Biology subjects

Ellis, S.

Publications and source records attributed to Ellis, S..

26 records · Page 2Linked to original sources

bioRxiv2022

Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

AbstractRibosomopathies are a class of disorders caused by defects in the structure or function of the ribosome and characterized by tissue-specific abnormalities. Diamond Blackfan anemia (DBA) arises from different mutations, predominantly in genes encoding ribosomal proteins (RPs). Apart from the anemia, skeletal defects are among the most common anomalies observed in patients with DBA, but they are virtually restricted to radial ray and other upper limb defects. What leads to these site-specific skeletal defects in DBA remains a mystery. Using a novel mouse model for RP haploinsufficiency, we observed specific, differential defects of the limbs. Using complementary in vitro and in vivo approaches, we demonstrate that reduced WNT signaling and subsequent increased {beta}-catenin degradation in concert with increased expression of p53 contribute to mesenchymal lineage failure. We observed differential defects in the proliferation and differentiation of mesenchymal stem cells (MSCs) from the forelimb versus the hind limbs of the RP haploinsufficient mice that persisted after birth and were partially rescued by allelic reduction of Trp53. These defects are associated with a global decrease in protein translation in RP haploinsufficient MSCs, with the effect more pronounced in cells isolated from the forelimbs. Together these results demonstrate translational differences inherent to the MSC, explaining the site-specific skeletal defects observed in DBA.

cell biology↗

bioRxiv2021

Isomeric lipid signatures reveal compartmentalised fatty acid metabolism in cancer

1.0Cellular energy and biomass demands of cancer drive a complex dynamic between uptake of extracellular fatty acids (FA) and de novo synthesis. Given that oxidation of de novo synthesised FAs for energy would result in net-energy loss, there is an implication that FAs from these two sources must have distinct metabolic fates - however hitherto FAs were considered part of a common pool. To probe FA metabolic partitioning, cancer cells were supplemented with stable-isotope labelled FAs. Structural analysis of the resulting glycerophospholipids revealed that labelled FAs from uptake were largely incorporated to canonical (sn-)positions on the glycerol backbone. Surprisingly, labelled FA uptake disrupted canonical isomer patterns of the unlabelled lipidome and induced repartitioning of n-3 and n-6 polyunsaturated-FAs into glycerophospholipid classes. These structural changes evidence differences in the metabolic fate of FAs derived from uptake or de novo sources and demonstrate unique signalling and remodelling behaviours usually hidden to conventional lipidomics. HighlightsO_LILipid isomers reveal discrete metabolic compartmentalisation in cancer C_LIO_LIFAs derived from uptake and de novo synthesis have different metabolic fates C_LIO_LIStearate uptake signals for PUFA (n-3 and n-6) repartitioning between lipid classes C_LIO_LIsn-positional isomers are a marker for aberrant lipid metabolism C_LI

cancer biology↗

bioRxiv2021

Development of a pest threshold decision support system for minimising damage to winter wheat from wheat bulb fly, Delia coarctata

Graphical AbstractIn this article we describe two predictive models that can be used for the integrated management of wheat bulb fly. Our first model is a pest level prediction model and our second model predicts the number of shoots a winter wheat crop will achieve by the terminal spikelet developmental stage. We revise and update current wheat bulb fly damage thresholds and combine this with our two models to devise a tolerance-based decision support system that can be used to minimise the risk of crop damage by wheat bulb fly. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/435242v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@ee5b9aorg.highwire.dtl.DTLVardef@c0197corg.highwire.dtl.DTLVardef@1c9519eorg.highwire.dtl.DTLVardef@d6a52_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryWheat bulb fly, Delia coarctata, is an important pest of winter wheat in the UK, causing significant damage of up to 4 t ha-1. Accepted population thresholds for D. coarctata are 250 eggs m-2 for crops sown up to the end of October and 100 eggs m-2 for crops sown from November. Fields with populations of D. coarctata that exceed the thresholds are at higher risk of experiencing economically damaging pest infestations. In the UK, recent withdrawal of insecticides means that only a seed treatment is available for chemical control of D. coarctata, however this is only effective for late-sown crops (November onwards) and accurate estimations of annual population levels are required to ensure a seed treatment is applied if needed. As a result of the lack of post-drilling control strategies, the management of D. coarctata is becoming increasingly reliant on non-chemical methods of control. Control strategies that are effective in managing similar stem-boring pests of wheat include sowing earlier and using higher seed rates to produce crops with more shoots and greater tolerance to shoot damage. In this study we develop two predictive models that can be used for integrated D. coarctata management. The first is an updated pest level prediction model that predicts D. coarctata populations from meteorological parameters with a predictive accuracy of 70%, which represents a significant improvement on the previous D. coarctata population prediction model. Our second model predicts the maximum number of shoots for a winter wheat crop that would be expected at the terminal spikelet development stage. This shoot number model uses information about the thermal time from plant emergence to terminal spikelet, leaf phyllochron length, plant population, and sowing date to predict the degree of tolerance a crop will have against D. coarctata. The shoot number model was calibrated against data collected from five field experiments and tested against data from four experiments. Model testing demonstrated that the shoot number model has a predictive accuracy of 70%. A decision support system using these two models for the sustainable management of D. coarcata risk is described.

plant biology↗

bioRxiv2021

Sphingolipid Control of Fibroblast Heterogeneity Revealed by Single-Cell Lipidomics

Human cells produce thousands of lipids that impact a wide range of biological processes in ways we are only starting to characterize. The cellular composition in lipids changes during differentiation events and also varies across individual cells of the same type. Yet, the precise differences in lipid composition that directly affect cell phenotypes remain unknown. Here we have measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging to single-cell transcriptomics. We found that the cell-to-cell variation of specific lipid metabolic pathways contributes to the establishment of cell states involved in wound repair and in skin cancer growth. Sphingolipid composition defined fibroblast subpopulations while sphingolipid metabolic rewiring drove cell state transitions. These data uncover a role for cell-to-cell lipid heterogeneity in the determination of cell states and reveal a new regulatory component to the homeostasis and self-organization of multicellular systems.

biochemistry↗

bioRxiv2020

Common datastream permutations of animal social network data are not appropriate for hypothesis testing using regression models

O_LISocial network methods have become a key tool for describing, modelling, and testing hypotheses about the social structures of animals. However, due to the non-independence of network data and the presence of confounds, specialized statistical techniques are often needed to test hypotheses in these networks. Datastream permutations, originally developed to test the null hypothesis of random social structure, have become a popular tool for testing a wide array of null hypotheses. In particular, they have been used to test whether exogenous factors are related to network structure by interfacing these permutations with regression models. C_LIO_LIHere, we show that these datastream permutations typically do not represent the null hypothesis of interest to researchers interfacing animal social network analysis with regression modelling, and use simulations to demonstrate the potential pitfalls of using this methodology. C_LIO_LIOur simulations show that utilizing common datastream permutations to test the coefficients of regression models can lead to extremely high type I (false-positive) error rates (> 30%) in the presence of non-random social structure. The magnitude of this problem is primarily dependent on the degree of non-randomness within the social structure and the intensity of sampling C_LIO_LIWe strongly recommend against utilizing datastream permutations to test regression models in animal social networks. We suggest that a potential solution may be found in regarding the problems of non-independence of network data and unreliability of observations as separate problems with distinct solutions. C_LI

animal behavior and cognition↗

bioRxiv2019

Targeting RNA Polymerase I transcription synergises with TOP1 inhibition in potentiating the DNA damage response in high-grade serous ovarian cancer

Limited effective therapeutic options are available for patients with recurrent high-grade serous carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. We have shown efficacy in poly-ADP ribose polymerase (PARP) inhibitor-resistant HGSC for the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 through its ability to activate a nucleolar-associated DNA damage response (DDR). Here, we screen the protein-coding genome to identify potential targets whose inhibition enhances the efficacy of CX-5461. We identify a network of cooperating inhibitory interactions, including components of homologous recombination (HR) DNA repair and DNA topoisomerase 1 (TOP1). We highlight that CX-5461 combined with topotecan, a TOP1 inhibitor used as salvage therapy in HGSC, induces robust cell cycle arrest and cell death in a panel of HR-proficient HGSC cell lines. The combination potentiates a nucleolar-associated DDR via recruitment of phosphorylated replication protein A (RPA) and ataxia telangiectasia and Rad3 related protein (ATR). CX-5461 plus low-dose topotecan cooperate to potently inhibit xenograft tumour growth, indicating the potential for this strategy to improve salvage therapeutic regimens to treat HGSC.

cancer biology↗

bioRxiv2019

Towards a Fine-scale Population Health Monitoring System

Understanding population health disparities is an essential component of equitable precision health efforts. Epidemiology research often relies on definitions of race and ethnicity, but these population labels may not adequately capture disease burdens specific to sub-populations. Here we propose a framework for repurposing data from Electronic Health Records (EHRs) in concert with genomic data to explore enrichment of disease within sub-populations. Using data from a diverse biobank in New York City, we genetically identified 17 sub-populations, and noted the presence of genetic founder effects in 7. By then linking community membership to the EHR, we were able to identify over 600 health outcomes that were statistically enriched within a specific population, with many representing known associations, and many others being novel. This work reinforces the utility of linking genomic data to EHRs, and provides a framework towards fine-scale monitoring of population health.

genomics↗

bioRxiv2019

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

cancer biology↗