New Publication: Regulatory feedback response mechanisms to phosphate starvation in rice

Absolutely delighted to see our most recent paper published in npj Systems Biology and Applications today. This paper involves the full MyCIB team (Charlie Hodgman, Chungui Lu and myself), with work carried out by Ishan Ajmera. Ishan joined us as an MSc student on the (now closed) MSc in Integrative Systems Biology, was one of our star students, stayed for PhD, and is now a post-doc in the school. This work is from his PhD, and is a beautiful example of how experiment and modelling can be used together to provide new understanding and testable hypotheses. Citation and Abstract:

Ajmera I, Shi J, Giri J, Wu P, Stekel DJ, Lu C and Hodgman TC 2018. Regulatory feedback response mechanisms to phosphate starvation in rice. npj Systems Biology and Applications 4:4. doi:10.1038/s41540-017-0041-0.

Abstract

Phosphorus is a growth-limiting nutrient for plants. The growing scarcity of phosphate stocks threatens global food security. Phosphate-uptake regulation is so complex and incompletely known that attempts to improve phosphorus use efficiency have had extremely limited success. This study improves our understanding of the molecular mechanisms underlying phosphate uptake by investigating the transcriptional dynamics of two regulators: the Ubiquitin ligase PHO2 and the long non-coding RNA IPS1. Temporal measurements of RNA levels have been integrated into mechanistic mathematical models using advanced statistical techniques. Models based solely on current knowledge could not adequately explain the temporal expression profiles. Further modeling and bioinformatics analysis have led to the prediction of three regulatory features: the PHO2 protein mediates the degradation of its own transcriptional activator to maintain constant PHO2 mRNA levels; the binding affinity of the transcriptional activator of PHO2 is impaired by a phosphate-sensitive transcriptional repressor/inhibitor; and the extremely high levels of IPS1 and its rapid disappearance upon Pi re-supply are best explained by Pi-sensitive RNA protection. This work offers both new opportunities for plant phosphate research that will be essential for informing the development of phosphate efficient crop varieties, and a foundation for the development of models integrating phosphate with other stress responses.

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New publication: Human dissemination of genes and microorganisms in Earth’s Critical Zone

Delighted that our second review on AMR in the environment is now available on Global Change Biology. This is as much longer article than the piece we wrote for Science. It was nice to have the opportunity to express my opinions about the challenges of modelling in AMR: complexities associated with the wide range of actors; wide range of temporal and spatial scales; and the challenge of calibrating models against empirical data.

Citation and abstract are:

Zhu Y-G, Gillings M, Simonet P, Stekel DJ, Banwart S and Penuelas J. 2018. Human dissemination of genes and microorganisms in Earth’s Critical Zone. Global Change Biology: doi:10.1111/gcb.14003.

Abstract

Earth’s Critical Zone sustains terrestrial life and consists of the thin planetary sur- face layer between unaltered rock and the atmospheric boundary. Within this zone, flows of energy and materials are mediated by physical processes and by the actions of diverse organisms. Human activities significantly influence these physical and bio- logical processes, affecting the atmosphere, shallow lithosphere, hydrosphere, and biosphere. The role of organisms includes an additional class of biogeochemical cycling, this being the flow and transformation of genetic information. This is partic- ularly the case for the microorganisms that govern carbon and nitrogen cycling. These biological processes are mediated by the expression of functional genes and their translation into enzymes that catalyze geochemical reactions. Understanding human effects on microbial activity, fitness and distribution is an important compo- nent of Critical Zone science, but is highly challenging to investigate across the enormous physical scales of impact ranging from individual organisms to the planet. One arena where this might be tractable is by studying the dynamics and dissemina- tion of genes for antibiotic resistance and the organisms that carry such genes. Here we explore the transport and transformation of microbial genes and cells through Earth’s Critical Zone. We do so by examining the origins and rise of antibiotic resis- tance genes, their subsequent dissemination, and the ongoing colonization of diverse ecosystems by resistant organisms.

MRF National PhD Programme in Antimicrobial Resistance – projects at Nottingham

The Medical Research FoundationMedical Research Foundation has funded a national PhD training programme in antimicrobial resistance. With £2.85M of funding, this will support 18 four year PhD scholarships (full fees and enhanced stipend) in 15 different institutions. Applications are now open with deadline 31st January and applicants have a choice of 54 projects.

The University of Nottingham will host one PhD student; applications are being taken for three projects, and the best student will get the scholarship. Our projects (for full details please follow the links) are:

The different projects will welcome applicants from a range of backgrounds, including microbiology, biotechnology, economics or maths. Please apply using the University of Nottingham postgraduate application page, stating the project, supervisor, and that you are applying for the MRF scholarship.

 

 

Welcome to Michelle Baker and Henry Todman

We are delighted to welcome two new lab members this month, Michelle Baker and Henry Todman. Both Michelle and Henry are joint appointments with the School of Mathematics, co-supervised with Theo Kypraios.

Michelle has rejoined our lab, following a post-doc with Jamie Twycross and Liz Sockett. Michelle’s previous stint with us was very productive, leading to our first AMR slurry modelling paper, which I am sure contributed to our grant success. Michelle will be with us for two years. Michelle writes:

I am a post-doctoral researcher in the field of mathematical biology, and am particularly interested in the study of bacteria and antibiotic resistance. I work in the EVAL-FARMS project using mathematical modelling to investigate the risk of emergence of antibiotic resistance from agricultural slurries. This interdisciplinary project allows me to work alongside experts from a wide range of disciplines to tackle the problem in an integrated way and to produce high quality research.

I completed my PhD in Mathematics here at the University of Nottingham, focussed on cytokine dynamics in arthritic disease. After completing my PhD I took up a research position supervised by Prof Liz Sockett and Dr Jamie Twycross, investigating the potential of predatory bacteria to be used as ‘living antibiotics’.

Henry Todman has joined us as a four year PhD student associated with the EVAL-FARMS project. Henry writes:

I am a mathematical modelling PhD student working with Dov, Theo Kypraios and Michelle Baker. My PhD research will primarily look at developing new mathematical models to assess the risks of bacterial population carrying antimicrobial resistance genes and fitting these models to experimental data produced from the EVAL-FARMS project. 

Prior to beginning my PhD, I studied Mathematics at the University of Warwick for my undergraduate degree, and also completed an MSc in Mathematical Medicine and Biology at the University of Nottingham. Over the course of my MSc I was exposed to a wide range of current research topics in mathematical biology, however, it was antimicrobial resistance that immediately captured my interest. This led me to complete my dissertation on the phage-mediated spread of AMR, and I am now eager to pursue this topic even further in my PhD.

Outside of work, I am a keen climber and you will often find me hanging off some rock in the Peak District, or taking part in bouldering competitions around the country.

 

New Publication: Reconstructing promoter activity from Lux bioluminescent reporters

Absolutely delighted to report that our paper has been published:

Iqbal M, Doherty N, Page AML, Qazi SNA, Ajmera I,  Lund PA, Kyraios T, Scott DJ, Hill PJ and Stekel DJ (2017) Reconstructing promoter activity from Lux bioluminescent reporters. PLOS Computational Biology 13(9): e1005731. https://doi.org/10.1371/journal.pcbi.1005731.

Abstract

The bacterial Lux system is used as a gene expression reporter. It is fast, sensitive and non-destructive, enabling high frequency measurements. Originally developed for bacterial cells, it has also been adapted for eukaryotic cells, and can be used for whole cell biosensors, or in real time with live animals without the need for euthanasia. However, correct interpretation of bioluminescent data is limited: the bioluminescence is different from gene expression because of nonlinear molecular and enzyme dynamics of the Lux system. We have developed a computational approach that, for the first time, allows users of Lux assays to infer gene transcription levels from the light output. This approach is based upon a new mathematical model for Lux activity, that includes the actions of LuxAB, LuxEC and Fre, with improved mechanisms for all reactions, as well as synthesis and turn-over of Lux proteins. The model is calibrated with new experimental data for the LuxAB and Fre reactions from Photorhabdus luminescens—the source of modern Lux reporters—while literature data has been used for LuxEC. Importantly, the data show clear evidence for previously unreported product inhibition for the LuxAB reaction. Model simulations show that predicted bioluminescent profiles can be very different from changes in gene expression, with transient peaks of light output, very similar to light output seen in some experimental data sets. By incorporating the calibrated model into a Bayesian inference scheme, we can reverse engineer promoter activity from the bioluminescence. We show examples where a decrease in bioluminescence would be better interpreted as a switching off of the promoter, or where an increase in bioluminescence would be better interpreted as a longer period of gene expression. This approach could benefit all users of Lux technology.

Author summary

Bioluminescent reporters are used in many areas of biology as fast, sensitive and non-destructive measures of gene expression. They have been developed for bacteria, adapted now for other kinds of organisms, and recently been used for whole cell biosensors, and for real-time live animal models for infection without the need for euthanasia. However, users of Lux technologies rely on the light output being similar to the gene expression they wish to measure. We show that this is not the case. Rather, there is a nonlinear relationship between the two: light output can be misleading and so limits the way that such data can be interpreted. We have developed a new computational method that, for the first time, allows users of Lux reporters to infer accurate gene transcription levels from bioluminescent data. We show examples where a small decrease in light would be better interpreted as promoter being switched off, or where an increase in light would be better interpreted as promoter activity for a longer time.

 

Thanks to all my brilliant collaborators and coauthors. Thanks also to the lovely referees (one of whom signed their review) who said of the article: “an extremely important contribution to the field” (Reviewer 1) and “a significant advance” (Reviewer 2) and  provided helpful and constructive feedback.