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Bioactive Natural Products: Detection, Isolation, and Structural Determination, Second Edition
by Steven M. Colegate Russell J. MolyneuxFollowing the successful format of the original, this new edition presents applications of the most recent techniques for the detection, isolation, and structural determination of bioactive natural products. It features new case studies and illustrations that demonstrate applications of techniques covered in the book. Complementing as much as replacing the first edition, most of the contributors are new. The text includes updates on chemical extraction, and NMR-based structure determination, and new contributions on liquid chromatography linked with mass and NMR spectroscopy, dereplication approaches, assessment of source material for natural products and novel bioassay development.
Bioactive Natural Products for Pharmaceutical Applications (Advanced Structured Materials #140)
by Dilipkumar Pal Amit Kumar NayakThis book covers the recent innovations relating to various bioactive natural products (such as alkaloids, glycosides, flavonoids, anthraquinones, steroids, polysaccharides, tannins and polyphenolic compounds, volatile oils, fixed oils, fats and waxes, proteins and peptides, vitamins, marine products, camptothecin, piperines, carvacrol, gedunin, GABA, ginsenosides) and their applications in the pharmaceutical fields related to academic, research and industry.
Bioactive Natural Products for the Management of Cancer: from Bench to Bedside
by Anil K. SharmaThis book illustrates the importance of the Natural Biometabolites, which offer a rich reservoir of candidate compounds for drug discovery in the battle against cancer. Recent research and development efforts concerning anti-cancer drugs derived from natural products have led to the identification of numerous candidate molecules that inhibit cancer cell proliferation and metastasis using a variety of mechanisms. Given its scope, the book offers a valuable resource for cancer biologists and general oncologists alike, while also benefitting research professionals in Science, Nursing, Medicine, Biochemistry, Genetics and Bioscience who wish to understand the fundamentals of prognosis and prediction in tumorigenesis. Moreover, the book provides an essential platform for understanding drug resistance mechanisms and combatting the growing menace of multidrug resistance.
Bioactive Natural products in Drug Discovery
by Joginder Singh Vineet Meshram Mahiti GuptaThis book highlights different natural products that are derived from the plants and microbes that have shown potential as the lead compounds against infectious diseases and cancer. Natural products represent an untapped source of strikingly diverse chemotypes with novel mechanisms of action and the potential to serve as anticancer and anti-infective agents. The book discusses a range of biotechnologically valuable bioactive compounds and secondary metabolites that have been derived from plant and microorganisms from various ecological niches. It also reviews the latest developments in the field of genomics, bioinformatics and industrial fermentation for harnessing the microbial products for commercial applications. In turn, the book’s closing section reviews important biotechnological applications of various natural products. Combining the expertise of specialists in this field, the book’s goal is to promote the further investigation of natural sources for the development of standardized, safe and effective therapies.
Bioactive Phytochemicals from Vegetable Oil and Oilseed Processing By-products (Reference Series in Phytochemistry)
by Mohamed Fawzy Ramadan HassanienThis book comprehensively reviews the phytochemistry, functional properties, and health-promoting effects of bioactive compounds found in oil processing by-products, and it also explores the food and non-food applications of these by-products. Several oilseeds, vegetables, and fruits are cultivated for their oils and fats, wherein the oil extraction industry generates a huge amount of waste (meal or cake). The valorisation of this waste would be very beneficial not only from the economic and environmental perspectives, but also for the potential applications in food, cosmetics and pharmaceutical industries, in which phytochemicals derived from vegetable oil and oilseed processing by-products play an important role in, for instance, extending the shelf life of several products and providing added-value properties with their antioxidant and antimicrobial properties. In this work, expert contributors discuss about the added-value of biowaste from common and non-traditional vegetable oils and oilseeds processing, as well as fruit oils processing, and offer an extensive overview of the different bioactive compounds found in extracts from oil processing by-products and their chemical composition. The book also collects several examples in which oil processing by-products are integrated into industrial activities such as food production, livestock production and in pharmaceutical and cosmetics industries. Professionals and scholars alike interested in the recycling of agro-industrial wastes derived from vegetable oil and oilseed processing by-products will find this book a handy reference tool.
Bioactive Phytochemicals in By-products from Bulb, Flower and Fruit Vegetables
by Mohamed Fawzy RamadanThis book collates bioactive compounds from the by-products of bulb, flower and fruit vegetables, and it explores vegetable processing by-products utilization. By-products and wastes from vegetable processing have been gathering attention in the food industry due to the management of residues that pose significant disposal challenges. This book not only addresses these concerns but also underscores the potential of these by-products as sources of value-added phytochemicals, with a focus on the recovery of bioactive phytochemicals and technologically critical secondary metabolites. This book covers vegetable by-products’ economic significance, ecological implications, and their applications spanning nutrition, health, and industry. Divided into 13 chapters, the book offers an overview of the phytochemical, nutritional, biochemical and physicochemical properties of vegetable processing wastes. It discusses process by-products of diverse vegetables, including fennel, garlic, onion, artichoke, cauliflower, broccoli, bitter melon, bell pepper, chili pepper, chayote, cucumber, eggplant, green plantain banana, pumpkin and tomato. In each chapter, readers will find an economic perspective for each biowaste, the chemical analysis of the bioactive compounds, their biological and functional properties, and relevant food and non-food applications of extracts and bioactive compounds from vegetable by-products. This book, coupled with its companion volume, "Bioactive Phytochemicals in By-products from Leaf, Stem, Root, and Tuber Vegetables," serves as an indispensable resource for students, scholars, and researchers seeking to deepen their understanding of this research area. It also extends its relevance to professionals within the food industry, offering the latest insights and findings from cutting-edge research.
Bioactive Phytochemicals in By-products from Leaf, Stem, Root and Tuber Vegetables
by Mohamed Fawzy RamadanThis book offers a comprehensive overview of bioactive phytochemicals within by-products from leaf, stem, root, and tuber vegetables, and it explores the valorisation of these vegetable cultivation and processing by-products, not only as a source of valuable bioenergy but also for health purposes. Divided into 16 chapters, the book begins with an introduction to the economic significance of biowaste generated from vegetable cultivation and processing, setting the stage for subsequent chapters that cover the phytochemical, nutritional, biochemical and physicochemical properties of vegetable processing wastes and their multifaceted applications. Readers will find valuable insights into the valorisation of process by-products from diverse vegetables like cabbage, spinach, watercress, asparagus, celery, kohlrabi, beetroot, carrot, celeriac, turnip, sweet potato, potato and taro. In each chapter, readers will find an economic perspective for each biowaste, the chemical analysis of the bioactive compounds, their biological and functional properties, and relevant food and non-food applications of extracts and bioactive compounds from vegetable by-products. This book, coupled with its companion volume, " Bioactive Phytochemicals in By-products from Bulb, Flower and Fruit Vegetables" serves as an indispensable tool for students, scholars, and researchers seeking to expand their knowledge within this field in agricultural and nutritional sciences. It also extends its relevance to professionals within the food industry, offering the latest insights and findings from cutting-edge research.
Bioactive Polyphenols from Wine Grapes (SpringerBriefs in Cell Biology)
by Ellen L Robb Jeffrey A StuartIs red wine good for you? And if so, why? How much? And what are the actual benefits? This addition to the SpringerBriefs in Cell Biology series thoroughly but succinctly answers these questions. It covers the biochemistry, health benefits and therapeutic potential of wine grapes. It begins with an overview of phytoalexin production in Vitis vinifera (Common Grape Vine), detailing the relationship of resveratrol to analogues such as pterostilbene, piceid and the viniferins (resveratrol oligomers). The discussion then turns to the hundreds of reports linking resveratrol and related grape vine polyphenols to various beneficial health effects especially cardio- and cerebro- vascular, metabolic, anti-inflammatory and more. Also addressed are the numerous intracellular mechanisms that have been shown to mediate the effects of these compounds in mammalian cells and tissues. Finally, the authors discuss aspects of polyphenol bioavailability and how this will influence choices taken for delivering these compounds as nutritional supplements. A brief chapter containing general conclusions and prospectus rounds out the information.
Bioactive Surfaces (Advances in Polymer Science #240)
by Jean-Francois Lutz Hans G. BörnerErik Wischerhoff, Nezha Badi, André Laschewsky and Jean-François Lutz Smart Polymer Surfaces: Concepts and Applications in Biosciences; S. Petersen, M. Gattermayer and M. Biesalski Hold on at the Right Spot: Bioactive Surfaces for the Design of Live-Cell Micropatterns; Julien Polleux Interfacing Cell Surface Receptors to Hybrid Nanopatterned Surfaces: A Molecular Approach for Dissecting the Adhesion Machinery; Abigail Pulsipher and Muhammad N. Yousaf Self-Assembled Monolayers as Dynamic Model Substrates for Cell Biology; D. Volodkin, A. Skirtach and H. Möhwald LbL Films as Reservoirs for Bioactive Molecules; R. Gentsch and H. G. Börner Designing Three-Dimensional Materials at the Interface to Biology; Joerg C. Tiller Antimicrobial Surfaces;
Bioactivity of Engineered Nanoparticles (Nanomedicine and Nanotoxicology)
by Bing Yan Hongyu Zhou Jorge L. Gardea-TorresdeyThis book brings together reviews from international experts who are exploring the biological activities of nanomaterials for medical applications or to better understand nanotoxicity. Topics include but are not limited to the following: 1) mechanistic understanding of nanostructure-bioactivity relationships; 2) the regulation of nanoparticles' bioactivity by means of chemical modification; 3) the new methodologies and standard methods used to assess nanoparticles' bioactivity; 4) the mechanisms involved in nanoparticle-biomolecule interactions and nanoparticle-cell interactions; and 5) biomedical applications of nanotechnology. The book will be a valuable resource for a broad readership in various subfields of chemical science, engineering, biology, environment, and medicine.
Bioadhesive Drug Delivery Systems
by Vincent M. Lenaerts Robert GurnyThis comprehensively written text covers, in-depth, all aspects of bioadhesive systems. Bioadhesive systems are presently playing a major role in the field because of their ability to maintain a dosage form at a precise body-site for a prolonged period of time over which the active principle is progressively released. Included in this book are descriptions of the different mucosae in healthy and pathological situations, a theoretical approach of polymers-mucin interactions, and a comparative description of the methods used to evaluate bioadhesion. Up-to-date reviews of pharmaceutical applications are also given - subdivided according to the route of administration and type of system. It also contains a chapter devoted to the fundamentals of bioadhesion. This reference is an indispensable guide for researchers in the pharmaceutical field as well as academic researchers.
Bioaerosol Characterisation, Transportation and Transmission: Fundamental, Modelling and Application
by Yihuan Yan Jiyuan TuThis book aims to predict and model the transport of bioaerosols, identify their transmission characteristics, and assess occupants’ infection risks. Although existing epidemiological books provide fundamental infection rate of existing diseases, the ability of predicting emerging disease transmission in the air and assessing occupants’ infection risks to the bioaerosols is significantly lacking. This book is considered as a professional book that provides in-depth discussion of the aforementioned issues and provides potential approaches to solve these issues would be highly demanded by readers in this emerging research field. This book offers essential and systematic analysis on the fate of bioaerosols from their release in the air to the final destination in human’s respiratory systems through direct 3D visualizations techniques. It also provides quantifiable method to assess each occupant’s infection risks to the infectious bioaerosols in indoor environments. The readers will gain essential fundamental characteristics of bioaerosols (active time, viability, etc.) and will gain the advanced skills on how to integrate these properties into numerical modeling and assess the occupants’ exposure risks.
Bioaerosol Detection Technologies (Integrated Analytical Systems)
by Per Jonsson Göran Olofsson Torbjörn TjärnhageThis book is intended to give technological background and practical examples, but also to give general insight into the on-going technology development in the area of biodetection. The content is therefore suitable for an array of stakeholders (decision makers, purchasing officers, etc. ) and end-users of biodetection equipment within the areas of health, environment, safety and security, and military preparation. The book is divided into three sections. The first section discusses the fundamental physical and biological properties of bioaerosol's. The second section goes into more detail and discusses in-depth the most commonly used detection principles. The third section of the book is devoted to technologies that have been used in standoff applications. The last section of the book gives an overview of trends in bioaerosol detection. The reader of this book will gain knowledge about the different biodetection technologies and thus better judge their capabilities in relation to desired applications.
Bioaerosols Handbook
by Christopher S. Cox; Christopher M. WathesThis comprehensive handbook provides up-to-date knowledge and practical advice from established authorities in aerosol science. It covers the principles and practices of bioaerosol sampling, descriptions and comparisons of bioaerosol samplers, calibration methods, and assay techniques, with an emphasis on practicalities, such as which sampler to use and where it should be placed. The text also offers critiques concerning handling the samples to provide representative and meaningful assays for their viability, infectivity, and allergenicity. A wide range of microbes-viz., viruses, bacteria, fungi and pollens, and their fragments-are considered from such perspectives.Bioaerosols Handbook is divided into four parts, providing a wide-ranging reference work, as well as a practical guide on how best to sample and assay bioaerosols using current technology.
Bioaesthetics: Making Sense of Life in Science and the Arts (Posthumanities #43)
by Carsten StrathausenIn recent years, bioaesthetics has used the latest discoveries in evolutionary studies and neuroscience to provide new ways of looking at art and aesthetics. Carsten Strathausen&’s remarkable exploration of this emerging field is the first comprehensive account of its ideas, as well as a timely critique of its limitations. Strathausen familiarizes readers with the basics of bioaesthetics, grounding them in its philosophical underpinnings while articulating its key components. Importantly, he delves into the longstanding problem of the &“two cultures&” that separate the arts and the sciences. Seeking to make bioaesthetics a more robust way of thinking, Strathausen then critiques it for failing to account for science&’s historical and cultural assumptions. At its worst, he says, biologism reduces artworks to mere automatons that rubber-stamp pre-established scientific truths. Written with a sensitive understanding of science&’s strengths, and willing to refute its best arguments, Bioaesthetics helps readers separate the sensible from the specious. At a time when humanities departments are shrinking—and when STEM education is on the rise—Bioaesthetics makes vital points about the limitations of science, while lodging a robust defense of the importance of the humanities.
Bioanalysis of Pharmaceuticals
by Stig Pedersen-Bjergaard Steen Honoré Hansenharmaceuticals: Sample Preparation, Separation Techniques and Mass Spectrometry: Is an introductory student textbook discussing the different principles and concepts clearly and comprehensively, with many relevant and educational examples Focuses on substances that are administered as human drugs, including low-molecular drug substances, peptides, and proteins Presents both the basic principles that are regularly taught in universities, along with the practical use of bioanalysis as carried out by researchers in the pharmaceutical industry and in hospital laboratories Is aimed at undergraduate students, scientists, technicians and researchers in industry working in the areas of pharmaceutical analyses, biopharmaceutical analyses, biological and life sciences.The book includes multiple examples to illustrate the theory and application, with many practical aspects including calculations, thus helping the student to learn how to convert the data recorded by instruments into the real concentration of the drug substances within the biological sample.
Bioanalytical Aspects in Biological Therapeutics
by Xiaohui Xu Weifeng XuBioanalytical Aspects in Biological Therapeutics Deepen your understanding of how critical data are generated from bioanalysis In Bioanalytical Aspects in Biological Therapeutics, a team of renowned chemists, immunologists, and biologists delivers a timely and practical exploration of the diverse scientific and technical literature on the bioanalytical investigation of current biotherapeutics under development. The book discusses the challenges and considerations for bioanalytical support, covering a wide range of central topics in the field, including overview and basic immunology for testing of biological therapeutics, pharmacokinetic aspects, clinical immunogenicity prediction and testing, biomarker testing, biotransformation assessment for biologics, statistical aspects of bioanalytical testing, regulatory expectations, and more. Drug development and analysis professionals will learn how critical data are generated from bioanalysis and how proven tools and methods are applied to the development of biologics. Alongside coverage of topics like PK, immunogenicity, neutralizing antibody assays, and the importance of quality control for reagents, readers will benefit from: A thorough overview of the development of biotherapeutics and the role played by bioanalytical tests, as well as basic immunology for bioanalytical testing of biological therapeutics Comprehensive explorations of platform and instrument considerations in bioanalytical testing, pharmacokinetics assays, and biomarker analysis using LC-MS, LBA, and other technologies Practical discussions of immunogenicity prediction, preclinical and clinical anti-drug antibody assays, and bioanalytical schemes for anti-drug neutralizing antibody assays In-depth examinations of critical reagents in bioanalysis Regulatory expectations for bioanalytical method development, validation, and sample testing Perfect for pharmaceutical scientists in industry, Bioanalytical Aspects in Biological Therapeutics will also earn a place in the libraries of pharmaceutical regulators and other professionals working in pharmaceutical companies, as well as graduate students studying bioanalytical assays for biological therapeutics.
Bioanalytical Chemistry
by Susan R. Mikkelsen Eduardo CortónA timely, accessible survey of the multidisciplinary field of bioanalytical chemistry Provides an all in one approach for both beginners and experts, from a broad range of backgrounds, covering introductions, theory, advanced concepts and diverse applications for each method Each chapter progresses from basic concepts to applications involving real samples Includes three new chapters on Biomimetic Materials, Lab-on-Chip, and Analytical Methods Contains end-of-chapter problems and an appendix with selected answers
Bioanalytics: Analytical Methods and Concepts in Biochemistry and Molecular Biology
by Friedrich Lottspeich Joachim W. EngelsAnalytical methods are the essential enabling tools of the modern biosciences. This book presents a comprehensive introduction into these analytical methods, including their physical and chemical backgrounds, as well as a discussion of the strengths and weakness of each method. It covers all major techniques for the determination and experimental analysis of biological macromolecules, including proteins, carbohydrates, lipids and nucleic acids. The presentation includes frequent cross-references in order to highlight the many connections between different techniques. The book provides a bird´s eye view of the entire subject and enables the reader to select the most appropriate method for any given bioanalytical challenge. This makes the book a handy resource for students and researchers in setting up and evaluating experimental research. The depth of the analysis and the comprehensive nature of the coverage mean that there is also a great deal of new material, even for experienced experimentalists. The following techniques are covered in detail: - Purification and determination of proteins - Measuring enzymatic activity - Microcalorimetry - Immunoassays, affinity chromatography and other immunological methods - Cross-linking, cleavage, and chemical modification of proteins - Light microscopy, electron microscopy and atomic force microscopy - Chromatographic and electrophoretic techniques - Protein sequence and composition analysis - Mass spectrometry methods - Measuring protein-protein interactions - Biosensors - NMR and EPR of biomolecules - Electron microscopy and X-ray structure analysis - Carbohydrate and lipid analysis - Analysis of posttranslational modifications - Isolation and determination of nucleic acids - DNA hybridization techniques - Polymerase chain reaction techniques - DNA sequence and epigenetic modification analysis - Analysis of protein-nucleic acid interactions - Analysis of sequence data - Proteomics, metabolomics, peptidomics and toponomics - Chemical biology
Bioanorganische Chemie: Metalloproteine, Methoden und Modelle
by Peter Klüfers Sonja Herres-PawlisMit dieser Einfuhrung in die faszinierende Welt der Metalloproteine lernen Chemiker, Biochemiker und Biotechnologen Mechanismen, Methoden und Modellvorstellungen der bioanorganischen Chemie kennen. In einer Synthese aus aktuellen Arbeiten an Metalloenzymzentren und den Grundlagen der Koordinationschemie fuhren die Autoren in dieses spannende und im Wortsinne komplexe Thema ein. Der erste Teil des Buches stellt anhand ausgewahlter Metalloproteine dar, dass die Natur die koordinationschemischen Prinzipien "kennt" und in einer Weise nutzt, die vorbildhaft fur die Entwicklung synthetischer Katalysatoren sein kann. Einige der verwendeten Konzepte werden in Einschuben naher beleuchtet. Der zweite Teil vermittelt die Grundlagen der verschiedenen instrumentellen Methoden fur die Untersuchung von Metalloproteinen, von der Kristallographie uber die Vielfalt an spektroskopischen Methoden (UV, Raman, Fluoreszenz, EPR, Mo?bauer etc.) bis hin zu elektrochemischen und computerchemischen Methoden. Durch die Betonung der koordinationschemischen Grundlagen biochemischer Funktion ist dieses Lehrbuch eine wichtige Erganzung zu den Standardlehrbuchern der Biochemie und der anorganischen Chemie. Der modulare Aufbau erleichtert dabei den Einsatz fur unterschiedliche Lehrveranstaltungen und Studiengange.
Bioarchaeological and Forensic Perspectives on Violence
by Debra L. Martin Cheryl P. AndersonEvery year, there are over 1. 6 million violent deaths worldwide, making violence one of the leading public health issues of our time. And with the 20th century just behind us, it's hard to forget that 191 million people lost their lives directly or indirectly through conflict. This collection of engaging case studies on violence and violent deaths reveals how violence is reconstructed from skeletal and contextual information. By sharing the complex methodologies for gleaning scientific data from human remains and the context they are found in, and complementary perspectives for examining violence from both past and contemporary societies, bioarchaeology and forensic anthropology prove to be fundamentally inseparable. This book provides a model for training forensic anthropologists and bioarchaeologists, not just in the fundamentals of excavation and skeletal analysis, but in all subfields of anthropology, to broaden their theoretical and practical approach to dealing with everyday violence.
Bioarchaeology
by Clark Spencer LarsenThese important essays address the biological consequences of the arrival of Europeans in the New World and on the lifeways of native populations following contact in the late 16th century. Moving away from monocausal explanations of population change, they maintain that disease should be viewed as only a facet of a complex problem and that issues relating to diet, nutrition, activity, the work environment, and social and political change are equally important.
Bioarchaeology: An Integrated Approach to Working with Human Remains (Manuals in Archaeological Method, Theory and Technique #6)
by Ventura R. Pérez Debra L. Martin Ryan P. HarrodBioarchaeology is the analysis of human remains within an interpretative framework, including a wide range of contextual information. This comprehensive and much-needed manual provides both a starting point and a reference for archaeologists working in this integrative field. The authors cover a range of bioarchaeological methods and theory including: · Ethical issues involved in dealing with human remains, specifically related to NAGPRA · Field and taphonomic clues · Lab and Forensic techniques · Best practices methods for Excavation techniques · Special applications of Bioarchaeology · Theoretical frameworks of Bioarchaeology With case studies from over twenty years each of bioarchaeological research, the authors integrate theoretical and methodological discussion with a wide range of field studies, from different geographic areas, time periods, and data types, to demonstrate the full scope of this important field of study.
The Bioarchaeology of Artificial Cranial Modifications
by Vera TieslerThe artificial shaping of the skull vault of infants expresses fundamental aspects of crafted beauty, of identity, status and gender in a way no other body practice does. Combining different sources of information, this volume contributes new interpretations on Mesoamerican head shaping traditions. Here, the head with its outer insignia was commonly used as a metaphor for designating the "self" and personhood and, as part of the body, served as a model for the indigenous universe. Analogously, the outer "looks" of the head and its anatomical constituents epitomized deeply embedded worldviews and longstanding traditions. It is in this sense that this book explores both the quotidian roles and long-standing ideological connotations of cultural head modifications in Mesoamerica and beyond, setting new standards in the discussion of the scope, caveats, and future directions involved in this study. The systematic examination of Mesoamerican skeletal series fosters an explained review of indigenous cultural history through the lens of emblematic head models with their nuanced undercurrents of religious identity and ethnicity, social organization and dynamic cultural shift. The embodied expressions of change are explored in different geocultural settings and epochs, being most visible in the centuries surrounding the Maya collapse and following the cultural clash implied by the European conquest. These glimpses on the Mesoamerican past through head practices are novel, as is the general treatment of methodology and theoretical frames. Although it is anchored in physical anthropology and archaeology (specifically bioarchaeology), this volume also integrates knowledge derived from anatomy and human physiology, historical and iconographic sources, linguistics (polisemia) and ethnography. The scope of this work is rounded up by the transcription and interpretation of the many colonial eye witness accounts on indigenous head treatments in Mesoamerica and beyond.
The Bioarchaeology of Dissection and Autopsy in the United States (Bioarchaeology and Social Theory)
by Kenneth C. NystromEncountering evidence of postmortem examinations- dissection or autopsy in historic skeletal collections is relativelyrare, but recently there has been an increase in the number of reportedinstances. And much of what has been evaluated has been largely descriptiveand historical. The Bioarchaeology ofDissection and Autopsy brings together in a single volume the skeletal evidence ofpostmortem examination in the United States. Ranging from the earlycolonial period to the early 1900's, from a coffeehouse at ColonialWilliamsburg to a Quaker burial vault in lower Manhattan, the contributions to this volume demonstrate the interpretive significance of a historically andtheoretically contextualizedbioarchaeology. The authors employ a wide range of perspectives, demonstrating how bioarchaeological evidence can be used to address a widerange of themes including social identity and marginalization, racialization,the nature of the body and fragmentation, and the emergence of medical practiceand authority in the United States.