Oxidative Stress in Cancer Hayes, John D.; Dinkova-Kostova, Albena T.; Tew, Kenneth D.
Cancer cell,
08/2020, Volume:
38, Issue:
2
Journal Article
Peer reviewed
Open access
Contingent upon concentration, reactive oxygen species (ROS) influence cancer evolution in apparently contradictory ways, either initiating/stimulating tumorigenesis and supporting ...transformation/proliferation of cancer cells or causing cell death. To accommodate high ROS levels, tumor cells modify sulfur-based metabolism, NADPH generation, and the activity of antioxidant transcription factors. During initiation, genetic changes enable cell survival under high ROS levels by activating antioxidant transcription factors or increasing NADPH via the pentose phosphate pathway (PPP). During progression and metastasis, tumor cells adapt to oxidative stress by increasing NADPH in various ways, including activation of AMPK, the PPP, and reductive glutamine and folate metabolism.
In Section 1 of this article, the author discusses the succession of models of adult writing that he and his colleagues have proposed from 1980 to the present. He notes the most important changes ...that differentiate earlier and later models and discusses reasons for the changes. In Section 2, he describes his recent efforts to model young children’s expository writing. He proposes three models that constitute an elaboration of Bereiter and Scardamalia’s knowledge-telling model. In Section 3, he describes three running computer programs that simulate the action of the models described in Section 2.
The Promise and Challenge of Stochastic Computing Alaghi, Armin; Qian, Weikang; Hayes, John P.
IEEE transactions on computer-aided design of integrated circuits and systems,
08/2018, Volume:
37, Issue:
8
Journal Article
Peer reviewed
Open access
Stochastic computing (SC) is an unconventional method of computation that treats data as probabilities. Typically, each bit of an <inline-formula> <tex-math notation="LaTeX">{N} ...</tex-math></inline-formula>-bit stochastic number (SN) <inline-formula> <tex-math notation="LaTeX">{X} </tex-math></inline-formula> is randomly chosen to be 1 with some probability <inline-formula> <tex-math notation="LaTeX">p_{X} </tex-math></inline-formula>, and <inline-formula> <tex-math notation="LaTeX">{X} </tex-math></inline-formula> is generated and processed by conventional logic circuits. For instance, a single AND gate performs multiplication. The value X of an SN is measured by the density of 1 s in it, an information-coding scheme also found in biological neural systems. SC has uses in massively parallel systems and is very tolerant of soft errors. Its drawbacks include low accuracy, slow processing, and complex design needs. Its ability to efficiently perform tasks like communication decoding and neural network inference has rekindled interest in the field. Many challenges remain to be overcome, however, before SC becomes widespread. In this paper, we discuss the evolution of SC, mostly focusing on recent developments. We highlight the main challenges and discuss potential methods of overcoming them.
•Nrf2 is part of a complex regulatory network that responds to environmental cues.•Nrf2 allows adaptation by inducing cytoprotective genes and maintaining redox homeostasis.•Nrf2 transcription is ...positively regulated by AhR, ARNT, NF-κB, Jun, and Myc.•Nrf2 protein stability is controlled by CRLKeap1, SCFβ-TrCP, CRIF1, Siah2, and RNF4.•Nrf2 influences metabolism, including lipid, carbohydrate, amino acid, and nucleotide.
Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, also called Nfe2l2) is a transcription factor that regulates the cellular redox status. Nrf2 is controlled through a complex transcriptional/epigenetic and post-translational network that ensures its activity increases during redox perturbation, inflammation, growth factor stimulation and nutrient/energy fluxes, thereby enabling the factor to orchestrate adaptive responses to diverse forms of stress. Besides mediating stress-stimulated induction of antioxidant and detoxification genes, Nrf2 contributes to adaptation by upregulating the repair and degradation of damaged macromolecules, and by modulating intermediary metabolism. In the latter case, Nrf2 inhibits lipogenesis, supports β-oxidation of fatty acids, facilitates flux through the pentose phosphate pathway, and increases NADPH regeneration and purine biosynthesis; these observations suggest Nrf2 directs metabolic reprogramming during stress.
Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidant and detoxification genes in response to ...redox stress. NRF2 is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Tumours from ∼15% of patients with lung cancer harbour somatic mutations in
KEAP1 that prevent effective NRF2 repression. Recently, two
NRF2 mutation ‘hot-spots’ were identified in ∼10% of patients with lung cancer, enabling the transcription factor to evade KEAP1-mediated repression. Somatic mutations in
KEAP1 and
NRF2 provide an insight into the molecular mechanisms by which NRF2 is regulated. Moreover, constitutive NRF2 activation might cause drug resistance in tumours, and an understanding of how the transcription factor is regulated indicates ways in which this could be overcome.
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Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found ...to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. The effects of GSK3 phosphorylation on substrates include alteration of enzyme activity, protein localisation, protein:protein interaction and protein stability. This latter form of regulation of GSK3 substrates is the focus of this review. There is an ever-growing list of GSK3 substrates that upon phosphorylation are targeted to the beta-transducin repeat containing protein (β-TrCP), thereby allowing ubiquitination of bound protein by cullin-1 and so initiating destruction at the proteasome. We propose the existence of a GSK3-β-TrCP ‘destruction hit-list’ that allows co-ordinated removal (or stabilisation) of a set of proteins with a common physiological purpose, through control of GSK3. We identify 29 proteins where there is relatively strong evidence for regulation by a GSK3-β-TrCP axis and note common features of regulation and pathophysiology. Furthermore, we assess the potential of pre-phosphorylation (priming) of these targets (normally a prerequisite for GSK3 recognition) to provide a second layer of regulation delineated by the priming kinase that allows GSK3 to mark them for destruction. Finally, we discuss whether this knowledge improves options for therapeutic intervention.
The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, with gene called NFE2L2) is a master regulator of the antioxidant response. In the last decade, interest has ...intensified in this research area as its importance in several physiological and pathological processes has become widely recognized; these include redox signalling and redox homoeostasis, drug metabolism and disposition, intermediary metabolism, cellular adaptation to stress, chemoprevention and chemoresistance, toxicity, inflammation, neurodegeneration, lipogenesis and aging. Regulation of Nrf2 is complex and although much attention has focussed on its repression by Kelch-like ECH-associated protein-1 (Keap1), recently it has become increasingly apparent that it is also controlled by cross-talk with other signalling pathways including the glycogen synthase kinase-3 (GSK-3)-β-transducin repeat-containing protein (β-TrCP) axis, ERAD (endoplasmic reticulum-associated degradation)-associated E3 ubiquitin-protein ligase (Hrd1, also called synoviolin), nuclear factor-kappa B (NF-κB), Notch and AMP kinase. Due to its beneficial role in several diseases, Nrf2 has become a major therapeutic target, with novel natural, synthetic and targeted small molecules currently under investigation to modulate the pathway and in clinical trials.
Electric powertrain Hayes, John G; Goodarzi, G. Abas
2018/01/01, 2018, 2017-11-13
eBook
The why, what and how of the electric vehicle powertrain Empowers engineering professionals and students with the knowledge and skills required to engineer electric vehicle powertrain architectures, ...energy storage systems, power electronics converters and electric drives.The modern electric powertrain is relatively new for the automotive industry, and engineers are challenged with designing affordable, efficient and high-performance electric powertrains as the industry undergoes a technological evolution. Co-authored by two electric vehicle (EV) engineers with decades of experience designing and putting into production all of the powertrain technologies presented, this book provides readers with the hands-on knowledge, skills and expertise they need to rise to that challenge. This four-part practical guide provides a comprehensive review of battery, hybrid and fuel cell EV systems and the associated energy sources, power electronics, machines, and drives. The first part of the book begins with a historical overview of electromobility and the related environmental impacts motivating the development of the electric powertrain. Vehicular requirements for electromechanical propulsion are then presented. Battery electric vehicles (BEV), fuel cell electric vehicles (FCEV), and conventional and hybrid electric vehicles (HEV) are then described, contrasted and compared for vehicle propulsion. The second part of the book features in-depth analysis of the electric powertrain traction machines, with a particular focus on the induction machine and the surface- and interior-permanent magnet ac machines. The brushed dc machine is also considered due to its ease of operation and understanding, and its historical place, especially as the traction machine on NASA's Mars rovers. The third part of the book features the theory and applications for the propulsion, charging, accessory, and auxiliary power electronics converters. Chapters are presented on isolated and non-isolated dc-dc converters, traction inverters, and battery charging. The fourth part presents the introductory and applied electromagnetism required as a foundation throughout the book. - Introduces and holistically integrates the key EV powertrain technologies. - Provides a comprehensive overview of existing and emerging automotive solutions. - Provides experience-based expertise for vehicular and powertrain system and sub-system level study, design, and optimization. - Presents many examples of powertrain technologies from leading manufacturers. - Discusses the dc traction machines of the Mars rovers, the ultimate EVs from NASA. - Investigates the environmental motivating factors and impacts of electromobility. - Presents a structured university teaching stream from introductory undergraduate to postgraduate. - Includes real-world problems and assignments of use to design engineers, researchers, and students alike. - Features a companion website with numerous references, problems, solutions, and practical assignments. - Includes introductory material throughout the book for the general scientific reader. - Contains essential reading for government regulators and policy makers. Electric Powertrain: Energy Systems, Power Electronics and Drives for Hybrid, Electric and Fuel Cell Vehicles is an important professional resource for practitioners and researchers in the battery, hybrid, and fuel cell EV transportation industry. The book is a structured holistic textbook for the teaching of the fundamental theories and applications of energy sources, power electronics, and electric machines and drives to engineering undergraduate and postgraduate students. Textbook Structure and Suggested Teaching Curriculum This is primarily an engineering textbook covering the automotive powertrain, energy storage and energy conversion, power electronics, and electrical machines. A significant additional focus is placed on the engineering design, the energy for transportation, and the related environmental impacts. This textbook is an educational tool for practicing engineers and others, such as transportation policy planners and regulators. The modern automobile is used as the vehicle upon which to base the theory and applications, which makes the book a useful educational reference for our industry colleagues, from chemists to engineers. This material is also written to be of interest to the general reader, who may have little or no interest in the power electronics and machines. Introductory science, mathematics, and an inquiring mind suffice for some chapters. The general reader can read the introduction to each of the chapters and move to the next as soon as the material gets too advanced for him or her. Part I Vehicles and Energy Sources Chapter 1 Electromobility and the Environment Chapter 2 Vehicle Dynamics Chapter 3 Batteries Chapter 4 Fuel Cells Chapter 5 Conventional and Hybrid Powertrains Part II Electrical Machines Chapter 6 Introduction to Traction Machines Chapter 7 The Brushed DC Machine Chapter 8 Induction Machines Chapter 9 Surface-permanent-magnet AC Machines Chapter 10: Interior-permanent-magnet AC Machines Part III Power Electronics Chapter 11 DC-DC Converters Chapter 12 Isolated DC-DC Converters Chapter 13 Traction Drives and Three-phase InvertersChapter 14 Battery Charging Chapter 15 Control of the Electric Drive Part IV Basics Chapter 16 Introduction to Electromagnetism, Ferromagnetism, and Electromechanical Energy Conversion The first third of the book (Chapters 1 to 6), plus parts of Chapters 14 and 16, can be taught to the general science or engineering student in the second or third year. It covers the introductory automotive material using basic concepts from mechanical, electrical, environmental, and electrochemical engineering. Chapter 14 on electrical charging and Chapter 16 on electromagnetism can also be used as a general introduction to electrical engineering. The basics of electromagnetism, ferromagnetism and electromechanical energy conversion (Chapter 16) and dc machines (Chapter 7) can be taught to second year (sophomore) engineering students who have completed introductory electrical circuits and physics. The third year (junior) students typically have covered ac circuit analysis, and so they can cover ac machines, such as the induction machine (Chapter 8) and the surface permanent-magnet ac machine (Chapter 9). As the students typically have studied control theory, they can investigate the control of the speed and torque loops of the motor drive (Chapter 15). Power electronics, featuring non-isolated buck and boost converters (Chapter 11), can also be introduced in the third year. The final-year (senior) students can then go on to cover the more advanced technologies of the interior-permanent-magnet ac machine (Chapter 10). Isolated power converters (Chapter 12), such as the full-bridge and resonant converters, inverters (Chapter 13), and power-factor-corrected battery chargers (Chapter 14), are covered in the power electronics section. This material can also be covered at the introductory postgraduate level. Various homework, simulation, and research exercises are presented throughout the textbook. The reader is encouraged to attempt these exercises as part of the learning experience. Instructors are encouraged to contact the author, John Hayes , direct to discuss course content or structure.
Nuclear factor-erythroid 2 p45 (NF-E2 p45)-related factor 2 (Nrf2) is a master regulator of redox homoeostasis that allows cells to adapt to oxidative stress and also promotes cell proliferation. In ...this review, we describe the molecular mechanisms by which oxidants/electrophilic agents and growth factors increase Nrf2 activity. In the former case, oxidants/electrophiles increase the stability of Nrf2 by antagonizing the ability of Kelch-like ECH-associated protein 1 (Keap1) to target the transcription factor for proteasomal degradation via the cullin-3 (Cul3)-RING ubiquitin ligase CRL(Keap1). In the latter case, we speculate that growth factors increase the stability of Nrf2 by stimulating phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/Akt signalling, which in turn results in inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) and in doing so prevents the formation of a DSGIS motif-containing phosphodegron in Nrf2 that is recognized by the β-transducin repeat-containing protein (β-TrCP) Cul1-based E3 ubiquitin ligase complex SCF(β-TrCP). We present data showing that in the absence of Keap1, the electrophile tert-butyl hydroquinone (tBHQ) can stimulate Nrf2 activity and induce the Nrf2-target gene
quinone oxidoreductase-1 (NQO1), whilst simultaneously causing inhibitory phosphorylation of GSK-3β at Ser(9). Together, these observations suggest that tBHQ can suppress the ability of SCF(β-TrCP) to target Nrf2 for proteasomal degradation by increasing PI3K-PKB/Akt signalling. We also propose a scheme that explains how other protein kinases that inhibit GSK-3 could stimulate induction of Nrf2-target genes by preventing formation of the DSGIS motif-containing phosphodegron in Nrf2.
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in ...the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.
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