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.

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.

 

 

New publication: microbial mass movements

Delighted that our perspective in Science has been published.

Zhu Y-G, Gillings M, Simonet P, Stekel DJ, Banwart S and Penuelas J. Microbial mass movements. Science 357: 1099-1100.

My involvement is relatively minor: we have written a much longer piece (which we are looking to publish also) to which I have contributed a fairly substantial section on modelling – and then when Michael Gillings put together this short perspective for Science, he compressed everything I wrote into a single sentence! Maybe it is an improvement 🙂 Anyway, it is a real privelege to have coauthored which such amazing international scientists, and a delight that we have had it published in such a great journal.

Summary

For several billion years, microorganisms and the genes they carry have mainly been moved by physical forces such as air and water currents. These forces generated biogeographic patterns for microorganisms that are similar to those of animals and plants (1). In the past 100 years, humans have changed these dynamics by transporting large numbers of cells to new locations through waste disposal, tourism, and global transport and by modifying selection pressures at those locations. As a consequence, we are in the midst of a substantial alteration to microbial biogeography. This has the potential to change ecosystem services and biogeochemistry in unpredictable ways.

Nearly new publication: Metal Resistance and Its Association With Antibiotic Resistance. Advances in Microbial Physiology

Last month the review that Sankalp and I contributed to was published on line by Advances in Microbial Physiology. This review was led by Jon Hobman, with considerable writing by Chandan Pal. It is a real honour to have co-authored with the amazing Joakim Larsson. My own contribution was small: Sankalp contributed some review material on modelling, and I got stuck in with Joakim and Jon in the editing phase to ensure we had a coherent story. Overall, this is a very nice and timely review, and we have had a lot of interest in it already. Citation and abstract:

Pal C, Asiani K, Arya S, Rensing C, Stekel DJ, Larsson DGJ and Hobman JL 2017. Metal Resistance and Its Association With Antibiotic Resistance. Advances in Microbial Physiology. DOI: https://doi.org/10.1016/bs.ampbs.2017.02.001.

Abstract

Antibiotic resistance is recognised as a major global threat to public health by the World Health Organization. Currently, several hundred thousand deaths yearly can be attributed to infections with antibiotic-resistant bacteria. The major driver for the development of antibiotic resistance is considered to be the use, misuse and overuse of antibiotics in humans and animals. Nonantibiotic compounds, such as antibacterial biocides and metals, may also contribute to the promotion of antibiotic resistance through co-selection. This may occur when resistance genes to both antibiotics and metals/biocides are co-located together in the same cell (co-resistance), or a single resistance mechanism (e.g. an efflux pump) confers resistance to both antibiotics and biocides/metals (cross-resistance), leading to co-selection of bacterial strains, or mobile genetic elements that they carry. Here, we review antimicrobial metal resistance in the context of the antibiotic resistance problem, discuss co-selection, and highlight critical knowledge gaps in our understanding.

First use of bioRxiv: Reconstructing Promoter Activity From Lux Bioluminescent Reporters

Today I have made a new publication foray and submitted a manuscript to bioRxiv. This is the main paper to have come out of work on our BBSRC Lux grant. We are yet to find a peer-review home – but one of our co-authors has already had a conversation with someone who wants to use the method – so it was time to put the manuscript out there while we continue with the peer-review process. R code and Biomodels submission will follow. The manuscript details are:

New publication:So why have you added me? Adolescent girls’ technology-mediated attachments and relationships.

Work from Di’s PhD has just been published! This is very much Di’s work. My contribution was making the figures in R. Very proud of Di! This is my first social research article – my publication record becomes increasingly eclectic.

Levine DT and Stekel DJ 2016. So why have you added me? Adolescent girls’ technology-mediated attachments and relationships. Computers in Human Behaviour 63:25-34.

Highlights

  • Adolescent girls can develop attachment with others through, and with, technology.
  • Adolescent girls use technology to meet others and mediate relationships.
  • Facets of relationships can be understood as functions of secure relationships.
  • Functions include proximity-seeking, trust, exploration and return to secure base.
  • Technology use can amplify girls’ secure relationships with peers and parents.

Abstract

Technology plays an almost ubiquitous role in contemporary British society. Despite this, we do not have a well-theorised understanding of the ways adolescent girls use digital devices in the context of their developing secure relationships with their families and friends. This study aims to address this gap in understanding. Fifteen young women based in the Midlands and from across the socio-economic spectrum participated between 2012 and 2013. Participants completed three research tools exploring technology-mediated attachment and relationships, and participated in a face-to-face interview. The findings suggest that it is possible for girls to develop attachments with others through, and with, technology; technology use brings people together and mediates relationships in a range of ways encapsulated by attachment functions. The study highlights the ongoing importance of parental and peer relationships by suggesting that technology can act as a means by which the positive and negative attributes of existing relationships can be amplified.