102 research outputs found

    Structure, Activity, and Function of Protein Methyltransferases

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    This collection of review articles describes the structure, function and mechanism of individual protein methyltransferase enzymes including protein lysine methyltransferases, protein arginine methyltransferases, and also the less abundant protein histidine methyltransferases and protein N-terminal end methyltransferases. The topics covered in the individual reviews include structural aspects (domain architecture, homologs and paralogs, and structure), biochemical properties (mechanism, sequence specificity, product specificity, regulation, and histone and non-histone substrates), cellular features (subcellular localization, expression patterns, cellular roles and function, biological effects of substrate protein methylation, connection to cell signaling pathways, and connection to chromatin regulation) and their role in diseases. This review book is a useful resource for scientists working on protein methylation and protein methyltransferases and those interested in joining this emerging research field

    Effects of compounds on C. elegans DMD model health

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    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene. The dystrophin gene encodes a cytoskeletal protein with the same name that is responsible for ensuring the strength, stability, and functionality of myofibers. In DMD the dystrophin protein is either absent or there are insufficient levels of functional dystrophin resulting in progressive muscular damage and degeneration. This results in muscular weakness, motor delays, loss of ambulation, and a shortened life expectancy due to respiratory impairment and cardiomyopathy. Treatment options are limited and mainly focused on alleviating symptoms; they are not a cure. The main therapeutic treatment used are glucocorticoids, these can be used for a couple of years, but treatment is often ceased due to undesirable side effects. An emerging therapy is the use of exon-skipping but currently these can only be used for patients amenable to skipping of exons 45, 51, and 53 (approximately 30% of patients). There is therefore a great need for alternative therapies. This thesis uses C. elegans as a model for DMD. We demonstrate throughout that the C. elegans DMD model has clinical relevance as it shares some of the underlying pathophysiology that are also displayed in patients, including mitochondrial dysfunction and calcium dysregulation. It also has several clinically relevant phenotypes that can be exploited including movement and strength decline and changes in gait. Finally, the current standard treatment used to treat patients with DMD, prednisone, has also been identified as being beneficial in the DMD C. elegans model as well. Hydrogen sulfide (H2S) compounds were trialled as a potential treatment for DMD in this thesis. The rationale behind this was that H2S compounds had been demonstrated previously to improve lifespan in ageing animals. There are some similarities between ageing and DMD muscle, the former being associated with sarcopenia and the latter with progressive muscle degeneration. It therefore seemed reasonable to expect an improvement in the DMD animals given there was one in ageing animals. In Chapter 3, we started by trialling a non-targeted H2S compound sodium GYY4137 (NaGYY) and showed that this compound does improve movement, strength, and gait in the DMD model. The basis of this improvement was likely mitochondrial, and the mechanism of action was like that of prednisone. In Chapter 4, to confirm the basis of this we then used a mitochondrially targeted H2S compound, AP39, and demonstrated that this compound was also able to improve movement and strength in DMD animals. This provided further evidence to suggest that at least part of the mechanism of NaGYY was through improvements in mitochondrial dysfunction. We then further probed the mechanism of action of AP39 in the mitochondria and established that AP39 is likely donating electrons to complex III of the electron transport chain (ETC) and thus causing an increase in ATP content. In Chapter 5, we show that there is a decline in the gene expression of enzymes responsible for sulfur metabolism that are resulting in a H2S deficit. We also demonstrate that supplementing sulfur in a different way (via sulfur containing amino acids) is also beneficial in the C. elegans DMD model. This highlights a potential novel underlying pathophysiology of DMD in a defective sulfur metabolism pathway and the potential of using H2S as a biomarker for disease progression. To conclude we have shown that supplementing H2S compounds and sulfur containing amino acids are potential treatments for DMD and potential alternatives to prednisone. We have also demonstrated that manipulation of the sulfur metabolism pathway warrants further study in DMD. Future work includes trialling these therapies in the DMD mouse model and beyond and identifying whether the defective sulfur metabolism pathway and H2S deficit corresponds with higher organisms

    A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder

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    This collection of articles provides an overview of the current and future methods for applying a personalized medicine approach to the diagnosis, management, and treatment of autism spectrum disorder

    Drug Repurposing

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    This book focuses on various aspects and applications of drug repurposing, the understanding of which is important for treating diseases. Due to the high costs and time associated with the new drug discovery process, the inclination toward drug repurposing is increasing for common as well as rare diseases. A major focus of this book is understanding the role of drug repurposing to develop drugs for infectious diseases, including antivirals, antibacterial and anticancer drugs, as well as immunotherapeutics

    Recent progress in DNA methyltransferase inhibitors as anticancer agents

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    DNA methylation mediated by DNA methyltransferase is an important epigenetic process that regulates gene expression in mammals, which plays a key role in silencing certain genes, such as tumor suppressor genes, in cancer, and it has become a promising therapeutic target for cancer treatment. Similar to other epigenetic targets, DNA methyltransferase can also be modulated by chemical agents. Four agents have already been approved to treat hematological cancers. In order to promote the development of a DNA methyltransferase inhibitor as an anti-tumor agent, in the current review, we discuss the relationship between DNA methylation and tumor, the anti-tumor mechanism, the research progress and pharmacological properties of DNA methyltransferase inhibitors, and the future research trend of DNA methyltransferase inhibitors

    Creatine Supplementation for Health and Clinical Diseases

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    Creatine plays a critical role in cellular metabolism, primarily by binding with phosphate to form phosphocreatine (PCr) as well as shuttling high-energy phosphate compounds in and out of the mitochondria for metabolism. Increasing the dietary availability of creatine increases the tissue and cellular availability of PCr, and thereby enhances the ability to maintain high-energy states during intense exercise. For this reason, creatine monohydrate has been extensively studied as an ergogenic aid for exercise, training, and sport. Limitations in the ability to synthesize creatine and transport and/or store dietary creatine can impair metabolism and is a contributor to several disease states. Additionally, creatine provides an important source of energy during metabolically stressed states, particularly when oxygen availability is limited. Thus, researchers have assessed the role of creatine supplementation on health throughout the lifespan, as well as whether creatine availability may improve disease management and/or therapeutic outcomes. This book provides a comprehensive overview of scientific and medical evidence related to creatine's role in metabolism, health throughout the lifespan, and our current understanding of how creatine can promote brain, heart, vascular and immune health; reduce the severity of musculoskeletal and brain injury; and may provide therapeutic benefits in glucose management and diabetes, cancer therapy, inflammatory bowel disease, and post-viral fatigue

    Microbial Secondary Metabolites and Biotechnology

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    Many research teams are working to demonstrate that microorganisms can be our daily partners, due to the great diversity of biochemical transformations and molecules they are able to produce. This Special Issue highlights several facets of the production of microbial metabolites of interest. From the discovery of new strains or new bioactive molecules issued from novel environments, to the increase in their synthesis by traditional or innovative methods, different levels of biotechnological processes are addressed. Combining the new dimensions of "Omics" sciences, such as genomics, transcriptomics or metabolomics, microbial biotechnologies are opening up incredible opportunities for discovering and improving microorganisms and their production

    Phototrophic Bacteria

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    Microorganisms is pleased to publish this book, which reprints papers that appeared in a Special Issue on “Phototrophic Bacteria”, with Guest Editors Robert Blankenship and Matthew Sattley. This Special Issue included research on all types of phototrophic bacteria, including both anoxygenic and oxygenic forms. Research on these bacterial organisms has greatly advanced our understanding of the basic principles that underlie the energy storage that takes place in all types of photosynthetic organisms, including both bacterial and eukaryotic forms. Topics of interest include: microbial physiology, microbial ecology, microbial genetics, evolutionary microbiology, systems microbiology, agricultural microbiology, microbial biotechnology, and environmental microbiology, as all are related to phototrophic bacteria

    The Shared Genetic Architecture of Modifiable Risk for Dementia and its Influence on Brain Health

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    Targeting modifiable risk factors for dementia may prevent or delay dementia. However, the mechanisms by which risk factors influence dementia remain unclear and current research often ignores commonality between risk factors. Therefore, my thesis aimed to model the shared genetic architecture of modifiable risk for dementia and explored how these shared pathways may influence dementia and brain health. I used linkage disequilibrium score regression and genomic structural equation modelling (SEM) to create a multivariate model of the shared genetics between Alzheimer’s disease (AD) and its modifiable risk factors. Although AD was genetically distinct, there was widespread genetic overlap between most of its risk factors. This genetic overlap formed an overarching Common Factor of general modifiable dementia risk, in addition to 3 subclusters of distinct sets of risk factors. Next, I performed two multivariate genome-wide association studies (GWASs) to identify the risk variants that underpinned the Common Factor and the 3 subclusters of risk factors. Together, these uncovered 590 genome-wide significant loci for the four latent factors, 34 of which were novel findings. Using post-GWAS analyses I found evidence that the shared genetics between risk factors influence a range of neuronal functions, which were highly expressed in brain regions that degenerate in dementia. Pathway analysis indicated that shared genetics between risk factors may impact dementia pathogenesis directly at specific loci. Finally, I used Mendelian randomisation to test whether the shared genetic pathways between modifiable dementia risk factors were causal for AD. I found evidence of a causal effect of the Common Factor on AD risk. Taken together, my thesis provides new insights into how modifiable risk factors for dementia interrelate on a genetic level. Although the shared genetics between modifiable risk factors for dementia seem to be distinct from dementia pathways on a genome-wide level, I provide evidence that they influence general brain health, and so they may increase dementia risk indirectly by altering cognitive reserve. However, I also found that shared genetics risk between risk factors in certain genomic regions may directly influence dementia pathogenesis, which should be explored in future work to determine whether these regions represent targets to prevent dementia
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