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The world of Flashpoint featuring The Flash
\"Flashpoint has changed the DC universe, and nothing is as it was before. Now, the Flash has never become the hero he was meant to be, and those closest to him feel the greatest effects of the timestorm enveloping the entire universe. Now, Central City's greatest hero is the mysterious Citizen Cold-- but as Cold's enemies in the Rogues seek vengeance on him, can he keep his long-hidden past a secret? Now-- his evil unchecked by the Flash-- Gorilla Grodd could conquer an entire continent, and in 'Legion of doom' -- Heatwave takes over the world's most secure prison-- with the world's most dangerous prisoners inside of it. And in 'Kid Flash lost,' Bart Allen will find himself adrift in time, the only one who can stop the storm threatening to engulf all of reality-- a storm possibly caused by the machinations of Reverse Flash!\" -- p. [4] of cover.
Book
Epigenome-wide association studies: current knowledge, strategies and recommendations
The aetiology and pathophysiology of complex diseases are driven by the interaction between genetic and environmental factors. The variability in risk and outcomes in these diseases are incompletely explained by genetics or environmental risk factors individually. Therefore, researchers are now exploring the epigenome, a biological interface at which genetics and the environment can interact. There is a growing body of evidence supporting the role of epigenetic mechanisms in complex disease pathophysiology. Epigenome-wide association studies (EWASes) investigate the association between a phenotype and epigenetic variants, most commonly DNA methylation. The decreasing cost of measuring epigenome-wide methylation and the increasing accessibility of bioinformatic pipelines have contributed to the rise in EWASes published in recent years. Here, we review the current literature on these EWASes and provide further recommendations and strategies for successfully conducting them. We have constrained our review to studies using methylation data as this is the most studied epigenetic mechanism; microarray-based data as whole-genome bisulphite sequencing remains prohibitively expensive for most laboratories; and blood-based studies due to the non-invasiveness of peripheral blood collection and availability of archived DNA, as well as the accessibility of publicly available blood-cell-based methylation data. Further, we address multiple novel areas of EWAS analysis that have not been covered in previous reviews: (1) longitudinal study designs, (2) the chip analysis methylation pipeline (ChAMP), (3) differentially methylated region (DMR) identification paradigms, (4) methylation quantitative trait loci (methQTL) analysis, (5) methylation age analysis and (6) identifying cell-specific differential methylation from mixed cell data using statistical deconvolution.
Journal Article
X-Men : Gambit : the complete collection. Vol. 2
\"The Cajun rages on! Join Gambit on a time-tossed trip to the 19th century, and discover how the Thieves' Guild was shaped by Candra...and Mr. Sinister! Back in the present, Remy needs help - and Rogue flies to his aid! Thanks to Gambit's evolving powers, he can finally greet her with a kiss - but as his abilities get more unstable, any thoughts of romance will be short-lived. Gambit's destiny looms as he takes leadership of the Guild - assuming he can survive an Assassination Game against deadly villains like Bullseye, Constrictor, Zaran, Deadpool...and Archangel? And what are X-Cutioner and Ego the Living Planet doing here?! Gambit will finally discover the secret of his mysterious patron, the New Son - but is he hero or villain, and what will Gambit have to sacrifice to triumph?\"--Page [4] of cover.
BOOK
TAPES: A tool for assessment and prioritisation in exome studies
Next-generation sequencing continues to grow in importance for researchers. Exome sequencing became a widespread tool to further study the genomic basis of Mendelian diseases. In an effort to identify pathogenic variants, reject benign variants and better predict variant effects in downstream analysis, the American College of Medical Genetics (ACMG) published a set of criteria in 2015. While there are multiple publicly available software's available to assign the ACMG criteria, most of them do not take into account multi-sample variant calling formats. Here we present a tool for assessment and prioritisation in exome studies (TAPES, https://github.com/a-xavier/tapes), an open-source tool designed for small-scale exome studies. TAPES can quickly assign ACMG criteria using ANNOVAR or VEP annotated files and implements a model to transform the categorical ACMG criteria into a continuous probability, allowing for a more accurate classification of pathogenicity or benignity of variants. In addition, TAPES can work with cohorts sharing a common phenotype by utilising a simple enrichment analysis, requiring no controls as an input as well as providing powerful filtering and reporting options. Finally, benchmarks showed that TAPES outperforms available tools to detect both pathogenic and benign variants, while also integrating the identification of enriched variants in study cohorts compared to the general population, making it an ideal tool to evaluate a smaller cohort before using bigger scale studies.
Journal Article
Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease – A Systematic Review
Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn’s disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.
Journal Article
Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker
Epigenetic reprogramming in cancer genomes creates a distinct methylation landscape encompassing clustered methylation at regulatory regions separated by large intergenic tracks of hypomethylated regions. This methylation landscape that we referred to as Methylscape is displayed by most cancer types, thus may serve as a universal cancer biomarker. To-date most research has focused on the biological consequences of DNA Methylscape changes whereas its impact on DNA physicochemical properties remains unexplored. Herein, we examine the effect of levels and genomic distribution of methylcytosines on the physicochemical properties of DNA to detect the Methylscape biomarker. We find that DNA polymeric behaviour is strongly affected by differential patterning of methylcytosine, leading to fundamental differences in DNA solvation and DNA-gold affinity between cancerous and normal genomes. We exploit these Methylscape differences to develop simple, highly sensitive and selective electrochemical or colorimetric one-step assays for the detection of cancer. These assays are quick, i.e., analysis time ≤10 minutes, and require minimal sample preparation and small DNA input.
DNA methylation is an epigenetic modification that control genetic programs. Here, the authors found that the methylation landscape influences the physicochemical properties of DNA and that it can serve as a universal cancer biomarker, and developed a one-step assay for the detection of cancer DNA.
Journal Article
Modifier genes and Lynch syndrome: some considerations
Lynch Syndrome (LS) is a highly variable entity with some patients presenting at very young ages with malignancy whereas others may never develop a malignancy yet carry an unequivocal genetic predisposition to disease. The most frequent LS malignancy remains colorectal cancer, a disease that is thought to involve genetic as well as environmental factors in its aetiology. Environmental insults are undeniably associated with cancer risk, especially those imparted by such activities as smoking and excessive alcohol consumption. Notwithstanding, in an inherited predisposition the expected exposures to an environmental insult are considered to be complex and require knowledge about the respective exposure and how it might interact with a genetic predisposition. Typically, smoking is one of the major confounders when considering environmental factors that can influence disease expression on a background of significant genetic risk. In addition to environmental triggers, the risk of developing a malignancy for people carrying an inherited predisposition to disease can be influenced by additional genetic factors that do not necessarily segregate with a disease predisposition allele. The purpose of this review is to examine the current state of modifier gene detection in people with a genetic predisposition to develop LS and present some data that supports the notion that modifier genes are gene specific thus explaining why some modifier gene studies have failed to identify associations when this is not taken into account.
Journal Article
MicroRNAs miR-17 and miR-20a Inhibit T Cell Activation Genes and Are Under-Expressed in MS Whole Blood
It is well established that Multiple Sclerosis (MS) is an immune mediated disease. Little is known about what drives the differential control of the immune system in MS patients compared to unaffected individuals. MicroRNAs (miRNAs) are small non-coding nucleic acids that are involved in the control of gene expression. Their potential role in T cell activation and neurodegenerative disease has recently been recognised and they are therefore excellent candidates for further studies in MS. We investigated the transcriptome of currently known miRNAs using miRNA microarray analysis in peripheral blood samples of 59 treatment naïve MS patients and 37 controls. Of these 59, 18 had a primary progressive, 17 a secondary progressive and 24 a relapsing remitting disease course. In all MS subtypes miR-17 and miR-20a were significantly under-expressed in MS, confirmed by RT-PCR. We demonstrate that these miRNAs modulate T cell activation genes in a knock-in and knock-down T cell model. The same T cell activation genes are also up-regulated in MS whole blood mRNA, suggesting these miRNAs or their analogues may provide useful targets for new therapeutic approaches.
Journal Article
c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis
The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14
ARF
in human and p19
ARF
in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.
c-Myc and p53 operate in a negative feedback manner to maintain cellular homeostasis. Here, the authors report a long noncoding RNA, MILIP as a downstream target of c-Myc and that MILIP represses p53 to support tumorigenicity.
Journal Article
Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis
Multiple Sclerosis (MS) has a complex pathophysiology that involves genetic and environmental factors. DNA methylation (DNAm) is one epigenetic mechanism that can reversibly modulate gene expression. Cell specific DNAm changes have been associated with MS, and some MS therapies such as dimethyl fumarate can influence DNAm. Interferon Beta (IFNβ), was one of the first disease modifying therapies in multiple sclerosis (MS). However, how IFNβ reduces disease burden in MS is not fully understood and little is known about the precise effect of IFNβ treatment on methylation.
The objective of this study was to determine the changes in DNAm associated with INFβ use, using methylation arrays and statistical deconvolutions on two separate datasets (total n
= 64, n
= 285).
We show that IFNβ treatment in people with MS modifies the methylation profile of interferon response genes in a strong, targeted, and reproducible manner. Using these identified methylation differences, we constructed a methylation treatment score (MTS) that is an accurate discriminator between untreated and treated patients (Area under the curve = 0.83). This MTS is time-sensitive and in consistent with previously identified IFNβ treatment therapeutic lag. This suggests that methylation changes are required for treatment efficacy. Overrepresentation analysis found that IFNβ treatment recruits the endogenous anti-viral molecular machinery. Finally, statistical deconvolution revealed that dendritic cells and regulatory CD4+ T cells were most affected by IFNβ induced methylation changes.
In conclusion, our study shows that IFNβ treatment is a potent and targeted epigenetic modifier in multiple sclerosis.
Journal Article