Biology subjects

Williams, R.

Publications and source records attributed to Williams, R..

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bioRxiv2021

Conformational changes in twitchin kinase in vivo revealed by FRET imaging of freely moving C. elegans

The force-induced unfolding and refolding of proteins is speculated to be a key mechanism in the sensing and transduction of mechanical signals in the living cell. Yet, little evidence has been gathered for its existence in vivo. Prominently, stretch-induced unfolding is postulated to be the activation mechanism of the twitchin/titin family of autoinhibited sarcomeric kinases linked to the mechanical stress response of muscle. To test the occurrence of mechanical kinase activation in living working muscle, we generated transgenic C. elegans expressing twitchin containing FRET moieties flanking the kinase domain and developed a quantitative technique for extracting FRET signals in freely moving C. elegans, using tracking and simultaneous imaging of animals in three channels (donor fluorescence, acceptor fluorescence, and transmitted light). Computer vision algorithms were used to extract fluorescence signals and muscle contraction states in each frame, in order to obtain fluorescence and body curvature measurements with spatial and temporal precision in vivo. The data revealed statistically significant periodic changes in FRET signals during muscle activity, consistent with a periodic change in the conformation of twitchin kinase. We conclude that stretch-unfolding of twitchin kinase occurs in the active muscle, whereby mechanical activity titrates the signalling pathway of this cytoskeletal kinase. We anticipate that the methods we have developed here could be applied to obtaining in vivo evidence for force-induced conformational changes or elastic behavior of other proteins not only in C. elegans but in other animals in which there is optical transparency (e.g zebrafish).

biophysics↗

bioRxiv2021

Global warming readiness: Feasibility of enhanced biological phosphorus removal from wastewater at 35oC

Recent research has shown enhanced biological phosphorus removal (EBPR) from municipal wastewater at warmer temperatures around 30{degrees}C to be stable in both laboratory-scale reactors and full-scale treatment plants. In the context of a changing climate, the feasibility of EBPR at even higher temperatures is of interest. We operated two lab-scale EBPR sequencing batch reactors with alternating anaerobic and aerobic phases for over 300 days at 30{degrees}C and 35{degrees}C, respectively, and followed the dynamics of the communities of phosphorus accumulating organisms (PAOs) and competing glycogen accumulating organisms (GAOs) using a combination of 16S rRNA gene metabarcoding, quantitative PCR and fluorescent in-situ hybridization analyses. Stable and nearly complete P removal was achieved at 30{degrees}C; similarly, long term P removal was stable at 35{degrees}C with effluent PO43--P concentrations < 0.5 mg/L on half of all monitored days. Diverse and abundant Ca. Accumulibacter amplicon sequence variants were closely related to those found in temperate environments, suggesting that EBPR at this temperature does not require a highly specialized PAO community. The slow-feeding strategy used effectively limited the carbon uptake rates of GAOs, allowing PAOs to outcompete GAOs at both temperatures. Candidatus Competibacter was the main GAO, along with cluster III Defluviicoccus members. These organisms withstood the slow-feeding regime, suggesting that their bioenergetic characteristics of carbon uptake differ from those of their tetrad-forming relatives. This specific lineage of GAOs warrants further study to establish how complete P removal can be maintained. Comparative cycle studies at two temperatures for each reactor revealed higher activity of Ca. Accumulibacter when the temperature was increased from 30{degrees}C to 35{degrees}C, suggesting that the stress was a result of the higher carbon (and/or P) metabolic rates of PAOs and GAOs, the resultant carbon deficiency, and additional community competition. An increase in the TOC to PO43--P ratio (from 25:1 to 40:1) effectively eased the carbon deficiency and benefited the proliferation of PAOs. In general, the slow-feeding strategy and sufficiently high carbon input benefited a high and stable EBPR at elevated temperature and represent basic conditions for full-scale applications.

microbiology↗

bioRxiv2020

The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

Wilms tumour (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to remove common cancer-associated epigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that were hypermethylated in WT cell lines compared to fetal kidney, of which ESRP2 (epithelial splicing regulatory protein 2), was the most promising gene for further study. ESRP2 was commonly repressed by DNA methylation in WT, and this was shown to occur early in WT development (in nephrogenic rests). ESRP2 expression could be reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was overexpressed in WT cell lines, it acted as an inhibitor of cellular proliferation in vitro, and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets, in addition to well-characterised targets of ESRP2. We propose a model in which the mesenchymal to epithelial transition that is essential for early kidney development, can be disrupted in to generate WT, either by genetic abnormalities such as WT1 mutations, or by epigenetic defects, such as ESRP2 methylation.

cancer biology↗

bioRxiv2020

Integrative systems approach reveals dynamics of microbiome-metal-ion axis in mesocosms representing tropical urban freshwater canal ecosystem

Freshwater ecosystems of tropical urban canals systems (TrUCS), are highly dynamic and experience constant pressures from interspersed effects of land-use and rain. The dynamic nature of TrUCS ecosystems presents a unique opportunity to unravel the signature interactions between the macro-organisms (top-down), sedimentary microbial communities (SedMICs), their functioning and the geochemical environment (bottom-up). A systems level understanding of the molecular and mechanistic basis of the highly dynamic behaviour that leads to specific ecosystem outcomes, is currently lacking. Therefore, a research framework to identify the direct link between top-down and bottom-up ecological effects on SedMICs in a highly dynamic urban canal sedimentary system is needed. Here, we present a framework of integrated multi-dimensional data across system-level biotic and abiotic ecological descriptors, such as environmental variables and active SedMICs. We followed the ecosystem shifts after a natural disturbance (rain) in two different anthropogenic disturbance (land-use) regimes. Shifts in profiles of metabolically active community were conserved across different land-use types, indicating resilience to perturbation is an intrinsic property of the TrUCs ecosystem. Three distinct phases, which were dominated sequentially by autotrophy, anoxic-heterotrophy and oxic-heterotrophy, were identified within these shifts. The first two phases were influenced by the bottom-up effects of specific metal-ion combinations of nitrates and sulfates with magnesium, aluminum and iron, and the third phase was triggered by top-down influences of bioturbation. This generalized systems-level approach, which provides an ecosystem-centric understanding of TrUCS and integrates them in sustainable management practices, can also be extended to other freshwater ecosystems.

ecology↗

bioRxiv2020

The isolate Caproiciproducens sp. 7D4C2 produces n-caproate at mildly acidic conditions from hexoses: genome and rBOX comparison with related strains and chain-elongating bacteria

BackgroundBulk production of medium-chain carboxylates (MCCs) with 6-12 carbon atoms is of great interest to biotechnology. Open cultures (e.g., reactor microbiomes) have been utilized to generate MCCs in bioreactors. When in-line MCC extraction and prevention of product inhibition is required, the bioreactors have been operated at mildly acidic pH (5.0-5.5). However, model chain-elongating bacteria grow optimally at neutral pH values. Here, we isolated a chain-elongating bacterium (strain 7D4C2) that thrives at mildly acidic pH. We studied its metabolism and compared its whole genome and the reverse {beta}-oxidation (rBOX) genes to other bacteria. ResultsStrain 7D4C2 produces lactate, acetate, n-butyrate, n-caproate, biomass, and H2/CO2 from hexoses. With only fructose as substrate (pH 5.5), the maximum n-caproate specificity (i.e., products per other carboxylates produced) was 60.9 {+/-} 1.5%. However, this was considerably higher at 83.1 {+/-} 0.44% when both fructose and n-butyrate (electron acceptor) were combined as a substrate. A comparison of serum bottles with fructose and n-butyrate with an increasing pH value from 4.5 to 9.0 showed a decreasing n-caproate specificity from [~]92% at mildly acidic pH (pH 4.5-5.0) to [~]24% at alkaline pH (pH 9.0). Moreover, when carboxylates were extracted from the broth (undissociated n-caproic acid was [~]0.3 mM), the n-caproate selectivity (i.e., product per substrate fed) was 42.6 {+/-} 19.0% higher compared to serum bottles without extraction. Based on the 16S rRNA gene sequence, strain 7D4C2 is most closely related to the isolates Caproicibacter fermentans (99.5%) and Caproiciproducens galactitolivorans (94.7%), which are chain-elongating bacteria that are also capable of lactate production. Whole-genome analyses indicate that strain 7D4C2, C. fermentans, and C. galactitolivorans belong to the same genus of Caproiciproducens. Their rBOX genes are conserved and located next to each other, forming a gene cluster, which is different than for other chain-elongating bacteria such as Megasphaera spp. ConclusionsCaproiciproducens spp., comprising strain 7D4C2, C. fermentans, C. galactitolivorans, and several unclassified strains, are chain-elongating bacteria that encode a highly conserved rBOX gene cluster. Caproiciproducens sp. 7D4C2 (DSM 110548) was studied here to understand n-caproate production better at mildly acidic pH within microbiomes and has the additional potential as a pure-culture production strain to convert sugars into n-caproate.

microbiology↗

bioRxiv2020

Dopamine-gated memory selection during slow wave sleep

The human brain selectively stores knowledge of the world to optimise future behaviour, automatically rehearsing, contextualising or discarding information to create a robust record of experiences. Storage or forgetting evolves over time, particularly during sleep. We have previously shown that dopamine given in the form of L-DOPA tablets improves long-term memory in Parkinsons disease, but only when given overnight. L-DOPA is already prescribed widely with a good safety profile and could potentially be rapidly repurposed to improve cognitive performance and improve quality of life in, for example, early Alzheimers Disease, if we understood the best time of day to prescribe. Therefore, we sought to test how dopamine shaped long-term memory formation before and during sleep in a double-blind randomised placebo-controlled cross-over trial of healthy older adults (n = 35). We administered L-DOPA after word-list learning to be active during repeat exposure to a proportion of the words and during subsequent nocturnal sleep. Nocturnal dopamine accelerated forgetting for words presented once but it did not affect memory for words presented twice. During slow wave sleep, L-DOPA also increased spindle amplitude around slow oscillation peaks. Larger dopamine-induced difference in word memory was associated with a larger increase in spindle amplitude. Dopamine-dependent memory processing may therefore modulate spindles dependent on slow-oscillation phase. Further, overnight dopamine increased total slow wave sleep duration by approximately 11%. This pharmaceutical modification of slow wave sleep may have potential health-enhancing benefits in old age that could include cognitive enhancement and Alzheimers prevention. One Sentence SummaryDopamine before sleep promotes forgetting of weak memory traces associated with increased spindle amplitude around the peak of a slow oscillations.

neuroscience↗

bioRxiv2020

SARS-CoV-2 genomes recovered by long amplicon tiling multiplex approach using nanopore sequencing and applicable to other sequencing platforms

Genomic surveillance has become a useful tool for better understanding virus pathogenicity, origin and spread. Obtaining accurately assembled, complete viral genomes directly from clinical samples is still a challenging. Here, we describe three protocols using a unique primer set designed to recover long reads of SARS-CoV-2 directly from total RNA extracted from clinical samples. This protocol is useful, accessible and adaptable to laboratories with varying resources and access to distinct sequencing methods: Nanopore, Illumina and/or Sanger.

molecular biology↗

bioRxiv2020

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

BackgroundAllograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT). MethodsThe DVL3 cell line was derived from a transgenic trp53-/-/Pten-/- mouse model and characterised both in vitro and in vivo. The DVL3 cells were allografted and response to RT was investigated and compared to the TRAMP-C1 model. Extensive tumour profiling in the DVL3 model was performed using flow cytometry, immunohistochemistry and RNA-seq. ResultsIn vitro the DVL3 cells expressed basal and luminal markers. DVL3 cells formed tumours with distinct glandular morphology which expressed androgen receptor, similar to human localised PC. DVL3 tumour growth was delayed following administration of fractionated RT, with infiltration of myeloid derived suppressor cells (MDSC). ConclusionsThe DVL3 allograft model represents substantial progress in PCa modelling, displaying; luminal differentiation, strong AR expression, and an immunosuppressive microenvironment, similar to observations in high-risk PCa patients. This model is ideally suited for development and validation of novel therapeutics, in particular immune-modulatory agents in combination with RT.

cancer biology↗

bioRxiv2020

In vitro biosynthesis of poly-β-1,4-glucan derivatives using a promiscuous glycosyltransferase

The {beta}-1,4-glucose linkage of cellulose is the most abundant polymeric linkage on earth and as such is of considerable interest in biology and biotechnology. It remains challenging to synthesize this linkage in vitro due to a lack of suitable biocatalysts; the natural cellulose biosynthetic machinery is a membrane-associated complex with processive activity that cannot be easily manipulated to synthesize tailor-made oligosaccharides and their derivatives. Here we identify a promiscuous activity of a soluble recombinant biocatalyst, Neisseria meningitidis glycosyltransferase LgtB, suitable for the polymerization of glucose from UDP-glucose via the generation of {beta}-1,4-glycosidic linkages. We employed LgtB to synthesize natural and derivatized cello-oligosaccharides and we demonstrate how LgtB can be incorporated in biocatalytic cascades and chemo-enzymatic strategies to synthesize cello-oligosaccharides with tailored functionalities. We also show how the resulting glycan structures can be applied as chemical probes to report on activity and selectivity of plant cell wall degrading enzymes, including lytic polysaccharide monooxygenases. We anticipate that this biocatalytic approach to derivatized cello-oligosaccharides via glucose polymerization will open up new applications in biology and nanobiotechnology.

biochemistry↗

bioRxiv2020

The Power of Citizen Science to Quantify Ecological Risks in Cities

Urbanization is an extreme form of habitat modification that can alter ecological relationships among organisms, but these can be hard to study because much of the urban landscape is inaccessible private property. We show that citizen science can be a powerful tool to overcome this challenge. We used photo-vouchered observations submitted to the citizen science platform iNaturalist to assess predation and parasitism across urbanization gradients in a secretive yet widespread species, the Southern Alligator Lizard (Elgaria multicarinata), in Southern California, USA. From photographs, we quantified predation risk by assessing tail injuries and quantified parasitism rates by counting tick loads on lizards. We estimated urbanization intensity by determining percent impervious surface around each lizard observation. We found that tail injuries increased with age of the lizard and with urbanization, suggesting that urban areas are riskier habitats, likely because of elevated populations of predators such as outdoor cats. Conversely, parasitism decreased with urbanization likely due to a loss of mammalian hosts and anti-tick medications used on companion animals. Moreover, our citizen science approach allowed us to generate a large dataset on a secretive species extremely rapidly and at an immense spatial scale that facilitated quantitative measures of urbanization (e.g. percent impervious surface cover) as opposed to qualitative measures (e.g. urban vs rural). This study demonstrates that citizen science is allowing researchers to answer ecological questions that otherwise would go unanswered.

ecology↗

bioRxiv2020

Characterising open chromatin identifies novel cis-regulatory elements important for paraxial mesoderm formation and axis extension

The development of multicellular organisms is exquisitely regulated through differential gene activity, which governs cell differentiation programs. However, many details of spatiotemporal control of gene regulation are still poorly understood. We used the accessibility of chick embryos to examine genome-wide signatures characterizing the progressive differentiation of paraxial mesoderm along the head-to-tail axis. Paraxial mesoderm becomes organized into repetitive units, termed somites, the hallmark of the segmented vertebrate body plan. New somite pairs form periodically as the axis extends at the posterior end. This process generates a developmental gradient within a single embryo, with anterior somites more advanced in their differentiation compared to posterior somites. Following somite formation, cell rearrangements generate compartments, comprising lineages of the musculoskeletal system, including cartilage of the vertebral column and ribs, and skeletal muscle cells of the trunk and limbs. To examine how paraxial mesoderm becomes regionalized and patterned to eventually generate these discrete lineages, we investigated dynamic changes of the transcriptome and of chromatin accessibility using RNA-seq and ATAC-seq across a spatiotemporal series along the embryonic axis. Footprint analysis uncovers differential coverage of binding sites for a number of key transcription factors known to be involved in axial patterning and differentiation, including HOX genes. Furthermore, associating accessible chromatin with nearby expressed genes identifies candidate cis-regulatory elements (CRE). As exemplars we use TCF15 and MEOX1, which are crucial for somite formation and differentiation, to experimentally validate CREs in vivo using fluorescent reporters. Time-lapse microscopy reveals CRE spatiotemporal activity and mutation analysis uncovers necessary upstream regulators. The CRE for MEOX1 is conserved and recognized in Xenopus. In addition, a human element is active in chicken. In vivo epigenome editing of TCF15 and MEOX1 CREs disrupts gene expression regulation and recapitulates phenotypic abnormalities of anterior-posterior axis extension.

developmental biology↗

bioRxiv2019

A Systematic Review of the Biomechanical Effects of Harness and Head-Collar use in Dogs

The number of dogs in the UK is on the rise, as are canine sports involving the use of a harness to allow the dog to pull against an interface in the same way as a husky might pull a sled. Service dogs and those involved in essential work commonly wear a harness throughout their working lives, yet little is understood regarding the biomechanical impact of their use. This systematic review was conducted to review reported evidence of the biomechanical effects of harness and head collar (Halti) use in dogs.\n\nSearches were applied covering 1910 to 2018 on the following databases: PubMed, Web of Science and Writtle Discovery.\n\nThree publications were identified as suitable which were then critically evaluated using predefined criteria and ARRIVE based guidelines for bias assessment. Only one was considered to provide the most reliable data regarding the influence of harnesses on gait, whilst the remainder were considered to suffer a variety of issues including poor sample size, repeatability and study execution. The most appropriate study found that wearing a chest strap harness reduced shoulder extension in both walk and trot by up to 8{degrees} of movement, whilst a Y-shaped harness commonly marketed as non-restrictive reduced shoulder extension by up to 10{degrees} of movement, suggesting that the use of harness type restraints can affect canine gait, whereas no studies were found relating to the biomechanical effects of head-collar usage.

zoology↗

bioRxiv2019

Conservation genomic analysis reveals ancient introgression and declining levels of genetic diversity in Madagascar’s hibernating dwarf lemurs

Madagascars biodiversity is notoriously threatened by deforestation and climate change. Many of these organisms are rare, cryptic, and severely threatened, making population-level sampling unrealistic. Such is the case with Madagascars dwarf lemurs (genus Cheirogaleus), the only obligate hibernating primate. We here apply comparative genomic approaches to generate the first genome-wide estimates of genetic diversity within dwarf lemurs. We generate a reference genome for the fat-tailed dwarf lemur, Cheirogaleus medius, and use this resource to facilitate analyses of high-coverage (~30x) genome sequences for wild-caught individuals representing species: C. sp. cf. medius, C. major, C. crossleyi and C. sibreei. This study represents the largest contribution to date of novel genomic resources for Madagascars lemurs. We find concordant phylogenetic relationships among the four lineages of Cheirogaleus across most of the genome, and yet detect a number of discordant genomic regions consistent with ancient admixture. We hypothesized that these regions could have resulted from adaptive introgression related to hibernation, indeed finding that genes associated with hibernation are present, though most significantly, that gene ontology categories relating to transcription are over-represented. We estimate levels of heterozygosity and find particularly low levels in an individual sampled from an isolated population of C. medius that we refer to as C. sp. cf. medius. Results are consistent with a recent decline in effective population size, which is evident across species. Our study highlights the power of comparative genomic analysis for identifying species and populations of conservation concern, as well as for illuminating possible mechanisms of adaptive phenotypic evolution.

genomics↗

bioRxiv2019

A large proportion of poor birth outcomes among Aboriginal Western Australians are attributable to smoking, alcohol and substance misuse, and assault

BackgroundAboriginal infants have poorer birth outcomes than non-Aboriginal infants. Harmful use of tobacco, alcohol, and other substances is higher among Aboriginal women, as is violence, due to factors such as intergenerational trauma and poverty. We estimated the proportion of small for gestational age (SGA) births, preterm births, and perinatal deaths that could be attributed to these risks. MethodsBirth, hospital, mental health, and death records for Aboriginal singleton infants born in Western Australia from 1998-2010 and their parents were linked. Using logistic regression with a generalized estimating equation approach, associations with birth outcomes and population attributable fractions were estimated after adjusting for demographic factors and maternal health during pregnancy. ResultsOf 28,119 births, 16% of infants were SGA, 13% were preterm, and 2% died perinatally. 51% of infants were exposed in utero to at least one of the risk factors and the fractions attributable to them were 37% (SGA), 16% (preterm) and 20% (perinatal death). ConclusionsA large proportion of adverse outcomes were attributable to the modifiable risk factors of substance use and assault. Significant improvements in Aboriginal perinatal health are likely to follow reductions in these risk factors. These results highlight the importance of identifying and implementing risk reduction measures which are effective in, and supported by, Aboriginal women, families, and communities.

epidemiology↗

bioRxiv2019

Differential effects of emerging broad-spectrum streetlight technologies on landscape-scale bat activity

Urbanization has greatly reduced the extent of high quality habitat available to wildlife with detrimental consequences documented across a range of taxa. Roads and artificial lighting regimes are dominant features of the modern environment, and there is currently a rapid worldwide transition towards energy-efficient, broad-spectrum white-light streetlight technologies such as metal halide (MH) and more recently, light-emitting diode (LED), despite little being known about their broad ecological impacts. Here, in a five-year citizen science study across the island of Jersey, we combine detailed lighting and habitat data with ultrasonic bat survey data collected from 2011 to 2015 (before and after a LED lighting technology transition), to analyse the landscape-scale effects of different broad-spectrum streetlight technologies on activity of a widespread, generalist bat species. In contrast to many experimental studies, we show that the local density of both traditional yellow high-pressure sodium (HPS) and more modern LED streetlights have significant negative effects on activity of the common pipistrelle (Pipistrelluspipistrellus) compared to unlit areas, while accounting for spatial bias, bat population trends over time, surrounding habitat type and road-type. In contrast, we find no discernable impact of the density of ultra-violet emitting MH lighting on bat activity. This is the first large-scale evidence that emerging artificial lighting technologies have differential impacts on activity, even for a bat species generally characterised as light-tolerant and commonly found in urban areas. Importantly, our landscape-level approach also demonstrates that the degree of urbanization and road type have even larger negative impacts on bat activity, independent of artificial lighting regime. Our findings emphasise the need for improving landscape-scale understanding of the ecological impacts of new lighting technologies prior to widespread uptake, and have important implications for future streetlight installation programmes and urban planning more generally.

ecology↗

bioRxiv2018

Whole genome sequencing Mycobacterium tuberculosis directly from sputum identifies more genetic diversity than sequencing from culture

BackgroundRepeated culture reduces within-sample Mycobacterium tuberculosis genetic diversity due to selection of clones suited to growth in culture and/or random loss of lineages, but it is not known to what extent omitting the culture step altogether alters genetic diversity. We compared M. tuberculosis whole genome sequences generated from 33 paired clinical samples using two methods. In one method DNA was extracted directly from sputum then enriched with custom-designed SureSelect (Agilent) oligonucleotide baits and in the other it was extracted from mycobacterial growth indicator tube (MGIT) culture.\n\nResultsDNA directly sequenced from sputum showed significantly more within-sample diversity than that from MGIT culture (median 5.0 vs 4.5 heterozygous alleles per sample, p=0.04). Resistance associated variants present as HAs occurred in four patients, and in two cases may provide a genotypic explanation for phenotypic resistance.\n\nConclusionsCulture-free M. tuberculosis whole genome sequencing detects more within-sample diversity than a leading culture-based method and may allow detection of mycobacteria that are not actively replicating.

genomics↗

bioRxiv2018

Using the drug-protein interactome to identify anti-ageing compounds for humans

Advancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established its association with ageing at multiple levels of biological actions including pathways, functions and protein interactions. Finally, combining all the data, we calculated a comprehensive ranked list of drugs that predicted tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.\n\nAuthor SummaryHuman life expectancy is continuing to increase worldwide, as a result of successive improvements in living conditions and medical care. Although this trend is to be celebrated, advancing age is the major risk factor for multiple impairments and chronic diseases. As a result, the later years of life are often spent in poor health and lowered quality of life. However, these effects of ageing are not inevitable, because very long-lived people often suffer rather little ill-health at the end of their lives. Furthermore, laboratory experiments have shown that animals fed with specific drugs can live longer and with fewer age-related diseases than their untreated companions. We therefore need to identify drugs with anti-ageing properties for humans. We have therefore used computers to search for drugs that affect components and processes known to be important in human ageing. This approach worked, because it was able to re-discover several drugs known to increase lifespan in animal models, plus some new ones, including one that we tested experimentally and validated in this study. These drugs are now a high priority for animal testing and for exploring effects on human ageing.

bioinformatics↗

bioRxiv2018

The intrinsic predictability of ecological time series and its potential to guide forecasting

Successfully predicting the future states of systems that are complex, stochastic and potentially chaotic is a major challenge. Model forecasting error (FE) is the usual measure of success; however model predictions provide no insights into the potential for improvement. In short, the realized predictability of a specific model is uninformative about whether the system is inherently predictable or whether the chosen model is a poor match for the system and our observations thereof. Ideally, model proficiency would be judged with respect to the systems intrinsic predictability - the highest achievable predictability given the degree to which system dynamics are the result of deterministic v. stochastic processes. Intrinsic predictability may be quantified with permutation entropy (PE), a model-free, information-theoretic measure of the complexity of a time series. By means of simulations we show that a correlation exists between estimated PE and FE and show how stochasticity, process error, and chaotic dynamics affect the relationship. This relationship is verified for a dataset of 461 empirical ecological time series. We show how deviations from the expected PE-FE relationship are related to covariates of data quality and the nonlinearity of ecological dynamics.\n\nThese results demonstrate a theoretically-grounded basis for a model-free evaluation of a systems intrinsic predictability. Identifying the gap between the intrinsic and realized predictability of time series will enable researchers to understand whether forecasting proficiency is limited by the quality and quantity of their data or the ability of the chosen forecasting model to explain the data. Intrinsic predictability also provides a model-free baseline of forecasting proficiency against which modeling efforts can be evaluated.\n\nGlossaryActive information: The amount of information that is available to forecasting models (redundant information minus lost information; Fig. 1).\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=45 SRC=\"FIGDIR/small/350017_fig1a.gif\" ALT=\"Figure 1A\">\nView larger version (9K):\norg.highwire.dtl.DTLVardef@934d9eorg.highwire.dtl.DTLVardef@ccdc10org.highwire.dtl.DTLVardef@1839ed9org.highwire.dtl.DTLVardef@31bd70_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1A.C_FLOATNO The total information content of an observation of a system at a given state in time, St, is depicted by filled circles with past states (St-1 and St-2) represented by shades of grey, i) lack of overlap between past and present states illustrating a case where no information is transmitted from past states (i.e. a purely stochastic system), with low redundancy and high Shannon entropy rate, ii) intermediate overlap indicating a case when some information is transferred from past to present (i.e. a deterministic system strongly driven by stochastic forcing), with intermediate redundancy and Shannon entropy rate, iii) large overlap indicating a case when the current state is mostly determined by the previous state (i.e. a highly deterministic system), with high redundancy and low Shannon entropy rate. Note that both the redundancy and Shannon entropy rate of a system are intrinsic properties of the system and will only change if the system itself changes.\n\nC_FIG Forecasting error (FE): A measure of the discrepancy between a models forecasts and the observed dynamics of a system. Common measures of forecast error are root mean squared error and mean absolute error.\n\nEntropy: Measures the average amount of information in the outcome of a stochastic process.\n\nInformation: Any entity that provides answers and resolves uncertainty about a process. When information is calculated using logarithms to the base two (i.e. information in bits), it is the minimum number of yes/no questions required, on average, to determine the identity of the symbol (Jost 2006). The information in an observation consists of information inherited from the past (redundant information), and of new information.\n\nIntrinsic predictability: the maximum achievable predictability of a system (Beckage et al. 2011).\n\nLost information: The part of the redundant information lost due to measurement or sampling error, or transformations of the data (Fig. 1).\n\nNew information, Shannon entropy rate: The Shannon entropy rate quantifies the average amount of information per observation in a time series that is unrelated to the past, i.e., the new information (Fig. 1).\n\nNonlinearity: When the deterministic processes governing system dynamics depend on the state of the system.\n\nPermutation entropy (PE): permutation entropy is a measure of the complexity of a time series (Bandt & Pompe, 2002) that is negatively correlated with a systems predictability (Garland et al. 2015). Permutation entropy quantifies the combined new and lost information. PE is scaled to range between a minimum of 0 and a maximum of 1.\n\nRealized predictability: the achieved predictability of a system from a given forecasting model.\n\nRedundant information: The information inherited from the past, and thus the maximum amount of information available for use in forecasting (Fig. 1).\n\nSymbols, words, permutations: symbols are simply the smallest unit in a formal language such as the letters in the English alphabet i.e., {\"A\", \"B\",..., \"Z\"}. In information theory the alphabet is more abstract, such as elements in the set {\"up\", \"down\"} or {\"1\", \"2\", \"3\"}. Words, of length m refer to concatenations of the symbols (e.g., up-down-down) in a set. Permutations are the possible orderings of symbols in a set. In this manuscript, the words are the permutations that arise from the numerical ordering of m data points in a time series.\n\nWeighted permutation entropy (WPE): a modification of permutation entropy (Fadlallah et al., 2013) that distinguishes between small-scale, noise-driven variation and large-scale, system-driven variation by considering the magnitudes of changes in addition to the rank-order patterns of PE.

ecology↗