Imperial College London

Nick S Jones

Faculty of Natural SciencesDepartment of Mathematics

Professor of Mathematical Sciences
 
 
 
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Contact

 

+44 (0)20 7594 1146nick.jones

 
 
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Location

 

301aSir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

97 results found

Hoffmann T, Jones NS, Inference of a universal social scale and segregation measures using social connectivity kernels, Journal of the Royal Society Interface, ISSN: 1742-5662

How people connect with one another is a fundamental question in the social sciences, and the resulting social networks can have a profound impact on our daily lives. Blau offered a powerful explanation: people connect with one another based on their positions in a social space. Yet a principled measure of social distance, allowing comparison within and between societies, remains elusive.We use the connectivity kernel of conditionally-independent edge models to develop a family of segregation statistics with desirable properties: they offer an intuitive and universal characteristic scale on social space (facilitating comparison across datasets and societies), are applicable to multivariate and mixed node attributes, and capture segregation at the level of individuals, pairs of individuals, and society as a whole. We show that the segregation statistics can induce a metric on Blau space (a space spanned by the attributes of the members of society) and provide maps of two societies.Under a Bayesian paradigm, we infer the parameters of the connectivity kernel from eleven ego-network datasets collected in four surveys in the United Kingdom and United States. The importance of different dimensions of Blau space is similar across time and location, suggesting a macroscopically stable social fabric. Physical separation and age differences have the most significant impact on segregation within friendship networks with implications for intergenerational mixing and isolation in later stages of life.

Journal article

Sethi S, Ewers R, Jones N, Signorelli A, Picinali L, Orme CDLet al., 2020, SAFE Acoustics: an open-source, real-time eco-acoustic monitoring network in the tropical rainforests of Borneo, Methods in Ecology and Evolution, Vol: 11, Pages: 1182-1185, ISSN: 2041-210X

1. Automated monitoring approaches offer an avenue to unlocking large‐scale insight into how ecosystems respond to human pressures. However, since data collection and data analyses are often treated independently, there are currently no open‐source examples of end‐to‐end, real‐time ecological monitoring networks. 2. Here, we present the complete implementation of an autonomous acoustic monitoring network deployed in the tropical rainforests of Borneo. Real‐time audio is uploaded remotely from the field, indexed by a central database, and delivered via an API to a public‐facing website.3. We provide the open‐source code and design of our monitoring devices, the central web2py database, and the ReactJS website. Furthermore, we demonstrate an extension of this infrastructure to deliver real‐time analyses of the eco‐acoustic data. 4. By detailing a fully functional, open source, and extensively tested design, our work will accelerate the rate at which fully autonomous monitoring networks mature from technological curiosities, and towards genuinely impactful tools in ecology.

Journal article

Lechuga-Vieco AV, Latorre-Pellicer A, Johnston IG, Prota G, Gileadi U, Justo-Méndez R, Acín-Pérez R, Martínez-de-Mena R, Fernández-Toro JM, Jimenez-Blasco D, Mora A, Nicolás-Ávila JA, Santiago DJ, Priori SG, Bolaños JP, Sabio G, Criado LM, Ruíz-Cabello J, Cerundolo V, Jones NS, Enríquez JAet al., 2020, Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics, Science Advances, Vol: 6, Pages: eaba5345-eaba5345, ISSN: 2375-2548

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type–specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.

Journal article

Sethi S, Jones NS, Fulcher B, Picinali L, Clink DJ, Klinck H, Orme CDLO, Wrege P, Ewers Ret al., 2020, Characterising soundscapes across diverse ecosystems using a universal acoustic feature-set, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 17049-17055, ISSN: 0027-8424

Natural habitats are being impacted by human pressures at an alarming rate. Monitoring these ecosystem-level changes often requires labor-intensive surveys that are unable to detect rapid or unanticipated environmental changes. Here we have developed a generalizable, data-driven solution to this challenge using eco-acoustic data. We exploited a convolutional neural network to embed soundscapes from a variety of ecosystems into a common acoustic space. In both supervised and unsupervised modes, this allowed us to accurately quantify variation in habitat quality across space and in biodiversity through time. On the scale of seconds, we learned a typical soundscape model that allowed automatic identification of anomalous sounds in playback experiments, providing a potential route for real-time automated detection of irregular environmental behavior including illegal logging and hunting. Our highly generalizable approach, and the common set of features, will enable scientists to unlock previously hidden insights from acoustic data and offers promise as a backbone technology for global collaborative autonomous ecosystem monitoring efforts.

Journal article

Fulcher B, Lubba C, Sethi S, Jones Net al., 2020, A self-organizing, living library of time-series data, Scientific Data, Vol: 7, ISSN: 2052-4463

Time-series data are measured across the sciences, from astronomy to biomedicine, but meaningful cross-disciplinary interactions are limited by the challenge of identifying fruitful connections. Here we introduce the web platform, CompEngine, a self-organizing, living library of time-series data, that lowers the barrier to forming meaningful interdisciplinary connections between time series. Using a canonical feature-based representation, CompEngine places all time series in a common feature space, regardless of their origin, allowing users to upload their data and immediately explore diverse data with similar properties, and be alerted when similar data is uploaded in future. In contrast to conventional databases which are organized by assigned metadata, CompEngine incentivizes data sharing by automatically connecting experimental and theoretical scientists across disciplines based on the empirical structure of the data they measure. CompEngine’s growing library of interdisciplinary time-series data also enables the comprehensive characterization of time-series analysis algorithms across diverse types of empirical data.

Journal article

Insalata F, Hoitzing H, Aryaman J, Jones Net al., 2020, Survival of the Densest Explains the Expansion of Mitochondrial Deletions in Skeletal Muscle Fibres, 48th European Mathematical Genetics Meeting (EMGM), Publisher: KARGER, Pages: 211-211, ISSN: 0001-5652

Conference paper

Lechuga-Vieco AV, Latorre-Pellicer A, Johnston IG, Prota G, Gileadi U, Justo-Méndez R, Acín-Pérez R, Martínez-de-Mena R, Fernández-Toro JM, Jimenez-Blasco D, Mora A, Nicolás-Ávila JA, Santiago DJ, Priori SG, Bolaños JP, Sabio G, Criado LM, Ruíz-Cabello J, Cerundolo V, Jones NS, Enríquez JAet al., 2020, Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics., Sci Adv, Vol: 6

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.

Journal article

Heaton LLM, Jones NS, Fricker MD, 2020, A mechanistic explanation of the transition to simple multicellularity in fungi., Nature Communications, Vol: 11, ISSN: 2041-1723

Development of multicellularity was one of the major transitions in evolution and occurred independently multiple times in algae, plants, animals, and fungi. However recent comparative genome analyses suggest that fungi followed a different route to other eukaryotic lineages. To understand the driving forces behind the transition from unicellular fungi to hyphal forms of growth, we develop a comparative model of osmotrophic resource acquisition. This predicts that whenever the local resource is immobile, hard-to-digest, and nutrient poor, hyphal osmotrophs outcompete motile or autolytic unicellular osmotrophs. This hyphal advantage arises because transporting nutrients via a contiguous cytoplasm enables continued exploitation of remaining resources after local depletion of essential nutrients, and more efficient use of costly exoenzymes. The model provides a mechanistic explanation for the origins of multicellular hyphal organisms, and explains why fungi, rather than unicellular bacteria, evolved to dominate decay of recalcitrant, nutrient poor substrates such as leaf litter or wood.

Journal article

Hoffmann T, Peel L, Lambiotte R, Jones Net al., 2020, Community detection in networks without observing edges, Science Advances, Vol: 6, Pages: 1-12, ISSN: 2375-2548

We develop a Bayesian hierarchical model to identify communities of time series. Fitting the model provides an end-to-end community detection algorithmthat does not extract information as a sequence of point estimates but propagates uncertainties from the raw data to the community labels. Our approachnaturally supports multiscale community detection as well as the selection ofan optimal scale using model comparison. We study the properties of the algorithm using synthetic data and apply it to daily returns of constituents of theS&P100 index as well as climate data from US cities.

Journal article

McGrath T, Spreckley E, Rodriguez A, Viscomi C, Alamshah A, Akalestou E, Murphy K, Jones Net al., 2019, The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents, PLoS Biology, Vol: 17, ISSN: 1544-9173

Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that capturesthe complexity of feeding behaviour. We construct an accurate stochasticmodel of rodent feeding at the bout level in order to perform quantitativebehavioural analysis. Analysing the different effects on feeding behaviour ofPYY3-36, lithium chloride, GLP-1 and leptin shows the precise behaviouralchanges caused by each anorectic agent. Our analysis demonstrates that thechanges in feeding behaviour evoked by the anorectic agents investigated donot mimic the behaviour of well-fed animals, and that the intermeal intervalis influenced by fullness. We show how robust homeostatic control of feedingthwarts attempts to reduce food intake, and how this might be overcome. Insilico experiments suggest that introducing a minimum intermeal interval ormodulating upper gut emptying can be as effective as anorectic drug administration.

Journal article

Latorre-Pellicer A, Lechuga-Vieco AV, Johnston IG, Hämäläinen RH, Pellico J, Justo-Méndez R, Fernández-Toro JM, Clavería C, Guaras A, Sierra R, Llop J, Torres M, Criado LM, Suomalainen A, Jones NS, Ruíz-Cabello J, Enríquez JAet al., 2019, Regulation of mother-to-offspring transmission of mtDNA heteroplasmy, Cell Metabolism, Vol: 30, Pages: 1120-1130.e5, ISSN: 1550-4131

mtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission.

Journal article

Lubba CH, Sethi SS, Knaute P, Schultz SR, Fulcher BD, Jones NSet al., 2019, catch22: CAnonical time-series CHaracteristics, Data Mining and Knowledge Discovery, Vol: 33, Pages: 1821-1852, ISSN: 1384-5810

Capturing the dynamical properties of time series concisely as interpretable feature vectors can enable efficient clustering and classification for time-series applications across science and industry. Selecting an appropriate feature-based representation of time series for a given application can be achieved through systematic comparison across a comprehensive time-series feature library, such as those in the hctsa toolbox. However, this approach is computationally expensive and involves evaluating many similar features, limiting the widespread adoption of feature-based representations of time series for real-world applications. In this work, we introduce a method to infer small sets of time-series features that (i) exhibit strong classification performance across a given collection of time-series problems, and (ii) are minimally redundant. Applying our method to a set of 93 time-series classification datasets (containing over 147,000 time series) and using a filtered version of the hctsa feature library (4791 features), we introduce a set of 22 CAnonical Time-series CHaracteristics, catch22, tailored to the dynamics typically encountered in time-series data-mining tasks. This dimensionality reduction, from 4791 to 22, is associated with an approximately 1000-fold reduction in computation time and near linear scaling with time-series length, despite an average reduction in classification accuracy of just 7%. catch22 captures a diverse and interpretable signature of time series in terms of their properties, including linear and non-linear autocorrelation, successive differences, value distributions and outliers, and fluctuation scaling properties. We provide an efficient implementation of catch22, accessible from many programming environments, that facilitates feature-based time-series analysis for scientific, industrial, financial and medical applications using a common language of interpretable time-series properties.

Journal article

Aryaman J, Bowles C, Jones NS, Johnston IGet al., 2019, Mitochondrial network state scales mtDNA genetic dynamics, Genetics, Vol: 212, Pages: 1429-1443, ISSN: 0016-6731

Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion/fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.

Journal article

Burgstaller J, Kolbe T, Havlicek V, Hembach S, Poulton J, Piálek J, Steinborn R, Rulicke T, Brem G, Jones NS, Johnston Iet al., 2019, Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations, Nature Communications, Vol: 9, ISSN: 2041-1723

Vital mitochondrial DNA (mtDNA) populations exist in cells and may consist of heteroplasmic mixtures of mtDNA types. The evolution of these heteroplasmic populations through development, ageing, and generations is central to genetic diseases, but is poorly understood in mammals. Here we dissect these population dynamics using a dataset of unprecedented size and temporal span, comprising 1947 single-cell oocyte and 899 somatic measurements of heteroplasmy change throughout lifetimes and generations in two genetically distinct mouse models. We provide a novel and detailed quantitative characterisation of the linear increase in heteroplasmy variance throughout mammalian life courses in oocytes and pups. We find that differences in mean heteroplasmy are induced between generations, and the heteroplasmy of germline and somatic precursors diverge early in development, with a haplotype-specific direction of segregation. We develop stochastic theory predicting the implications of these dynamics for ageing and disease manifestation and discuss its application to human mtDNA dynamics.

Journal article

Hoitzing H, Gammage PA, Haute LV, Minczuk M, Johnston IG, Jones NSet al., 2019, Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations, PLoS Computational Biology, Vol: 15, ISSN: 1553-734X

The dynamics of the cellular proportion of mutant mtDNA molecules is crucial for mitochondrial diseases. Cellular populations of mitochondria are under homeostatic control, but the details of the control mechanisms involved remain elusive. Here, we use stochastic modelling to derive general results for the impact of cellular control on mtDNA populations, the cost to the cell of different mtDNA states, and the optimisation of therapeutic control of mtDNA populations. This formalism yields a wealth of biological results, including that an increasing mtDNA variance can increase the energetic cost of maintaining a tissue, that intermediate levels of heteroplasmy can be more detrimental than homoplasmy even for a dysfunctional mutant, that heteroplasmy distribution (not mean alone) is crucial for the success of gene therapies, and that long-term rather than short intense gene therapies are more likely to beneficially impact mtDNA populations.

Journal article

Brittain R, Jones N, Ouldridge T, 2019, Biochemical Szilard engines for memory-limited inference, New Journal of Physics, Vol: 21, ISSN: 1367-2630

By designing and leveraging an explicit molecular realisation of a measurement-and-feedback-powered Szilard engine, we investigate the extraction of work from complex environments by minimal machines with finite capacity for memory and decision-making. Living systems perform inference to exploit complex structure, or correlations, in their environment, but the physical limits and underlying cost/benefit trade-offs involved in doing so remain unclear. To probe these questions, we consider a minimal model for a structured environment—a correlated sequence of molecules—and explore mechanisms based on extended Szilard engines for extracting the work stored in these non-equilibrium correlations. We consider systems limited to a single bit of memory making binary 'choices' at each step. We demonstrate that increasingly complex environments allow increasingly sophisticated inference strategies to extract more free energy than simpler alternatives, and argue that optimal design of such machines should also consider the free energy reserves required to ensure robustness against fluctuations due to mistakes.

Journal article

Lubba CH, Le Guen Y, Jarvis S, Jones NS, Cork SC, Eftekhar A, Schultz SRet al., 2019, Correction to: PyPNS: Multiscale Simulation of a Peripheral Nerve in Python., Neuroinformatics

The original version of this article unfortunately contained a mistake. The following text: "This project has received funding from European Research Council (ERC) Synergy Grant no. 319818." is missing in the Acknowledgments.

Journal article

Insalata F, Hoitzing H, Jones N, 2019, A mathematical model of expansion of disadvantaged but altruistic mitochondrial mutants in skeletal muscle fibres, Publisher: WILEY, Pages: 61-61, ISSN: 0014-2972

Conference paper

Aryaman J, Johnston I, Jones N, 2019, Mitochondrial heterogeneity, Frontiers in Genetics, Vol: 9, ISSN: 1664-8021

Cell-to-cell heterogeneity drives a range of (patho)physiologically important phenomena, such as cell fate and chemotherapeutic resistance. The role of metabolism, and particularly of mitochondria, is increasingly being recognized as an important explanatory factor in cell-to-cell heterogeneity. Most eukaryotic cells possess a population of mitochondria, in the sense that mitochondrial DNA (mtDNA) is held in multiple copies per cell, where the sequence of each molecule can vary. Hence, intra-cellular mitochondrial heterogeneity is possible, which can induce inter-cellular mitochondrial heterogeneity, and may drive aspects of cellular noise. In this review, we discuss sources of mitochondrial heterogeneity (variations between mitochondria in the same cell, and mitochondrial variations between supposedly identical cells) from both genetic and non-genetic perspectives, and mitochondrial genotype-phenotype links. We discuss the apparent homeostasis of mtDNA copy number, the observation of pervasive intra-cellular mtDNA mutation (which is termed “microheteroplasmy”), and developments in the understanding of inter-cellular mtDNA mutation (“macroheteroplasmy”). We point to the relationship between mitochondrial supercomplexes, cristal structure, pH, and cardiolipin as a potential amplifier of the mitochondrial genotype-phenotype link. We also discuss mitochondrial membrane potential and networks as sources of mitochondrial heterogeneity, and their influence upon the mitochondrial genome. Finally, we revisit the idea of mitochondrial complementation as a means of dampening mitochondrial genotype-phenotype links in light of recent experimental developments. The diverse sources of mitochondrial heterogeneity, as well as their increasingly recognized role in contributing to cellular heterogeneity, highlights the need for future single-cell mitochondrial measurements in the context of cellular noise studies.

Journal article

Lubba CT, Le Guen Y, Jarvis S, Jones N, Cork S, Eftekhar A, Schultz Set al., 2019, PyPNS: multiscale simulation of a peripheral nerve in Python, Neuroinformatics, Vol: 17, Pages: 63-81, ISSN: 1539-2791

Bioelectronic Medicines that modulate the activity patterns on peripheral nerves have promise as a new way of treating diverse medical conditions from epilepsy to rheumatism. Progress in the field builds upon time consuming and expensive experiments in living organisms. To reduce experimentation load and allow for a faster, more detailed analysis of peripheral nerve stimulation and recording, computational models incorporating experimental insights will be of great help.We present a peripheral nerve simulator that combines biophysical axon models and numerically solved and idealised extracellular space models in one environment. We modeled the extracellular space as a three-dimensional resistive continuum governed by the electro-quasistatic approximation of the Maxwell equations. Potential distributions were precomputed in finite element models for different media (homogeneous, nerve in saline, nerve in cuff) and imported into our simulator. Axons, on the other hand, were modeled more abstractly as one-dimensional chains of compartments. Unmyelinated fibres were based on the Hodgkin- Huxley model; for myelinated fibres, we adapted the model proposed by McIntyre et al. in 2002 to smaller diameters. To obtain realistic axon shapes, an iterative algorithm positioned fibres along the nerve with a variable tortuosity fit to imaged trajectories. We validated our model with data from the stimulated rat vagus nerve. Simulation results predicted that tortuosity alters recorded signal shapes and increases stimulation thresholds. The model we developed can easily be adapted to different nerves, and may be of use for Bioelectronic Medicine research in the future.

Journal article

Lubba CH, Fulcher BD, Schultz SR, Jones NSet al., 2019, Efficient peripheral nerve firing characterisation through massive feature extraction, 9th IEEE/EMBS International Conference on Neural Engineering (NER), Publisher: IEEE, Pages: 179-182, ISSN: 1948-3546

Conference paper

Brittain R, Jones N, Ouldridge T, 2018, Biochemical Szilard engine for memory limited inference

Code and data for figures in 'Biochemical Szilard engine for memory limited inference'

Software

Sethi S, Ewers R, Jones N, Orme D, Picinali Let al., 2018, Robust, real-time and autonomous monitoring of ecosystems with an open, low-cost, networked device, Methods in Ecology and Evolution, Vol: 9, Pages: 2383-2387, ISSN: 2041-210X

1. Automated methods of monitoring ecosystems provide a cost-effective way to track changes in natural system's dynamics across temporal and spatial scales. However, methods of recording and storing data captured from the field still require significant manual effort. 2. Here we introduce an open source, inexpensive, fully autonomous ecosystem monitoring unit for capturing and remotely transmitting continuous data streams from field sites over long time-periods. We provide a modular software framework for deploying various sensors, together with implementations to demonstrate proof of concept for continuous audio monitoring and time-lapse photography. 3. We show how our system can outperform comparable technologies for fractions of the cost, provided a local mobile network link is available. The system is robust to unreliable network signals and has been shown to function in extreme environmental conditions, such as in the tropical rainforests of Sabah, Borneo. 4. We provide full details on how to assemble the hardware, and the open-source software. Paired with appropriate automated analysis techniques, this system could provide spatially dense, near real-time, continuous insights into ecosystem and biodiversity dynamics at a low cost.

Journal article

Garrod M, Jones NS, 2018, Large algebraic connectivity fluctuations in spatial network ensembles imply a predictive advantage from node location information, Physical Review E, Vol: 98, ISSN: 1539-3755

A random geometric graph (RGG) ensemble is defined by the disordered distribution of its node locations. We investigate how this randomness drives sample-to-sample fluctuations in the dynamical properties of these graphs. We study the distributional properties of the algebraic connectivity which is informative of diffusion and synchronization time scales in graphs. We use numerical simulations to provide a characterization of the algebraic connectivity distribution for RGG ensembles. We find that the algebraic connectivity can show fluctuations relative to its mean on the order of 30%, even for relatively large RGG ensembles (N=105). We explore the factors driving these fluctuations for RGG ensembles with different choices of dimensionality, boundary conditions, and node distributions. Within a given ensemble, the algebraic connectivity can covary with the minimum degree and can also be affected by the presence of density inhomogeneities in the nodal distribution. We also derive a closed-form expression for the expected algebraic connectivity for RGGs with periodic boundary conditions for general dimension.

Journal article

Keogh M, Wei W, Aryaman J, Walker L, van den Ameele J, Coxhead J, Wilson I, Bashton M, Beck J, West J, Chen R, Haudenschild C, Bartha G, Luo S, Morris C, Jones N, Attems J, Chinnery Pet al., 2018, High prevalence of focal and multi-focal somatic genetic variants in the human brain, Nature Communications, Vol: 9, ISSN: 2041-1723

Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.

Journal article

Wei W, Keogh MJ, Aryaman J, Golder Z, Kullar PJ, Wilson I, Talbot K, Turner MR, McKenzie C-A, Troakes C, Attems J, Smith C, Sarraj SA, Morris CM, Ansorge O, Jones NS, Ironside JW, Chinnery PFet al., 2018, Frequency and signature of somatic variants in 1461 human brain exomes, Genetics in Medicine, Vol: 21, Pages: 904-912, ISSN: 1098-3600

PURPOSE: To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders. METHODS: In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24. RESULTS: We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10-10 per base pair per individual. CONCLUSION: These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.

Journal article

Keogh MJ, Wei W, Aryaman J, Wilson I, Talbot K, Turner MR, McKenzie C-A, Troakes C, Attems J, Smith C, Al Sarraj S, Morris CM, Ansorge O, Pickering-Brown S, Jones N, Ironside JW, Chinnery PFet al., 2018, Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 89, Pages: 813-816, ISSN: 0022-3050

Journal article

Pezet M, Gomez-Duran A, Aryaman J, Jones NS, Chinnery PFet al., 2018, Understanding the mechanism underpinning the transmission of mtDNA mutations, 11th UK Neuromuscular Translational Research Conference, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: S35-S35, ISSN: 0960-8966

Conference paper

McGrath TM, Murphy KG, Jones NS, 2018, Quantitative approaches to energy and glucose homeostasis: machine learning and modelling for precision understanding and prediction, Journal of the Royal Society Interface, Vol: 15, ISSN: 1742-5662

Obesity is a major global public health problem. Understanding how energy homeostasis is regulated, and can become dysregulated, is crucial for developing new treatments for obesity. Detailed recording of individual behaviour and new imaging modalities offer the prospect of medically relevant models of energy homeostasis that are both understandable and individually predictive. The profusion of data from these sources has led to an interest in applying machine learning techniques to gain insight from these large, relatively unstructured datasets. We review both physiological models and machine learning results across a diverse range of applications in energy homeostasis, and highlight how modelling and machine learning can work together to improve predictive ability. We collect quantitative details in a comprehensive mathematical supplement. We also discuss the prospects of forecasting homeostatic behaviour and stress the importance of characterizing stochasticity within and between individuals in order to provide practical, tailored forecasts and guidance to combat the spread of obesity.

Journal article

Salnikov V, Cassese D, Lambiotte R, Jones NSet al., 2018, Co-occurrence simplicial complexes in mathematics: identifying the holes of knowledge., Appl Netw Sci, Vol: 3

In the last years complex networks tools contributed to provide insights on the structure of research, through the study of collaboration, citation and co-occurrence networks. The network approach focuses on pairwise relationships, often compressing multidimensional data structures and inevitably losing information. In this paper we propose for the first time a simplicial complex approach to word co-occurrences, providing a natural framework for the study of higher-order relations in the space of scientific knowledge. Using topological methods we explore the conceptual landscape of mathematical research, focusing on homological holes, regions with low connectivity in the simplicial structure. We find that homological holes are ubiquitous, which suggests that they capture some essential feature of research practice in mathematics. k-dimensional holes die when every concept in the hole appears in an article together with other k+1 concepts in the hole, hence their death may be a sign of the creation of new knowledge, as we show with some examples. We find a positive relation between the size of a hole and the time it takes to be closed: larger holes may represent potential for important advances in the field because they separate conceptually distant areas. We provide further description of the conceptual space by looking for the simplicial analogs of stars and explore the likelihood of edges in a star to be also part of a homological cycle. We also show that authors' conceptual entropy is positively related with their contribution to homological holes, suggesting that polymaths tend to be on the frontier of research.

Journal article

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