Integration and Control of Metabolic Processes

Author: Federation of Asian and Oceanian Biochemists. Congress



Category: Science

Page: 595

View: 757

Control of Metabolic Processes

Some authors discard all the above mechanisms and notions; they maintain that
the concentration ratios of certain coenzymes (e.g. NAD+/NADH) control
metabolism. Such metabolite concentration ratios are free variables in a
metabolic ...

Author: Athel Cornish-Bowden

Publisher: Springer Science & Business Media

ISBN: 1475798563

Category: Medical

Page: 454

View: 279

THIS BOOK collects together papers given at a NATO Advanced Research Workshop held at Il Ciocco (Lucca), Italy, from the 9th to the 15th April, 1989. It sets out to present the current state of understanding of the principles governing the way fluxes and concentrations are maintained and controlled in metabolic systems. Although this is a topic that has held the interest of biochemists for many years, it is only quite recently that the methods of analysing the kinetics of multi-enzyme pathways developed over the past two decades have come to be widely discussed or applied experimentally. Many biochemists remain sceptical that the new methods offer a real advance (except in complexity) over the landmark discoveries of the 1950s and 1960s relating to inhibition of enzymes at branch-points by the end products of metabolic pathways, and the interpretation of allosteric effects and cooperativity. Even those who have become convinced that the classical ideas provide only the starting point for understanding metabolic control have been by no means unanimous in their assess ment of the direction in which one should advance. In this book we have tried to include all of the current points of view, including the view that the classical theories tell us all that we need to know. We have not seen it as our role as editors to paper over the cracks that exist and to pretend that we can speak to the world with one voice.

Integration and Control of Metabolism

The text is divided into three essential areas of study: Fundamentals of metabolic control--dealing with the basic concepts of metabolic control and the role played by regulatory enzymes Control of cellular metabolism--including the ...

Author: Naa Adamafio

Publisher: iUniverse

ISBN: 0595340679

Category: Medical

Page: 160

View: 793

Fully understanding the complex process of the integration and control of metabolism in cellular organisms requires knowledge in several fundamental concepts. Drawing on nearly two decades of innovative studies, Doctors Naa Adamafio, Laud Okine, and Jonathan Adjimani specifically target the intricacies of metabolism and provide a comprehensive approach to the subject. The text is divided into three essential areas of study: Fundamentals of metabolic control-dealing with the basic concepts of metabolic control and the role played by regulatory enzymes Control of cellular metabolism-including the regulation of the metabolism of major biomolecules, such as carbohydrates, lipids, and compounds containing nitrogen The integration of metabolism-observing the methods in which various metabolic pathways within and between tissues and organs are integrated Whether you are an undergraduate student in biochemistry, a medical student in your preclinical years, or a teacher in the subject area, Integration and Control of Metabolism is a valuable medical resource.

Protein Tyrosine Phosphatase Control of Metabolism

Kendra K. Bence and Tony Tiganis Abstract The regulation of energy balance is
under tight homeostatic control. ... these brain regions critical cellular signaling
pathways have been identified that mediate a multitude of metabolic processes, ...

Author: Kendra K. Bence

Publisher: Springer Science & Business Media

ISBN: 1461478553

Category: Science

Page: 273

View: 662

Although phosphorylation of proteins on tyrosine is relatively rare compared to phosphorylation on serine or threonine residues, the past two decades of research into PTP function have led to a great appreciation of the critical role PTPs have in regulating basic cellular processes. Among these important roles is the regulation of cellular signaling pathways related to metabolism. This volume contains chapters which highlight many aspects of PTP function in the context of metabolism. Given the growing obesity and diabetes epidemics in the United States and throughout the world, the desire to identify possible therapeutic targets for treatment of these diseases is a high priority. In many ways, PTPs may be attractive drug targets since they are amenable to targeting with small molecules; however many challenges abound in making PTP inhibitors.

Sensory and Metabolic Control of Energy Balance

Numerous aspects of obesity are currently studied, including the essential role of
neural and endocrine control circuits, adaptive responses of catabolic and
anabolic pathways, metabolic fuel sensors, regulation of appetite and satiation, ...

Author: Wolfgang Meyerhof

Publisher: Springer Science & Business Media

ISBN: 9783642144264

Category: Science

Page: 208

View: 121

During the last two decades, the prevalence of obesity has dramatically increased in western and westernized societies. Its devastating health consequences include hypertension, cardiovascular diseases, or diabetes and make obesity the second leading cause of unnecessary deaths in the USA. As a consequence, obesity has a strong negative impact on the public health care systems. Recently emerging scienti?c insight has helped understanding obesity as a complex chronic disease with multiple causes. A multileveled gene–environment interaction appears to involve a substantial number of susceptibility genes, as well as associations with low physical activity levels and intake of high-calorie, low-cost, foods. Unfor- nately, therapeutic options to prevent or cure this disease are extremely limited, posing an extraordinary challenge for today’s biomedical research community. Obesity results from imbalanced energy metabolism leading to lipid storage. Only detailed understanding of the multiple molecular underpinnings of energy metabolism can provide the basis for future therapeutic options. Numerous aspects of obesity are currently studied, including the essential role of neural and endocrine control circuits, adaptive responses of catabolic and anabolic pathways, metabolic fuel sensors, regulation of appetite and satiation, sensory information processing, transcriptional control of metabolic processes, and the endocrine role of adipose tissue. These studies are predominantly fuelled by basic research on mammalian models or clinical studies, but these ?ndings were paralleled by important insights, which have emerged from studying invertebrate models.

Biological Complexity and the Dynamics of Life Processes

This matter has long been disregarded and the control of metabolism has been
studied in a reductionist manner. It was in fact considered that metabolic
pathways were each controlled by a small number of enzymes, or even by a
single ...

Author: J. Ricard

Publisher: Elsevier

ISBN: 9780080860954

Category: Science

Page: 355

View: 831

The aim of this book is to show how supramolecular complexity of cell organization can dramatically alter the functions of individual macromolecules within a cell. The emergence of new functions which appear as a consequence of supramolecular complexity, is explained in terms of physical chemistry. The book is interdisciplinary, at the border between cell biochemistry, physics and physical chemistry. This interdisciplinarity does not result in the use of physical techniques but from the use of physical concepts to study biological problems. In the domain of complexity studies, most works are purely theoretical or based on computer simulation. The present book is partly theoretical, partly experimental and theory is always based on experimental results. Moreover, the book encompasses in a unified manner the dynamic aspects of many different biological fields ranging from dynamics to pattern emergence in a young embryo. The volume puts emphasis on dynamic physical studies of biological events. It also develops, in a unified perspective, this new interdisciplinary approach of various important problems of cell biology and chemistry, ranging from enzyme dynamics to pattern formation during embryo development, thus paving the way to what may become a central issue of future biology.

Brain Somatic Cross Talk and the Central Control of Metabolism

Metabolism. M. J. Friedman1 Summary In mammals, a robust physiologic system
acts to maintain relative constancy of ... acts in part by modulating the activity of
efferent signals from the brain that regulate a number of metabolic processes.

Author: Claude Kordon

Publisher: Springer Science & Business Media

ISBN: 9783540000907

Category: Medical

Page: 193

View: 733

In mammals, a robust physiologic system acts to maintain relative constancy of weight. A key element of this system is leptin. The nature of this "brain-somatic" cross talk is as yet poorly understood, but it is likely to have important implications for the pathophysiology and treatment of obesity, diabetes and other metabolic disorders.

Energy Metabolism and the Regulation of Metabolic Processes in Mitochondria

KINETIC CONTROL OF ELECTRON FLOW Britton Chance, Maria Erecir'rska,
Edwin M. Chance, Alberto Boveris and ... Since thermodynamics itself does not
tell us anything about the actual reaction pathways or rates, the only way to fully ...

Author: Myron Mehlman

Publisher: Elsevier

ISBN: 0323141250

Category: Science

Page: 314

View: 224

Energy Metabolism and the Regulation of Metabolic Processes in Mitochondria contains papers presented at the 1972 symposium on metabolic regulation, held at the University of Nebraska Medical School in Omaha, Nebraska. The contributors provide alternative views and ideas in some aspects of metabolic regulation directly concerned with mitochondrial function. Separating 16 papers into chapters, this book first discusses the general aspects of control of the biological energy regulation and the kinetic and thermodynamic control of mitochondrial electron transport and energy coupling. It then covers significant topics on citric acid cycle, including its replenishment and depletion; anion transport and regulation; dynamics and substrate compartmentation; and feedback control. Other chapters examine the mechanisms of gluconeogenesis, lipogenesis, redox reaction, and phosphorylation in the mitochondria. Discussions on hormonal regulation of selected enzyme system directly related to mitochondrial function are provided in the concluding chapters. Biochemists, physiologists, pharmacologists, physicians, researchers, and all others interested in the concepts of mitochondrial function will find this book of great value.

Technological and Medical Implications of Metabolic Control Analysis

Genome Resources , 1800 - a Old Pecos Trail , Santa Fe , New Mexico 87505 ,
USA I ...

Author: Athel Cornish-Bowden

Publisher: Springer Science & Business Media

ISBN: 9780792361886

Category: Medical

Page: 374

View: 176

Two decades have passed since the mechanisms of protein synthesis became well enough understood to permit the genetic modification oforganisms. An impressive amount of new knowledge has emerged from the new technology, but much ofthe promise of20years ago has notyet been fulfilled. In biotechnology, efforts to increase the yields of commercially valuable metabolites have been less successful than ex pected, and when they have succeeded it has often been as much from selective breeding as from new methods. The cell is more complicated than what is presented in the classical teaching of biochemistry, it contains more structure than was dreamed of 20 years ago, and the behaviour ofany systemofenzymes is more elaborate than can be explained in terms ofa single supposedly rate-limiting enzyme. Even if classical enzymology and meta bolism may have seemed rather unfashionable during the rise ofmolecular biology, they remain central to any modification ofthe metabolic behaviour oforganisms. As such modification is essential in much ofbiotechnology and drug development, bio technologists can only ignore these topics at their peril.

Annual Plant Reviews Control of Primary Metabolism in Plants

control. of. plant. primary. metabolism. Mechthild. Tegeder. and. Andreas. P. M.
Weber. 4.1 Introduction A fundamental process in the physiology of plants is the
selective partitioning of organic metabolites among different organelles, cells, ...

Author: William Plaxton

Publisher: John Wiley & Sons

ISBN: 1405172096

Category: Science

Page: 408

View: 737

The ability to control the rates of metabolic processes in response to changes in the internal or external environment is an indispensable attribute of living cells that must have arisen with life’s origin. This adaptability is necessary for conserving the stability of the intracellular environment which is, in turn, essential for maintaining an efficient functional state. The advent of genomics, proteomics, and metabolomics has revolutionised the study of plant development and is now having a significant impact on the study of plant metabolism and its control. In the last few years, significant advances have been made, with the elucidation of enzyme gene families and the identification of new proteinaceous and allosteric regulators. The first part of this volume is devoted to generic aspects of metabolic control, with chapters on the key control points in pathways. Part Two considers the control of specific pathways, with detailed descriptions (including structures) and discussions of the regulation of these pathways, particularly in terms of the enzymology. The book is directed at researchers and professionals in plant biochemistry, physiology, molecular biology and cell biology.

Metabolic Issues of Clinical Nutrition

This process is highly regulated and integrated through neuro-hormonal control
processes at various levels of organization. Metabolism at the cellular level is
primarily regulated by cell-signaling pathways and substrate environments for ...

Author: Simon P. Allison

Publisher: Karger Medical and Scientific Publishers

ISBN: 3805577567

Category: Health & Fitness

Page: 271

View: 621

As widely spread health problems related to over-and undernutrition have grown nowadays to an epidemic extent and even prevail over infectious diseases, a better knowledge of the metabolic basis of clinical nutrition has become essential. The extremes of the nutritional spectrum, undernutrition and obesity, are no longer considered as isolated opposites with different effects on separate risk groups, but paradoxically prove to be interacting in a setting of rapidly changing lifestyles, as is presently the case worldwide. Recurring issues such as insulin resistance, changes in intermediary metabolism, fluid and electrolyte physiology, genetic and non-genetic inheritance are highlighted, as well as the biological linkage between maternal undernutrition and the development of obesity, diabetes and cardiovascular disease in later life. The problems at stake present a new and enormous challenge for future healthcare policies and, therefore, are better tackled today. This book will be an interesting source of knowledge for internists, family physicians, pediatricians, dieticians, endocrinologists, gastroenterologists, and public health officers.

Metabolic Pathways of Agrochemicals Insecticides and fungicides

The development of insect juvenile hormones ( JHS ) for application in insect
control had its origins in extensive research in ... A variety of physiological and
behavioural processes is controlled by the moulting homones ( ecdysoids ) and
the ...

Author: Terence Robert Roberts

Publisher: Royal Society of Chemistry

ISBN: 9780854044993

Category: Nature

Page: 1475

View: 608

Annotation Based on literature (and some unpublished work provided by agrochemical companies), this sizable single volume provides a summary of data and information on the metabolism and chemical degradation of agrochemicals in soils, plants, and animals. Entries are organized by class of chemical and cover most commercially available chemicals in use today--including modulators of insect growth and behavior, rodenticides and nematicides. Introductions to each section provide an overview of the metabolism of each major class. The editors include independent consultants and researchers from JSC International Ltd., Shell Research Ltd., E.I. Du Pont de Nemours & Co., and IACR- Rothamsted. Annotation c. Book News, Inc., Portland, OR (

Measurement Monitoring Modelling and Control of Bioprocesses

These structural features are pivotal for the design of process control strategies
based on metabolic networks. On the one hand, given the high number and
specificity of metabolites that cross the cellular membrane, the measurement of
the ...

Author: Carl-Fredrik Mandenius

Publisher: Springer

ISBN: 3642368387

Category: Science

Page: 285

View: 161

Automated Measurement and Monitoring of Bioprocesses: Key Elements of the M3C Strategy, by Bernhard Sonnleitner Automatic Control of Bioprocesses, by Marc Stanke, Bernd Hitzmann An Advanced Monitoring Platform for Rational Design of Recombinant Processes, by G. Striedner, K. Bayer Modelling Approaches for Bio-Manufacturing Operations, by Sunil Chhatre Extreme Scale-Down Approaches for Rapid Chromatography Column Design and Scale-Up During Bioprocess Development, by Sunil Chhatre Applying Mechanistic Models in Bioprocess Development, by Rita Lencastre Fernandes, Vijaya Krishna Bodla, Magnus Carlquist, Anna-Lena Heins, Anna Eliasson Lantz, Gürkan Sin and Krist V. Gernaey Multivariate Data Analysis for Advancing the Interpretation of Bioprocess Measurement and Monitoring Data, by Jarka Glassey Design of Pathway-Level Bioprocess Monitoring and Control Strategies Supported by Metabolic Networks, by Inês A. Isidro, Ana R. Ferreira, João J. Clemente, António E. Cunha, João M. L. Dias, Rui Oliveira Knowledge Management and Process Monitoring of Pharmaceutical Processes in the Quality by Design Paradigm, by Anurag S Rathore, Anshuman Bansal, Jaspinder Hans The Choice of Suitable Online Analytical Techniques and Data Processing for Monitoring of Bioprocesses, by Ian Marison, Siobhán Hennessy, Róisín Foley, Moira Schuler, Senthilkumar Sivaprakasam, Brian Freeland

Pediatric Gastrointestinal and Liver Disease E Book

... necrosis factor (TNF)-α Plasminogen activator inhibitor (PAI)-1 Leptin Inhibits
inflammatory and other metabolic processes Stimulates hepatic production ... Key
hormones and signaling agents involved in the control of energy intake (usually ...

Author: Robert Wyllie

Publisher: Elsevier Health Sciences

ISBN: 1437735665

Category: Medical

Page: 1104

View: 996

Pediatric Gastrointestinal and Liver Disease, by Drs. Robert Wyllie and Jeffrey S. Hyams provides the comprehensive reference you need to treat GI diseases in children. Review the latest developments in the field and get up-to-date clinical information on hot topics like polyps, capsule endoscopy, and pancreatic treatments. With expert guidance from an expanded international author base and online access to 475 board-review-style questions, this latest edition is a must-have for every practicing gastroenterologist. Confirm each diagnosis by consulting a section, organized by symptoms, that presents the full range of differential diagnoses and treatment options for each specific condition. Recognize disease processes at a glance with detailed diagrams that accurately illustrate complex concepts. Stay current with advances in the field by reviewing new chapters on Polyps and Polyposis Syndromes, Capsule Endoscopy and Small Bowel Enteroscopy, Small Bowel Transplantation, IBD, Short Gut Syndrome, Steatosis and Non-Alcoholic Fatty Liver Disease, and Pancreatic and Islet Cell Transplants. Gain fresh global perspectives from an expanded list of expert international contributors. Sharpen your visual recognition by accessing a color-plate section that displays additional endoscopy images. Prepare for certification or recertification with 475 online board review-style questions, answers, and rationales.

Function and Control of the Spx Family of Proteins Within the Bacterial Stress Response

These include complex programs of cellular differentiation and cell specialization
, systems of oxidative stress mitigation, and transcriptional control of metabolic
processes. Further understanding its integration into the stress response network

Author: Peter Zuber

Publisher: Springer Science & Business Media

ISBN: 1461469252

Category: Medical

Page: 49

View: 157

This SpringerBrief on Spx reviews the investigations that led to the discovery of Spx and its orthologs and ties together the results of various studies that have explored the function and control of spx in Gram-positive organisms. Spx of Bacillus subtilis has been extensively studied, but very little has been published about it. This book incorporates a number of studies that have been conducted in other Gram positive bacteria, which examined the role of Spx orthologs in stress response, bacterial development and virulence. The book contains an overview that will introduce the protein and its orthologous forms, its association with RNA polymerase, the species of Gram-positive bacteria in which it is found, and the conditions in which it is abundant and active. Spx is a member of a large group of proteins belonging to the ArsC/Spx protein family, so the review touches upon the bioinformatic support for the protein family composition and its meaning with regard to protein structure/function. ​

Fluid Electrolyte and Acid Base Physiology E Book

A “metabolic process” consists of a series of metabolic pathways that carry out a
specific function; its control can be deduced by examining its function. • To
determine the acid-base impact of a metabolic process, count the net valence of
all of ...

Author: Kamel S. Kamel

Publisher: Elsevier Health Sciences

ISBN: 143771062X

Category: Medical

Page: 626

View: 835

The revised and updated fourth edition of Fluid, Electrolyte and Acid-Base Physiology continues to offer expert advice on the bedside management of acid-base and electrolyte disorders. Distinguished authors synthesize key theoretical and clinical information in a way that is easy to understand and apply. Discussions on the latest science, as well as new cases, new discoveries, and new approaches in intensive care are just a few of the updates you’ll find to help you make the best management decisions. Clinical information is presented in an easy-to-understand style, and the integration of color offers increased visual guidance. What’s more, diagnostic flow charts and critical questions challenge your problem-solving skills and reinforce your decision-making expertise. Incorporates relevant information on energy metabolism and endocrine, gastrointestinal, respiratory, and cardiovascular physiology. Features a consistent, user-friendly format with diagnostic algorithms and helpful margin notes. Includes numerous case studies that illustrate how key management principles are applied in practice. Presents questions and explanations throughout that let you test your knowledge and hone your skills. Features entirely new cases with discussions that keep you on the cusp of current clinical dilemmas and standards of practice. Discusses new treatment options to help you provide optimal care. Presents new discoveries to bring you up to date on the latest findings in science and clinical practice. Offers new approaches in critical care keeping you current in this emerging area of nephrology.

Enzyme Kinetics Catalysis and Control

With the central metabolic pathways already well defined and with the broad
outlines of molecular biology emerging, modern enzyme science was
established by a generation of biochemists that included my mentors Herb
Fromm and Earl ...

Author: Daniel L. Purich

Publisher: Elsevier

ISBN: 0123809258

Category: Science

Page: 920

View: 691

Far more than a comprehensive treatise on initial-rate and fast-reaction kinetics, this one-of-a-kind desk reference places enzyme science in the fuller context of the organic, inorganic, and physical chemical processes occurring within enzyme active sites. Drawing on 2600 references, Enzyme Kinetics: Catalysis & Control develops all the kinetic tools needed to define enzyme catalysis, spanning the entire spectrum (from the basics of chemical kinetics and practical advice on rate measurement, to the very latest work on single-molecule kinetics and mechanoenzyme force generation), while also focusing on the persuasive power of kinetic isotope effects, the design of high-potency drugs, and the behavior of regulatory enzymes. Historical analysis of kinetic principles including advanced enzyme science Provides both theoretical and practical measurements tools Coverage of single molecular kinetics Examination of force generation mechanisms Discussion of organic and inorganic enzyme reactions

Medical Biochemistry

Each of these metabolic pathways is mediated by enzymes which are unique for
a given pathway and which are under control . Metabolic pathways do not usually
compete with each other for utilization of a substrate , and they operate only to ...

Author: N. V. Bhagavan

Publisher: Jones & Bartlett Learning

ISBN: 9780867200300

Category: Medical

Page: 980

View: 268

Thoroughly updated and in a new two-color format, this well- respected text presents the fundamentals of biochemistry and related topics to students pursuing a one- or two-semester course in pre-med biochemistry or medical programs. The second edition is equally applicable to other health-related fields such as clinical chemistry, medical technology or pharmacology. Medical Biochemistry, Fourth Edition, focuses on the foundations and clinically relevant applications of normal human biochemistry and pathology. Abundantly illustrated with four-color plates.Revised chapters on molecular biology reflect the latest research in the fieldTwo color throughout with four color platesReference quality appendices include practical information on clinical lab parameters used to diagnose a range of diseases

Comprehensive Insect Physiology Volume 8

4 COntrol Of MetaboliC PrOCéSS6S J. E. STEELE University of Western Ontario,
London, Ontario, Canada Introduction 99 1 Lipid metabolism 100 1.1
Hyperlipaemic agents 100 1.2 Hypolipaemic agents 105 1.3 Lipid metabolism in
fat body 106 1.3.1 Lipid synthesis 106 1.3.2 ... Control of Metabolic Processes

Author: G. A. Kerkut

Publisher: Elsevier

ISBN: 1483286215

Category: Science

Page: 639

View: 440

Endocrinology II concerns the actions of hormones in insects, complementing Volume 7 which is concerned with the production and chemistry of insect hormones. While the preceding volume is directed mainly towards the insect endocrinologist, this volume has much of intrinsic interest to the general physiologist. It deals with the regulation of metabolism, reproduction, cuticle properties, and certain aspects of behaviour from a systems point of view and amply documents how hormones have provided basic insights into the functioning of such systems. Interference in endocrine regulation could provide future systems for insect control and this volume will provide the foundation on which the future formulation of these strategies is based. More information on diverse aspects of insect hormone action is brought together here than in any previous single work and this volume will therefore be a valuable reference source for many years to come.

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics E Book

... 55).1 Homeostatic Control of Metabolic Pathways The metabolic pathways
under hormonal control are diverse and complex. ... Several counter-regulatory
hormones come into play to further regulate this process to ensure that blood
glucose ...

Author: Carl A. Burtis

Publisher: Elsevier Health Sciences

ISBN: 1455759422

Category: Medical

Page: 2256

View: 709

As the definitive reference for clinical chemistry, Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th Edition offers the most current and authoritative guidance on selecting, performing, and evaluating results of new and established laboratory tests. Up-to-date encyclopedic coverage details everything you need to know, including: analytical criteria for the medical usefulness of laboratory procedures; new approaches for establishing reference ranges; variables that affect tests and results; the impact of modern analytical tools on lab management and costs; and applications of statistical methods. In addition to updated content throughout, this two-color edition also features a new chapter on hemostasis and the latest advances in molecular diagnostics. Section on Molecular Diagnostics and Genetics contains nine expanded chapters that focus on emerging issues and techniques, written by experts in field, including Y.M. Dennis Lo, Rossa W.K. Chiu, Carl Wittwer, Noriko Kusukawa, Cindy Vnencak-Jones, Thomas Williams, Victor Weedn, Malek Kamoun, Howard Baum, Angela Caliendo, Aaron Bossler, Gwendolyn McMillin, and Kojo S.J. Elenitoba-Johnson. Highly-respected author team includes three editors who are well known in the clinical chemistry world. Reference values in the appendix give you one location for comparing and evaluating test results. NEW! Two-color design throughout highlights important features, illustrations, and content for a quick reference. NEW! Chapter on hemostasis provides you with all the information you need to accurately conduct this type of clinical testing. NEW! Six associate editors, Ann Gronowski, W. Greg Miller, Michael Oellerich, Francois Rousseau, Mitchell Scott, and Karl Voelkerding, lend even more expertise and insight to the reference. NEW! Reorganized chapters ensure that only the most current information is included.