A5017999075- Genetics and Neurodevelopmental Disorders
- Xenotransplantation and immune response
- Virus-based gene therapy research
- RNA Research and Splicing
- RNA modifications and cancer
- Herpesvirus Infections and Treatments
- RNA and protein synthesis mechanisms
- RNA regulation and disease
- Autism Spectrum Disorder Research
- Animal Genetics and Reproduction
- CRISPR and Genetic Engineering
- Animal Virus Infections Studies
- Genomic variations and chromosomal abnormalities
- Cytomegalovirus and herpesvirus research
- Toxoplasma gondii Research Studies
- Genomics and Chromatin Dynamics
- Chromatin Remodeling and Cancer
- CAR-T cell therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- Vector-Borne Animal Diseases
- Chronic Kidney Disease and Diabetes
- Viral-associated cancers and disorders
- Muscle Physiology and Disorders
- Metabolism and Genetic Disorders
- Lymphoma Diagnosis and Treatment
University of Edinburgh
2013-2024
MRC University of Glasgow Centre for Virus Research
2011-2018
University of Glasgow
2007-2017
Max Planck Institute for Molecular Genetics
2017
The Kids Research Institute Australia
2017
The University of Western Australia
2017
Glasgow Caledonian University
2008-2013
Medical Research Council
2011
Molecular Oncology (United States)
2009
Glasgow Royal Infirmary
2002
The genetic content of wild-type human cytomegalovirus was investigated by sequencing the 235 645 bp genome a low passage strain (Merlin). Substantial regions (genes RL1-UL11, UL105-UL112 and UL120-UL150) were also sequenced in several other strains, including two that had not been passaged cell culture. Comparative analyses, which employed published sequence high (AD169), indicated Merlin accurately reflects complement 165 genes, containing no obvious mutations than single nucleotide...
Deep sequencing was used to bring high resolution the human cytomegalovirus (HCMV) transcriptome at stage when infectious virion production is under way, and major findings were confirmed by extensive experimentation using conventional techniques. The majority (65.1%) of polyadenylated viral RNA transcription committed producing four noncoding transcripts (RNA2.7, RNA1.2, RNA4.9, RNA5.0) that do not substantially overlap designated protein-coding regions. Additional RNAs are transcribed...
Abstract Background Nrd1 and Nab3 are essential sequence-specific yeast RNA binding proteins that function as a heterodimer in the processing degradation of diverse classes RNAs. These also regulate several mRNA coding genes; however, it remains unclear exactly what percentage component transcriptome these control. To address this question, we used pyCRAC software package developed our laboratory to analyze CRAC PAR-CLIP data for Nrd1-Nab3-RNA interactions. Results We generated...
Acellular materials of xenogenic origin are used worldwide as xenografts, and phase I trials viable pig pancreatic islets currently being performed. However, limited information is available on transmission porcine endogenous retrovirus (PERV) after xenotransplantation the long-term immune response recipients to xenoantigens. We analyzed blood burn patients who had received living pig-skin dressings for up 8 wk presence PERV well level nature their long term (maximum, 34 y) against Ags....
Ribosome assembly in eukaryotes involves the activity of hundreds factors that direct hierarchical ribosomal proteins and numerous RNA folding steps. However, detailed insights into function events are lacking. To address this, we have developed ChemModSeq, a method combines structure probing, high-throughput sequencing statistical modeling, to quantitatively measure structural rearrangements during macromolecular complexes. By applying ChemModSeq purified 40S intermediates obtained...
Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay affected children. Deleterious mutations have been reported to occur throughout CDKL5 coding region. Several studies point a complex structure terms of exon usage transcript expression. Improvements molecular diagnosis more extensive research into neurobiology pathophysiology disorders necessitate an updated analysis gene. In this study, we...
RNA levels detected at steady state are the consequence of multiple dynamic processes within cell. In addition to synthesis and decay, transcripts undergo processing. Metabolic tagging with a nucleotide analog is one way determining relative contributions synthesis, decay conversion globally.By improving 4-thiouracil labeling in Saccharomyces cerevisiae we were able isolate produced during as little 1 minute, allowing detection nascent pervasive transcription. Nascent labeled for 1.5, 2.5 or...
Rett syndrome (RTT), caused by loss-of-function mutations in the MECP2 gene, is a neurological disorder characterized severe impairment of motor and cognitive functions. The aim this study was to investigate impact vector design, dosage, delivery route on efficacy safety gene augmentation therapy mouse models RTT. Our results show that AAV-mediated Mecp2 null mice systemic administration, utilizing minimal endogenous promoter, associated with narrow therapeutic window resulted liver toxicity...
Intravenous administration of adeno-associated virus serotype 9 (AAV9)/hMECP2 has been shown to extend the lifespan Mecp2−/y mice, but this delivery route induces liver toxicity in wild-type (WT) mice. To reduce peripheral transgene expression, we explored safety and efficacy AAV9/hMECP2 injected into cisterna magna (ICM). (1 × 1012 viral genomes [vg]; ICM) extended survival aggravated hindlimb clasping abnormal gait phenotypes. In WT 1 vg induced gait. A lower dose mitigated these adverse...
Abstract Renal tubular epithelial cells (RTECs) perform the essential function of maintaining constancy body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic imbalance, electrolyte abnormalities metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae high mortality. Here we report results kinome-wide RNAi screen for cellular pathways involved in AKI-associated...
To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, contexts population sequencing data and an updated characterization gene.We analyzed all known potentially pathogenic by combining from large-scale studies with available clinical cohorts combined this computational methods to predict pathogenicity.The study has identified several that can be reclassified as benign or likely benign. With addition novel variants, we confirm...
Conventional methods of gene transfer lead to inconsistent transgene expression within cells. This variability can be problematic, particularly in conditions like Rett syndrome (RTT), a neurological disorder caused by mutations the MECP2 (methyl-CpG binding protein 2) gene, because overexpression also cause adverse effects. To address these challenges, we devised regulation system called Expression Attenuation via Construct Tuning (EXACT), which uses self-contained, microRNA-based...
We uncovered a novel role for the spliceosome in regulating mRNA expression levels that involves splicing coupled to RNA decay, which we refer as spliceosome-mediated decay (SMD). Our transcriptome-wide studies identified numerous transcripts are not known have introns but spliced by at canonical splice sites Saccharomyces cerevisiae . Products of SMD primarily degraded nuclear surveillance machinery. demonstrate can significantly down-regulate levels; bromodomain factor 2 ( BDF2 )...
While the protein composition of various yeast 60S ribosomal subunit assembly intermediates has been studied in detail, little is known about RNA (rRNA) structural rearrangements that take place during early steps. Using a high-throughput structure probing method, we provide nucleotide resolution insights into rRNA nucleolar assembly. Our results suggest many rRNA-folding steps, such as folding 5.8S rRNA, occur at very specific stage assembly, and propose downstream nuclear events can only...
Multiple locus typing based on sequencing heterologous regions in 26 open reading frames (ORFs) of equine herpesvirus 1 (EHV-1) strains Ab4 and V592 was used to characterise 272 EHV-1 isolates from 238 outbreaks abortion, respiratory or neurological disease over a 28-year period. The analysis grouped the viruses into at least 10 13 unique long region (UL) clades previously recognised. Viruses same outbreak had identical multi-locus profiles. Sequencing ORF68 222 established divergence seven...
Equid herpesvirus 8 (EHV-8), formerly known as asinine 3, is an alphaherpesvirus that closely related to equid herpesviruses 1 and 9 (EHV-1 EHV-9). The pathogenesis of EHV-8 relatively little studied date has only been associated with respiratory disease in donkeys Australia horses China. A single genome sequence generated for strain Wh China, but apparently incomplete contains frameshifts two genes. In this study, the complete sequences four strains isolated Ireland between 2003 2015 were...
Previously a strategy for monitoring of pigs intended cell transplantation was developed and successfully applied to several representative herds in New Zealand. A designated pathogen-free (DPF) herd has been chosen as good candidate xenotransplantation. This previously tested free infectious agents relevant xenotransplantation we present here an depth study porcine endogenous retrovirus (PERV) transmission. panel assays that describes the constraints transmission PERV suggested. It includes...
The emergence of leukemia following gene transfer to restore common cytokine receptor γ chain (γC) function in X-linked severe combined immunodeficiency (SCID-X1) has raised important questions with respect therapy safety. To explore the risk factors involved, we tested oncogenic potential human γC new strains transgenic mice expressing under control CD2 promoter and locus region (LCR). These demonstrated mildly perturbed T-cell development, an increased proportion thymic CD8 cells, but...
It has been reported that peripheral blood mononuclear cells from miniature swine are capable of transmitting human tropic porcine endogenous retrovirus (PERV) recombinants to both and pig cells. suggested these exogenous and/or driven by one or more critical loci present in the genome.Genomic analysis a replication competent (HTRC) recombinant PERV-A/C identified PERV-C provirus region with homology sequences located on chromosome 7. In "null" swine, incapable vitro transmission PERV cells,...
Porcine endogenous retroviruses (PERV) represent a major safety concern in pig-to-human xenotransplantation. To date, no PERV infection of xenograft recipient has been recorded; however, PERVs are transmissible to human cells vitro. Some recombinants the A and C subgroups particularly efficient replication cells. Transcription described most pig cells, but their sequence insertion polymorphism genome impede identification transcriptionally active or silenced proviral copies. Furthermore,...
Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways governing NMJ stability are therefore of interest from both biological therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the formation maintenance post-synaptic elements NMJ, downstream tyrosine kinases 7 (DOK7) crucial activation MuSK pathway. Overexpression DOK7 using AAV9 has been shown to ameliorate...
Rett syndrome (RTT) is a neurological disorder that affects females and caused by loss-of-function mutations in the X-linked gene MECP2. Deletion of Mecp2 mice results constellation features resemble those seen RTT patients. Experiments have demonstrated restoration MeCP2, even at adult stages, reverses several aspects RTT-like pathology suggesting may be inherently treatable. This has provided an impetus to explore therapeutic approaches targeting level gene, including therapy, activation...