteristics were: median age 51yrs, 46% male, 59% Hispanic, 68% obese, 33% with diabetes and 31% had advanced fibrosis on histology. Overall, the c-statistic for FIB-4 was 0.79, but was worse in patients with diabetes, 0.68, than without, 0.85 (p=0.003). Accuracy also varied by weight, at 0.65, 0.85, 0.75, for normal-weight, overweight and obese, respectively, although not significantly (p=0.24). </p> <p>Conclusions: The findings highlight limitations of FIB-4 in screening for advanced liver fibrosis, particularly in individuals with diabetes.</p>
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