Biology subjects

Medlock, G. L.

Publications and source records attributed to Medlock, G. L..

4 recordsLinked to original sources

bioRxiv2018

Memote: A community-driven effort towards a standardized genome-scale metabolic model test suite

Several studies have shown that neither the formal representation nor the functional requirements of genome-scale metabolic models (GEMs) are precisely defined. Without a consistent standard, comparability, reproducibility, and interoperability of models across groups and software tools cannot be guaranteed.\n\nHere, we present memote (https://github.com/opencobra/memote) an open-source software containing a community-maintained, standardized set of metabolic model tests. The tests cover a range of aspects from annotations to conceptual integrity and can be extended to include experimental datasets for automatic model validation. In addition to testing a model once, memote can be configured to do so automatically, i.e., while building a GEM. A comprehensive report displays the models performance parameters, which supports informed model development and facilitates error detection.\n\nMemote provides a measure for model quality that is consistent across reconstruction platforms and analysis software and simplifies collaboration within the community by establishing workflows for publicly hosted and version controlled models.

systems biology↗

bioRxiv2018

A Novel Mouse Model of Campylobacter jejuni Enteropathy and Diarrhea

Campylobacter infections are among the leading bacterial causes of diarrhea and of environmental enteropathy (EE) and growth failure worldwide. However, the lack of an inexpensive small animal model of enteric disease with Campylobacter has been a major limitation for understanding its pathogenesis, interventions or vaccine development. We describe a robust standard mouse model that can exhibit reproducible bloody diarrhea or growth failure, depending on the zinc or protein deficient diet and on antibiotic alteration of normal microbiota prior to infection. Zinc deficiency and the use of antibiotics create a niche for Campylobacter infection to establish by narrowing the metabolic flexibility of these mice for pathogen clearance and by promoting intestinal and systemic inflammation. Several biomarkers and intestinal pathology in this model also mimic those seen in human disease. This model provides a novel tool to testing specific hypotheses regarding disease pathogenesis as well as vaccine development that is currently in progress.\n\nAuthor SummaryCampylobacter jejuni has been identified as one of the leading causes of enteropathy and diarrhea. In developing countries, these repeated enteric infections often result in growth deficits and cognitive impairment. There is a lack of small animal models of Campylobacter infection. This is a major hurdle in understanding the pathogenesis of Campylobacter infection in order to lead to therapeutic treatments and vaccines. We have developed a highly reproducible mouse model of Campylobacter infection that has clinical outcomes that match those of malnourished children. We hope that these insights into Campylobacter susceptibility will lead to the development of treatments against this major cause of diarrheal illness.

microbiology↗

bioRxiv2018

Metabolic mechanisms of interaction within a defined gut microbiota

Metabolic interactions among species are ubiquitous in nature, and the fitness costs and benefits they impose often reinforce and stabilize them over time. These interactions are of particular importance in the human gut, where they have functions ranging from enhancing digestion to preventing (or exacerbating) infections. The diversity and sheer number of species present lead to the potential for a multitude of metabolic interactions among species to occur. However, identifying the mechanism and consequences of metabolic interactions between even two species is incredibly challenging. Here, we develop, apply, and experimentally test a framework for identifying potential metabolic mechanisms associated with interspecies interactions. We perform pairwise growth and metabolome profiling of co-cultures of strains from the altered Schaedler flora (ASF), a defined murine microbiota. We then apply our novel framework, which we call the Constant Yield Expectation (ConYE) model, to dissect emergent metabolic behaviors that occur in co-culture. Using the ConYE model, we identify and interrogate an amino acid cross-feeding interaction that is likely to confer a growth benefit to one ASF strain (Clostridium sp. ASF356) in co-culture with another strain (Parabacteroides goldsteinii ASF519). We experimentally validate that the proposed interaction leads to a growth benefit for this strain via media supplementation experiments. Our results reveal the type and extent of emergent metabolic behavior in microbial communities and demonstrate how metabolomic data can be used to identify potential metabolic interactions between organisms such as gut microbes. Our in vitro characterization of the ASF strains and interactions between them also enhances our ability to interpret and design experiments that utilize ASF-colonized animals. We anticipate that this work will improve the tractability of studies utilizing mice colonized with the ASF. Here, we focus on growth-modulating interactions, but the framework we develop can be applied to generate specific hypotheses about mechanisms of interspecies interaction involved in any phenotype of interest within a microbial community.

microbiology↗

bioRxiv2017

Novel Co-Culture Plate Enables Growth Dynamic-Based Assessment Of Contact-Independent Microbial Interactions

Interactions between microbes are central to the dynamics of microbial communities. Understanding these interactions is essential for the characterization of communities, yet challenging to accomplish in practice. There are limited available tools for characterizing diffusion-mediated, contact-independent microbial interactions. A practical and widely implemented technique in such characterization involves the simultaneous co-culture of distinct bacterial species and subsequent analysis of relative abundance in the total population. However, distinguishing between species can be logistically challenging. In this paper, we present a low-cost, vertical membrane, co-culture plate to quantify contact-independent interactions between distinct bacterial populations in co-culture via real-time optical density measurements. These measurements can be used to facilitate the analysis of the interaction between microbes that are physically separated by a semipermeable membrane yet able to exchange diffusible molecules. We show that diffusion across the membrane occurs at a sufficient rate to enable effective interaction between physically separate cultures. Two bacterial species commonly found in the cystic fibrotic lung, Pseudomonas aeruginosa and Burkholderia cenocepacia, were co-cultured to demonstrate how this plate may be implemented to study microbial interactions. We have demonstrated that this novel co-culture device is able to reliably generate real-time measurements of optical density data that can be used to characterize interactions between microbial species.

microbiology↗