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"Bell, Christopher"
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Epigenomic insights into common human disease pathology
The epigenome—the chemical modifications and chromatin-related packaging of the genome—enables the same genetic template to be activated or repressed in different cellular settings. This multi-layered mechanism facilitates cell-type specific function by setting the local sequence and 3D interactive activity level. Gene transcription is further modulated through the interplay with transcription factors and co-regulators. The human body requires this epigenomic apparatus to be precisely installed throughout development and then adequately maintained during the lifespan. The causal role of the epigenome in human pathology, beyond imprinting disorders and specific tumour suppressor genes, was further brought into the spotlight by large-scale sequencing projects identifying that mutations in epigenomic machinery genes could be critical drivers in both cancer and developmental disorders. Abrogation of this cellular mechanism is providing new molecular insights into pathogenesis. However, deciphering the full breadth and implications of these epigenomic changes remains challenging. Knowledge is accruing regarding disease mechanisms and clinical biomarkers, through pathogenically relevant and surrogate tissue analyses, respectively. Advances include consortia generated cell-type specific reference epigenomes, high-throughput DNA methylome association studies, as well as insights into ageing-related diseases from biological ‘clocks’ constructed by machine learning algorithms. Also, 3rd-generation sequencing is beginning to disentangle the complexity of genetic and DNA modification haplotypes. Cell-free DNA methylation as a cancer biomarker has clear clinical utility and further potential to assess organ damage across many disorders. Finally, molecular understanding of disease aetiology brings with it the opportunity for exact therapeutic alteration of the epigenome through CRISPR-activation or inhibition.
Journal Article
Churchill and the Dardanelles
The failure of the Allied fleet to force a passage through the Straits of the Dardanelles in 1915 drove Winston Churchill from office (First Lord of the Admiralty) in disgrace and nearly destroyed his political career. For over a century, Churchill has been both praised and condemned for his role in launching this highly controversial campaign. For some, the Dardanelles offensive was a brilliant concept that might have dramatically shortened the First World War. To many others, however, Churchill was a reckless amateur who drove his unwilling and misinformed colleagues into a venture that was doomed to fail. This book, based on exhaustive archival research, provides a detailed and authoritative account of the Gallipoli campaign's origins and execution, stripping away the layers of myth that have long surrounded these dramatic events, and showing that no simple verdict is either possible or fair. Naval historian Christopher M. Bell untangles Churchill's complicated relationship with the dynamic First Sea Lord, Admiral Jacky Fisher, and reveals for the first time the behind-the-scenes machinations that led to Churchill's removal from office, including Fisher's covert campaign to undermine support for the Dardanelles operation, and the leaks by figures in high places that fuelled a bitter press campaign to drive Churchill from power. Equal attention is also given to the perhaps even more important story of Churchill and the Dardanelles after 1915. As Bell shows, Churchill spent a good deal of time and effort in the following two decades trying to refute his critics and convince the wider public that the campaign had in fact nearly succeeded. These efforts were so successful that the legacy of the Dardanelles did not stand in the way of Churchill becoming Prime Minister in May 1940--Provided by publisher.
BOOK
DNA methylation aging clocks: challenges and recommendations
Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.
Journal Article
Grump Groan Growl
Rhythmic text exposes a bad mood on the prowl, and advises the reader not to hide, but to let those feelings be.
Book
The use of X-ray computed tomography for advanced detection of Globodera pallida
Potato cyst nematodes (PCN), namely Globodera pallida , pose a significant threat to potato production worldwide. Accurately quantifying nematode population densities is crucial for effective management strategies. However, traditional detection methods are time-consuming and often imprecise. X-ray computed tomography (CT) offers high-resolution, non-destructive and three-dimensional (3D) imaging frequently used to visualise internal structures of objects, materials or biological tissues, allowing for detailed analysis of their composition, defects, and morphology. Here, we demonstrate the effectiveness of X-ray CT in detecting and quantifying PCN cysts in two different soil types. The ability to achieve 3D imaging and volume quantification of PCN cysts from soils allows accurate enumeration of their egg content. Combined with the potential to co-analyse other organisms within the same sample, we propose X-ray CT as an innovative tool for comprehensive soil health assessments and sustainable pest management in agriculture.
Journal Article
Decision in the Atlantic : the Allies and the longest campaign of the Second World War
\"The Battle of the Atlantic was the longest campaign of the Second World War. This volume highlights the scale and complexity of this bitterly contested campaign, one that encompassed far more than just attacks by German U-boats on Allied shipping. The team of leading scholars assembled in this study situates the German assault on seaborne trade within the wider Allied war effort and provides a new understanding of its place within the Second World War. Individual chapters offer original perspectives on a range of neglected or previously overlooked subjects: how Allied grand strategy shaped the war at sea; the choices facing Churchill and other Allied leaders and the tensions over the allocation of scarce resources between theaters; how the battle spread beyond the Atlantic Ocean in both military and economic terms; the management of Britain's merchant shipping repair yards; the defense of British coastal waters against German surface raiders; the contribution of air power to trade defense; antisubmarine escort training; the role of special intelligence; and the war against the U-boats in the Arctic and Pacific Oceans.\"--Provided by publisher.
Book
Plant-parasitic nematodes respond to root exudate signals with host-specific gene expression patterns
Plant parasitic nematodes must be able to locate and feed from their host in order to survive. Here we show that Pratylenchus coffeae regulates the expression of selected cell-wall degrading enzyme genes relative to the abundance of substrate in root exudates, thereby tailoring gene expression for root entry of the immediate host. The concentration of cellulose or xylan within the exudate determined the level of β-1,4-endoglucanase (Pc-eng-1) and β-1,4-endoxylanase (Pc-xyl) upregulation respectively. Treatment of P. coffeae with cellulose or xylan or with root exudates deficient in cellulose or xylan conferred a specific gene expression response of Pc-eng-1 or Pc-xyl respectively with no effect on expression of another cell wall degrading enzyme gene, a pectate lyase (Pc-pel). RNA interference confirmed the importance of regulating these genes as lowered transcript levels reduced root penetration by the nematode. Gene expression in this plant parasitic nematode is therefore influenced, in a host-specific manner, by cell wall components that are either secreted by the plant or released by degradation of root tissue. Transcriptional plasticity may have evolved as an adaptation for host recognition and increased root invasion by this polyphagous species.
Journal Article
Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus
Background
Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease.
Methods
We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium
®
HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes.
Results
Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of
UNC13B
, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy.
Conclusion
This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy.
Journal Article