ORCID Profile
0000-0002-8286-4683
Current Organisation
The University of Edinburgh
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Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.BRAINRES.2011.12.057
Abstract: Post-transcriptional regulation plays a major role in the generation of cell type ersity. In particular, alternative splicing increases ersification of transcriptome between tissues, in different cell types within a tissue, and even in different compartments of the same cell. The complexity of alternative splicing has increased during evolution. With increasing sophistication, however, comes greater potential for malfunction of these intricate processes. Indeed, recent years have uncovered a wealth of disease-causing mutations affecting RNA-binding proteins and non-coding regions on RNAs, highlighting the importance of studying disease mechanisms that act at the level of RNA processing. For instance, mutations in TARDBP and FUS, or a repeat expansion in the intronic region of the C9ORF72 gene, can all cause amyotrophic lateral sclerosis. We discuss how interspecies differences highlight the necessity for human model systems to complement existing non-human approaches to study neurodegenerative disorders. We conclude by discussing the improvements that could further increase the promise of human pluripotent stem for cell-based disease modeling. This article is part of a Special Issue entitled "RNA-Binding Proteins".
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 14-02-2017
DOI: 10.1101/108118
Abstract: RNA-binding proteins (RBPs) interact with and determine the fate of many cellular RNA transcripts. In doing so they help direct many essential roles in cellular physiology, whilst their perturbed activity can contribute to disease aetiology. In this chapter we detail a functional genomics approach, termed in idual nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP), that can determine the interactions of RBPs with their RNA targets in high throughput and at nucleotide resolution. iCLIP achieves this by exploiting UV-induced covalent crosslinks formed between RBPs and their target RNAs to both purify the RBP-RNA complexes under stringent conditions, and to cause reverse transcription stalling that then identifies the direct crosslink sites in the high throughput sequenced cDNA libraries.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2015
Publisher: American Chemical Society (ACS)
Date: 28-07-2020
Publisher: Public Library of Science (PLoS)
Date: 24-08-2018
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2016
DOI: 10.1101/068007
Abstract: Schizophrenia and the affective disorders, here comprising bipolar disorder and major depressive disorder, are psychiatric illnesses that lead to significant morbidity and mortality worldwide. Whilst understanding of their pathobiology remains limited, large case-control studies have recently identified single nucleotide polymorphisms (SNPs) associated with these disorders. However, discerning the functional effects of these SNPs has been difficult as the associated causal genes are unknown. Here we evaluated whether schizophrenia and affective disorder associated-SNPs are correlated with gene expression within human brain tissue. Specifically, to identify expression quantitative trait loci (eQTLs), we leveraged disorder-associated SNPs identified from six Psychiatric Genomics Consortium and CONVERGE Consortium studies with gene expression levels in post-mortem, neurologically-normal tissue from two independent human brain tissue expression datasets (UK Brain Expression Consortium (UKBEC) and Genotype-Tissue Expression (GTEx)). We identified 6 188 and 16 720 cis-acting SNPs exceeding genome-wide significance (p x10 −8 ) in the UKBEC and GTEx datasets, respectively. 1 288 cis-eQTLs were significant in a metaanalysis leveraging overlapping brain regions and were associated with expression of 15 genes, including three non-coding RNAs. One cis-eQTL, rs 16969968, results in a functionally disruptive missense mutation in CHRNA5 , a schizophrenia-implicated gene. Meta-analysis identified 297 trans -eQTLs associated with 24 genes that were significant in a region-specific manner. Importantly, comparing across tissues, we find that blood eQTLs largely do not capture brain cis-eQTLs. This study identifies putatively causal genes whose expression in region-specific brain tissue may contribute to the risk of schizophrenia and affective disorders.
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2018
DOI: 10.1101/394239
Abstract: Cellular DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill-defined. Given the centrality of RNA polymerase II (Pol II) promoter-proximal pause release in transcriptional control, we evaluated its importance in DDR. Here we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates Pol II elongation and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by genotoxic stress-enhanced binding of RBM7 to 7SK snRNA (7SK), the scaffold of the 7SK small nuclear ribonucleoprotein (7SK snRNP) which inhibits P-TEFb. In turn, P-TEFb relocates from 7SK snRNP to chromatin to induce transcription of short units including key DDR genes and multiple classes of non-coding RNAs. Critically, interfering with RBM7 or P-TEFb provokes cellular hypersensitivity to DNA damage-inducing agents through activation of apoptotic program. By alleviating the inhibition of P-TEFb, RBM7 thus facilitates Pol II elongation to enable a pro-survival transcriptional response that is crucial for cell fate upon genotoxic insult. Our work uncovers a new paradigm in stress-dependent control of Pol II pause release, and offers the promise for designing novel anti-cancer interventions using RBM7 and P-TEFb antagonists in combination with DNA-damaging chemotherapeutics.
Publisher: American Chemical Society (ACS)
Date: 16-11-2021
Abstract: Liquid metals (LMs) are electronic liquid with enigmatic interfacial chemistry and physics. These features make them promising materials for driving chemical reactions on their surfaces for designing nanoarchitectonic systems. Herein, we showed the interfacial interaction between eutectic gallium-indium (EGaIn) liquid metal and graphene oxide (GO) for the reduction of both substrate-based and free-standing GO. NanoIR surface mapping indicated the successful removal of carbonyl groups. Based on the gained knowledge, a composite consisting of assembled reduced GO sheets on LM microdroplets (LM-rGO) was developed. The LM enforced Ga
Publisher: Springer Science and Business Media LLC
Date: 05-2015
DOI: 10.1038/NATURE14466
Publisher: American Chemical Society (ACS)
Date: 30-08-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1NR02529E
Abstract: Biosensors are essential components for effective healthcare management.
Publisher: American Chemical Society (ACS)
Date: 08-10-2021
Publisher: Wiley
Date: 11-12-2021
Publisher: Springer Science and Business Media LLC
Date: 27-10-2017
DOI: 10.1038/S41467-017-01283-Z
Abstract: Astrocyte responses to neuronal injury may be beneficial or detrimental to neuronal recovery, but the mechanisms that determine these different responses are poorly understood. Here we show that ephrin type-B receptor 1 (EphB1) is upregulated in injured motor neurons, which in turn can activate astrocytes through ephrin-B1-mediated stimulation of signal transducer and activator of transcription-3 (STAT3). Transcriptional analysis shows that EphB1 induces a protective and anti-inflammatory signature in astrocytes, partially linked to the STAT3 network. This is distinct from the response evoked by interleukin (IL)-6 that is known to induce both pro inflammatory and anti-inflammatory processes. Finally, we demonstrate that the EphB1–ephrin-B1 pathway is disrupted in human stem cell derived astrocyte and mouse models of amyotrophic lateral sclerosis (ALS). Our work identifies an early neuronal help-me signal that activates a neuroprotective astrocytic response, which fails in ALS, and therefore represents an attractive therapeutic target.
Publisher: Wiley
Date: 25-11-2020
Publisher: Springer Science and Business Media LLC
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0CS01070G
Abstract: To harvest the unique properties offered by 2D HSs, creation of well-defined heterointerfaces on a large scale is a prerequisite, where the chemistry and nature of heterointerfaces define the targeted applications.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1038/MT.2009.306
Publisher: American Chemical Society (ACS)
Date: 06-10-2021
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 08-2021
Publisher: Wiley
Date: 10-06-2021
Abstract: Cytokines are critical mediators that oversee and regulate immune and inflammatory responses via complex networks and serve as biomarkers for many diseases. Quantification of cytokines has significant value in both clinical medicine and biology as the levels provide insights into physiological and pathological processes and can be used to aid diagnosis and treatment. Cytokines and their clinical significance are introduced from the perspective of their pro‐ and anti‐inflammatory effects. Factors affecting cytokines quantification in biological fluids, native levels in different body fluids, s le processing and storage conditions, sensitivity to freeze‐thaw, and soluble cytokine receptors are discussed. In addition, recent advances in in vitro and in vivo assays, biosensors based on different signal outputs and intracellular to extracellular protein expression are summarized. Various quantification platforms for high‐sensitivity and reliable measurement of cytokines in different scenarios are discussed, and commercially available cytokine assays are compared. A discussion of challenges in the development and advancement of technologies for cytokine quantification that aim to achieve real‐time multiplex cytokine analysis for point‐of‐care situations applicable for both biomedical research and clinical practice are discussed.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1EE00531F
Abstract: A succinct but critical survey of the recent progress in LMBs is presented, comprising their intriguing electrode chemistries, underlying electrochemical behaviors with various electrolytes, and sophisticated electrode–electrolyte interfaces in the context of the most recent research and development.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1NA00501D
Abstract: Hybrid piezo–triboelectric nanogenerators constitute a new class of self-powered systems that exploit the synergy of piezoelectric and triboelectric mechanisms to address the energy and power needs for portable and wearable electronic devices.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2011
DOI: 10.1007/S00109-011-0781-Z
Abstract: RNA interference (RNAi) represents a powerful post-transcriptional gene silencing network which fine-tunes gene expression in all eukaryotic cells. The endogenous triggers of RNAi, microRNAs (miRNAs), are proposed to regulate expression of up to a third of all protein-coding genes, and have been shown to have critical roles in developmental processes including in the central nervous system and skeletal muscle. Further, many have been reported to display differential expression in various disease states. Here we describe present understanding of the biogenesis and function of miRNAs, review current knowledge of miRNA abnormalities in both human neurological and skeletal muscle disease and discuss their potential as novel disease biomarkers. Finally, we highlight the many ways in which the miRNA pathway may be targeted for therapeutic benefit.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2019
Publisher: Wiley
Date: 12-09-2021
Abstract: The introduction of trace impurities within the doping processes of semiconductors is still a technological challenge for the electronics industries. By taking advantage of the selective enrichment of liquid metal interfaces, and harvesting the doped metal oxide semiconductor layers, the complexity of the process can be mitigated and a high degree of control over the outcomes can be achieved. Here, a mechanism of natural filtering for the preparation of doped 2D semiconducting sheets based on the different migration tendencies of metallic elements in the bulk competing for enriching the interfaces is proposed. As a model, liquid metal alloys with different weight ratios of Sn and Bi in the bulk are employed for harvesting Bi 2 O 3 ‐doped SnO nanosheets. In this model, Sn shows a much stronger tendency than Bi to occupy surface sites of the Bi–Sn alloys, even at the very high concentrations of Bi in the bulk. This provides the opportunity for creating SnO 2D sheets with tightly controlled Bi 2 O 3 dopants. By way of ex le, it is demonstrated how such nanosheets could be made selective to both reducing and oxidizing environmental gases. The process demonstrated here offers significant opportunities for future synthesis and fabrication processes in the electronics industries.
Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2012
Abstract: Mirtrons are introns that form pre-miRNA hairpins after splicing to produce RNA interference (RNAi) effectors distinct from Drosha-dependent intronic miRNAs. Here we present a design algorithm for artificial mirtrons and demonstrate, for the first time, efficient gene knockdown of myotonic dystrophy protein kinase (DMPK) target sequences in Renilla luciferase 3′ UTR and subsequently pathogenic DMPK mRNA, causative of Type I myotonic dystrophy, using artificial mirtrons cloned as eGFP introns. Deep sequencing of artificial mirtrons suggests that functional mature transcripts corresponding to the designed sequence were produced in high abundance. They were further shown to be splicing-dependent, Drosha-independent, and partially dependent on exportin-5, resulting in the precise generation of pre-miRNAs. In a murine myoblast line containing a pathogenic copy of human DMPK with more than 500 CUG repeats, the DMPK artificial mirtron corrected DM1-associated splicing abnormalities of the Serca-1 mRNA, demonstrating the therapeutic potential of mirtron-mediated RNAi. Thus, further development and exploitation of the unique properties of mirtrons will benefit future research and therapeutic RNAi applications as an alternative to conventional RNAi strategies.
Publisher: Springer New York
Date: 2018
DOI: 10.1007/978-1-4939-7213-5_29
Abstract: RNA-binding proteins (RBPs) interact with and determine the fate of many cellular RNA transcripts. In doing so they help direct many essential roles in cellular physiology, while their perturbed activity can contribute to disease etiology. In this chapter we detail a functional genomics approach, termed in idual nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP), that can determine the interactions of RBPs with their RNA targets in high throughput and at nucleotide resolution. iCLIP achieves this by exploiting UV-induced covalent cross-links formed between RBPs and their target RNAs to both purify the RBP-RNA complexes under stringent conditions, and to cause reverse transcription stalling that then identifies the direct cross-link sites in the high throughput sequenced cDNA libraries.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2021
DOI: 10.1038/S41598-021-86070-Z
Abstract: Single cell transcriptome profiling has emerged as a breakthrough technology for the high-resolution understanding of complex cellular systems. Here we report a flexible, cost-effective and user-friendly droplet-based microfluidics system, called the Nadia Instrument, that can allow 3′ mRNA capture of ~ 50,000 single cells or in idual nuclei in a single run. The precise pressure-based system demonstrates highly reproducible droplet size, low doublet rates and high mRNA capture efficiencies that compare favorably in the field. Moreover, when combined with the Nadia Innovate, the system can be transformed into an adaptable setup that enables use of different buffers and barcoded bead configurations to facilitate erse applications. Finally, by 3′ mRNA profiling asynchronous human and mouse cells at different phases of the cell cycle, we demonstrate the system's ability to readily distinguish distinct cell populations and infer underlying transcriptional regulatory networks. Notably this provided supportive evidence for multiple transcription factors that had little or no known link to the cell cycle (e.g. DRAP1, ZKSCAN1 and CEBPZ). In summary, the Nadia platform represents a promising and flexible technology for future transcriptomic studies, and other related applications, at cell resolution.
Publisher: Portland Press Ltd.
Date: 08-2014
DOI: 10.1042/BST20140102
Abstract: Alternative splicing is universally accredited for expanding the information encoded within the transcriptome. In recent years, several tightly regulated alternative splicing events have been reported which do not lead to generation of protein products, but lead to unstable mRNA isoforms. Instead these transcripts are targets for NMD (nonsense-mediated decay) or retained in the nucleus and degraded. In the present review I discuss the regulation of these events, and how many have been implicated in control of gene expression that is instrumental to a number of developmental paradigms. I further discuss their relevance to disease settings and conclude by highlighting technologies that will aid identification of more candidate events in future.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0TB01655A
Abstract: Broad-spectrum treatment of monoculture and mixed species biofilms using magnetically actuated, liquid metal particles.
Publisher: Elsevier BV
Date: 11-2018
Publisher: American Chemical Society (ACS)
Date: 11-2021
Publisher: Cold Spring Harbor Laboratory
Date: 06-01-2020
DOI: 10.1101/2020.01.06.895524
Abstract: Single cell transcriptome profiling has emerged as a breakthrough technology for the high-resolution understanding of complex cellular systems. Here we report a flexible, cost-effective and user-friendly droplet-based microfluidics system, called the Nadia Instrument, that can allow 3’ mRNA capture of ∼50,000 single cells or in idual nuclei in a single run. The precise pressure-based system demonstrates highly reproducible droplet size, low doublet rates and high mRNA capture efficiencies that compare favorably in the field. Moreover, when combined with the Nadia Innovate, the system can be transformed into an adaptable setup that enables use of different buffers and barcoded bead configurations to facilitate erse applications. Finally, by 3’ mRNA profiling asynchronous human and mouse cells at different phases of the cell cycle, we demonstrate the system’s ability to readily distinguish distinct cell populations and infer underlying transcriptional regulatory networks. Notably this identified multiple transcription factors that had little or no known link to the cell cycle (e.g. DRAP1, ZKSCAN1 and CEBPZ). In summary, the Nadia platform represents a promising and flexible technology for future transcriptomic studies, and other related applications, at cell resolution.
Publisher: Elsevier BV
Date: 02-2014
Publisher: Cold Spring Harbor Laboratory
Date: 05-2017
Abstract: Nonsense-mediated mRNA decay (NMD) controls gene expression by eliminating mRNAs with premature or aberrant translation termination. Degradation of NMD substrates is initiated by the central NMD factor UPF1, which recruits the endonuclease SMG6 and the deadenylation-promoting SMG5/7 complex. The extent to which SMG5/7 and SMG6 contribute to the degradation of in idual substrates and their regulation by UPF1 remains elusive. Here we map transcriptome-wide sites of SMG6-mediated endocleavage via 3′ fragment capture and degradome sequencing. This reveals that endogenous transcripts can have NMD-eliciting features at various positions, including upstream open reading frames (uORFs), premature termination codons (PTCs), and long 3′ UTRs. We find that NMD substrates with PTCs undergo constitutive SMG6-dependent endocleavage, rather than SMG7-dependent exonucleolytic decay. In contrast, the turnover of NMD substrates containing uORFs and long 3′ UTRs involves both SMG6- and SMG7-dependent endo- and exonucleolytic decay, respectively. This suggests that the extent to which SMG6 and SMG7 degrade NMD substrates is determined by the mRNA architecture.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2017
Publisher: Wiley
Date: 25-06-2012
DOI: 10.1002/WRNA.1122
Abstract: Post-transcriptional gene silencing (PTGS) via RNA interference (RNAi) is a vital gene regulatory mechanism for fine-tuning gene expression. RNAi effectors termed microRNAs (miRNAs) are implicated in various aspects of animal development and normal physiological function, while dysregulation has been linked to several pathologies. Several atypical miRNA biogenesis pathways have been identified, yet in most cases the reasons for their emergence remain unclear. One of these atypical pathways is the mirtron pathway, where short introns are excised by splicing to generate intermediates of the RNAi pathway, with no cleavage by the microprocessor. Closely related pathways involving tailed-mirtron and simtron biogenesis have also been described. There is extensive evidence that mirtrons function as miRNAs, and while some are evolutionarily conserved across similar species, others appear to have emerged relatively recently. In addition, through exploitation of the potent and sequence-specific silencing capabilities of RNAi, synthetic mirtrons may have potential for overcoming certain therapeutic challenges.
Publisher: Public Library of Science (PLoS)
Date: 21-10-2011
Publisher: Informa UK Limited
Date: 27-01-2021
Publisher: Springer Science and Business Media LLC
Date: 08-07-2020
Publisher: Cold Spring Harbor Laboratory
Date: 09-05-2016
Abstract: Polycomb repressive complex 2 (PRC2) modifies chromatin to maintain genes in a repressed state during development. PRC2 is primarily associated with CpG islands at repressed genes and also possesses RNA binding activity. However, the RNAs that bind PRC2 in cells, the subunits that mediate these interactions, and the role of RNA in PRC2 recruitment to chromatin all remain unclear. By performing iCLIP for PRC2 in comparison with other RNA binding proteins, we show here that PRC2 binds nascent RNA at essentially all active genes. Although interacting with RNA promiscuously, PRC2 binding is enriched at specific locations within RNAs, primarily exon–intron boundaries and the 3′ UTR. Deletion of other PRC2 subunits reveals that SUZ12 is sufficient to establish this RNA binding profile. Contrary to prevailing models, we also demonstrate that the interaction of PRC2 with RNA or chromatin is mutually antagonistic in cells and in vitro. RNA degradation in cells triggers PRC2 recruitment to CpG islands at active genes. Correspondingly, the release of PRC2 from chromatin in cells increases RNA binding. Consistent with this, RNA and nucleosomes compete for PRC2 binding in vitro. We propose that RNA prevents PRC2 recruitment to chromatin at active genes and that mutual antagonism between RNA and chromatin underlies the pattern of PRC2 chromatin association across the genome.
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 15-08-2017
Publisher: Elsevier BV
Date: 05-2017
Publisher: Springer Science and Business Media LLC
Date: 31-05-2016
DOI: 10.1038/NRG.2016.46
Publisher: American Chemical Society (ACS)
Date: 10-01-2020
Abstract: Antibiotic resistance has made the treatment of biofilm-related infections challenging. As such, the quest for next-generation antimicrobial technologies must focus on targeted therapies to which pathogenic bacteria cannot develop resistance. Stimuli-responsive therapies represent an alternative technological focus due to their capability of delivering targeted treatment. This study provides a proof-of-concept investigation into the use of magneto-responsive gallium-based liquid metal (LM) droplets as antibacterial materials, which can physically damage, disintegrate, and kill pathogens within a mature biofilm. Once exposed to a low-intensity rotating magnetic field, the LM droplets become physically actuated and transform their shape, developing sharp edges. When placed in contact with a bacterial biofilm, the movement of the particles resulting from the magnetic field, coupled with the presence of nanosharp edges, physically ruptures the bacterial cells and the dense biofilm matrix is broken down. The antibacterial efficacy of the magnetically activated LM particles was assessed against both Gram-positive and Gram-negative bacterial biofilms. After 90 min over 99% of both bacterial species became nonviable, and the destruction of the biofilms was observed. These results will impact the design of next-generation, LM-based biofilm treatments.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2019
End Date: 2024
Funder: Wellcome Trust
View Funded ActivityStart Date: 2019
End Date: 2021
Funder: Simons Foundation
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: Motor Neurone Disease Association
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: Wellcome Trust
View Funded Activity