The complex etiology of neurodegenerative diseases is not fully understood, and the characterization of cellular pathways that are dysfunctional in these diseases is key for therapeutic development. Chemical and genetic perturbagens can probe cellular pathways to shed insight about both disease etiology and potential therapeutic targets. We analyzed the functional effects of chemical perturbagens in neurodegenerative disease models as evidenced by changes in transcriptomic, metabolomic, epigenomic, and proteomic data ("multi-omics" data). Our studies revealed novel modes of action for small molecule compounds that promote survival in a model of Huntington's Disease, a fatal neurodegenerative disorder. Integration of our multi-omics data using an interpretable network approach revealed that the autophagy and bioenergetics cellular pathways are affected by different sets of compounds that promote survival. Using staining and western blot assays, we validated the effect on autophagy for one set of compounds and found that the compounds activate this pathway. Using a cellular bioenergetics assay, we found that a second set of compounds shifts the bioenergetic flux from mitochondrial respiration to glycolysis, validating our network results. In a second study related to Huntington's Disease, we analyzed the effects of two peripheral huntingtin gene silencing techniques in mouse liver. We show that the transcriptional and metabolomic changes associated with both genetic silencing methods converge on similar cellular pathways, such as the immune response and fatty acid metabolism. As a whole, this thesis presents new insights into the functional effects of perturbagens that could impact neurodegenerative disease pathology and drug discovery.

The how's and why's of successful drug repositioning Drug repositioning, also known as drug reprofiling or repurposing, has become an increasingly important part of the drug development process. This book examines the business, technical, scientific, and operational challenges and opportunities that drug repositioning offers. Readers will learn how to perform the latest experimental and computational methods that support drug repositioning, and detailed case studies throughout the book demonstrate how these methods fit within the context of a comprehensive drug repositioning strategy. Drug Repositioning is divided into three parts: Part 1, Drug Repositioning: Business Case, Strategies, and Operational Considerations, examines the medical and commercial drivers underpinning the quest to reposition existing drugs, guiding readers through the key strategic, technical, operational, and regulatory decisions needed for successful drug repositioning programs. Part 2, Application of Technology Platforms to Uncover New Indications and Repurpose Existing Drugs, sets forth computational-based strategies, tools, and databases that have been designed for repositioning studies, screening approaches, including combinations of existing drugs, and a look at the development of chemically modified analogs of approved agents. Part 3, Academic and Non-Profit Initiatives & the Role of Alliances in the Drug Repositioning Industry, explores current investigations for repositioning drugs to treat rare and neglected diseases, which are frequently overlooked by for-profit pharmaceutical companies due to their lack of commercial return. The book's appendix provides valuable resources for drug repositioning researchers, including information on drug repositioning and reformulation companies, databases, government resources and organizations, regulatory agencies, and drug repositioning initiatives from academia and non-profits. With this book as their guide, students and pharmaceutical researchers can learn how to use drug repositioning techniques to extend the lifespan and applications of existing drugs as well as maximize the return on investment in drug research and development.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, devastating and fatal disease characterized by selective loss of upper and lower motor neurons of the cerebral cortex, brainstem, spinal cord and muscle atrophy. In spite of many years of research, the pathogenesis of ALS is still not well understood. ALS is a multifaceted genetic disease, in which genetic susceptibility to motor neuron death interacts with environmental factors and there is still no cure for this deleterious disease. At present, there is only one FDA approved drug, Riluzole which according to past studies only modestly slows the progression of the disease, and improves survival by up to three months. The suffering of the ALS patients, and their families is enormous and the economic burden is colossal. There is therefore a pressing need for new therapies. Different molecular pathways and pathological mechanisms have been implicated in ALS. According to past studies, altered calcium homeostasis, abnormal mitochondrial function, protein misfolding, axonal transport defects, excessive production of extracellular superoxide radicals, glutamate-mediated excitotoxicity, inflammatory events, and activation of oxidative stress pathways within the mitochondria and endoplasmic reticulum can act as major contributor that eventually leads to loss of connection between muscle and nerve ultimately resulting to ALS. However, the detailed molecular and cellular pathophysiological mechanisms and origin and temporal progression of the disease still remained elusive. Ongoing research and future advances will likely advance our improve understanding about various involved pathological mechanism ultimately leading to discoveries of new therapeutic cures. Importantly, clinical biomarkers of disease onset and progression are thus also urgently needed to support the development of the new therapeutic agents and novel preventive and curative strategies. Effective translation from pre-clinical to clinical studies will further require extensive knowledge regarding drug activity, bioavailability and efficacy in both the pre-clinical and clinical setting, and proof of biological activity in the target tissue. During the last decades, the development of new therapeutic molecules, advance neuroimaging tools, patient derived induced stem cells and new precision medicine approaches to study ALS has significantly improved our understanding of disease. In particular, new genetic tools, neuroimaging methods, cellular probes, biomarker study and molecular techniques that achieve high spatiotemporal resolution have revealed new details about the disease onset and its progression. In our effort to provide the interested reader, clinician and researchers a comprehensive summaries and new findings in this field of ALS research, hereby we have created this electronic book which comprises of twenty seven chapters having various reviews, perspective and original research articles. All these chapters and articles in this book not only summarize the cutting-edge techniques, approaches, cell and animal models to study ALS but also provide unprecedented coverage of the current developments and new hypothesis emerging in ALS research. Some examples are novel genetic and cell culture based models, mitochondria-mediated therapy, oxidative stress and ROS mechanism, development of stem cells and mechanism-based therapies as well as novel biomarkers for designing and testing effective therapeutic strategies that can benefit ALS patients who are at the earlier stages in the disease. I am extremely grateful to all the contributors to this book and want to thank them for their phenomenal efforts. Manoj Kumar Jaiswal, Ph.D. February 5, 2017 New York, NY

Anticancer Treatments and Cardiotoxicity: Mechanisms, Diagnostic and Therapeutic Interventions presents cutting edge research on the adverse cardiac effects of both radiotherapy and chemotherapy, brought together by leaders in the field. Cancer treatment-related cardiotoxicity is the leading cause of treatment-associated mortality in cancer survivors and is one of the most common post-treatment issues among survivors of adult cancer. Early detection of the patients prone to developing cardiotoxicity, taking in to account the type of treatment, history and other risk factors, is essential in the fight to decrease cardiotoxic mortality. This illustrated reference describes the most effective diagnostic and imaging tools to evaluate and predict the development of cardiac dysfunction for those patients undergoing cancer treatment. In addition, new guidelines on imaging for the screening and monitoring of these patients are also presented. Anticancer Treatments and Cardiotoxicity is an essential reference for those involved in the research and treatment of cardiovascular toxicity. Provides algorithms essential for the use of imaging, and biomarkers for the screening and monitoring of patients Written by world-leading experts in the field of cardiotoxicity Includes high-quality images, case studies, and test questions Describes the most effective diagnostic and imaging tools to evaluate and predict the development of cardiac dysfunction for those patients undergoing cancer treatment

In Silico Drug Design: Repurposing Techniques and Methodologies explores the application of computational tools that can be utilized for this approach. The book covers theoretical background and methodologies of chem-bioinformatic techniques and network modeling and discusses the various applied strategies to systematically retrieve, integrate and analyze datasets from diverse sources. Other topics include in silico drug design methods, computational workflows for drug repurposing, and network-based in silico screening for drug efficacy. With contributions from experts in the field and the inclusion of practical case studies, this book gives scientists, researchers and R&D professionals in the pharmaceutical industry valuable insights into drug design. Discusses the theoretical background and methodologies of useful techniques of cheminformatics and bioinformatics that can be applied for drug repurposing Offers case studies relating to the in silico modeling of FDA-approved drugs for the discovery of antifungal, anticancer, antiplatelet agents, and for drug therapies against diseases Covers tools and databases that can be utilized to facilitate in silico methods for drug repurposing

As a guide for pharmaceutical professionals to the issues and practices of drug discovery toxicology, this book integrates and reviews the strategy and application of tools and methods at each step of the drug discovery process. • Guides researchers as to what drug safety experiments are both practical and useful • Covers a variety of key topics – safety lead optimization, in vitro-in vivo translation, organ toxicology, ADME, animal models, biomarkers, and –omics tools • Describes what experiments are possible and useful and offers a view into the future, indicating key areas to watch for new predictive methods • Features contributions from firsthand industry experience, giving readers insight into the strategy and execution of predictive toxicology practices

The genomic revolution has opened up systematic investigations and engineering designs for various life forms. Systems biology and synthetic biology are emerging as two complementary approaches, which embody the breakthrough in biology and invite application of engineering principles. Systems Biology and Synthetic Biology emphasizes the similarity between biology and engineering at the system level, which is important for applying systems and engineering theories to biology problems. This book demonstrates to students, researchers, and industry that systems biology relies on synthetic biology technologies to study biological systems, while synthetic biology depends on knowledge obtained from systems biology approaches.

Develop a deep understanding and working knowledge of point-process theory as well as its applications in finance.

This book discusses the primary functions of microtubule-associated proteins (MAPs) such as MAP2 and tau in neuronal morphogenesis, as well as relationships between neuronal differentiation and the expression of neuronal intermediate filaments (nestin, alpha internexin, and neurofilament triplet proteins). It emphasizes the importance of several cytoskeletal proteins for neuronal differentiation and morphogenesis, organelle transport, and synaptic functions. The book considers the involvement of tau MAPs in the formation of paired helical filaments in Alzheimer's disease, and it examines the mechanisms of organelle transports and molecular motors such as kinesin, braindynein, and kinesin superfamily proteins. Cytoskeletal proteins involved in synaptic formation and transmitter release and new synaptic junctional-associated proteins are explored as well.

Translational Bioinformatics in Healthcare and Medicine offers an overview of main principles of bioinformatics, biological databases, clinical informatics, health informatics, viroinformatics and real-case applications of translational bioinformatics in healthcare. Written by experts from both technology and clinical sides, the content brings together essential knowledge to make the best of recent advancements of the field. The book discusses topics such as next generation sequence analysis, genomics in clinical care, IoT applications, blockchain technology, patient centered interoperability of EHR, health data mining, and translational bioinformatics methods for drug discovery and drug repurposing. In addition, it discusses the role of bioinformatics in cancer research and viroinformatics approaches to counter viral diseases through informatics. This is a valuable resource for bioinformaticians, clinicians, healthcare professionals, graduate students and several members of biomedical field who are interested in learning more about how bioinformatics can impact in their research and practice. - Covers recent advancements in translational bioinformatics and its healthcare applications - Discusses integrative and multidisciplinary approaches to U-healthcare systems development and management - Bridges the gap among various knowledge domains in the field, integrating both technological and clinical knowledge into practical content