Genome Editing

Genome Editing
Author: Kiran Musunuru
Publsiher: Academic Press
Total Pages: 230
Release: 2021-03-05
ISBN 10: 0128236477
ISBN 13: 9780128236475
Language: EN, FR, DE, ES & NL

Genome Editing Book Review:

Genome Editing: A Practical Guide to Research and Clinical Applications is geared towards investigators interested in learning how to use CRISPR-Cas9-based technologies, with a focus on cardiovascular research and clinical applications. Covering a range of topics from the basics of genome editing to design considerations, to assessments and applications, this reference allows readers to get started and establish a full workflow from the beginning of the project to its full completion. With worked examples drawn from real-life experiments, as well as troubleshooting and pitfalls to avoid, the book serves as an essential reference for researchers and investigators in both cardiovascular and biomedical research. Help readers familiarise with the variety of genome-editing approaches that are being applied in cardiovascular research and medicine, i.e., both research applications and clinical applications Understand the use of genome editing through worked examples (based on real-life experiments) in which CRISPR-Cas9 is employed, online tools to design CRISPR-Cas9 reagents, methods to interpret data from genome-editing experiments, the downsides of genome-editing technology - both the scientific and ethical pitfalls to avoid Written in an easy-to-follow manner, guiding readers from the design of the project to its completion Includes unpublished and new methods

Human Genome Editing

Human Genome Editing
Author: National Academies of Sciences, Engineering, and Medicine,National Academy of Medicine,National Academy of Sciences,Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations
Publsiher: National Academies Press
Total Pages: 328
Release: 2017-08-13
ISBN 10: 0309452880
ISBN 13: 9780309452885
Language: EN, FR, DE, ES & NL

Human Genome Editing Book Review:

Genome editing is a powerful new tool for making precise alterations to an organism's genetic material. Recent scientific advances have made genome editing more efficient, precise, and flexible than ever before. These advances have spurred an explosion of interest from around the globe in the possible ways in which genome editing can improve human health. The speed at which these technologies are being developed and applied has led many policymakers and stakeholders to express concern about whether appropriate systems are in place to govern these technologies and how and when the public should be engaged in these decisions. Human Genome Editing considers important questions about the human application of genome editing including: balancing potential benefits with unintended risks, governing the use of genome editing, incorporating societal values into clinical applications and policy decisions, and respecting the inevitable differences across nations and cultures that will shape how and whether to use these new technologies. This report proposes criteria for heritable germline editing, provides conclusions on the crucial need for public education and engagement, and presents 7 general principles for the governance of human genome editing.

Cardiovascular Genomics

Cardiovascular Genomics
Author: Mohan K. Raizada,Julian F. R. Paton,Michael J. Katovich,Sergey Kasparov
Publsiher: Springer Science & Business Media
Total Pages: 362
Release: 2008-02-24
ISBN 10: 1592598838
ISBN 13: 9781592598830
Language: EN, FR, DE, ES & NL

Cardiovascular Genomics Book Review:

Recognized scientists and clinicians from around the world discuss the most recent molecular approaches to understanding the cardiovascular system in both health and disease. The authors focus on all components of the system, including blood vessels, heart, kidneys, and the brain, and cover disease states ranging from vascular and cardiac dysfunction to stroke and hypertension. The methods described for identifying the genes that cause susceptibility to cardiovascular diseases emphasize the possibility of discovering new drug targets. Authoritative and ground-breaking, Cardiovascular Genomics offers an unprecedented examination of both the cutting-edge scientific approaches now possible and the results obtained from them in the new science of cardiovascular genomics.

Translational Cardiometabolic Genomic Medicine

Translational Cardiometabolic Genomic Medicine
Author: Annabelle Rodriguez-Oquendo
Publsiher: Academic Press
Total Pages: 352
Release: 2015-09-07
ISBN 10: 0128004746
ISBN 13: 9780128004746
Language: EN, FR, DE, ES & NL

Translational Cardiometabolic Genomic Medicine Book Review:

Translational Cardiometabolic Genomic Medicine, edited by Dr. Annabelle Rodriguez-Oquendo, is an important resource to postgraduate (medical, dental and graduate) students, postdoctoral fellows, basic scientists, and physician scientists seeking to understand and expand their knowledge base in the field of genomic medicine as it is applied to cardiometabolic diseases. This handbook integrates cutting-edge experimental approaches such as chromatin immunoprecipitation paired end tagging (CHIA-PET), to population studies such as the Multi-Ethnic Study of Atherosclerosis. It encompasses a range of book chapters that highlight bioinformatic approaches to better understanding functionality of the noncoding regions of the human genome to the use of molecular diagnostic testing in predicting increased risk of cardiovascular diseases. Where applicable, this reference also includes chapters related to therapeutic options specifically aligned to molecular targets. Provides comprehensive research on translational genomic medicine Explains state-of-the-art genome editing for stem cells and mouse models with significant relevance to human cardiometabolic disease Includes discussions on the functional effects of single nucleotide polymorphisms and cardiometabolic diseases, stratified by sex and race Encompasses a range of book chapters that highlight bioinformatic approaches to better understanding functionality of the noncoding regions of the human genome

Cardiovascular Diseases

Cardiovascular Diseases
Author: Nikolaos Papageorgiou
Publsiher: Academic Press
Total Pages: 252
Release: 2016-08-05
ISBN 10: 0128033134
ISBN 13: 9780128033135
Language: EN, FR, DE, ES & NL

Cardiovascular Diseases Book Review:

Cardiovascular Diseases: Genetic Susceptibility, Environmental Factors and Their Interaction covers the special heritability characteristics and identifying genetic and environmental contributions to cardiovascular health. This important reference provides an overview of the genetic basis of cardiovascular disease and its risk factors. Included are important topics, ranging from lifestyle choices, risk factors, and exposure, to pollutants and chemicals. Also covered are the influences of Mendelian traits and familial aggregation and the interactions and interrelationships between genetics and environmental factors which, when compared, provide a sound understanding of the interplay between inherited and acquired risk factors. The book provides a much needed reference for this rapidly growing field of study. By combining the latest research within the structured chapters of this reference, a better understanding of genetic and environmental contribution to cardiovascular disease is found, helping to substantiate further investigations in the field and design prevention and treatment strategies. Provides an overview of the genetic basis of cardiovascular disease and its risk factors Reviews several large population-based studies which indicate that exposure to several environmental factors may increase CVD morbidity and mortality, exploring the plausibility of this association by data from animal studies Reflects on future studies to help understanding the role of genes and environmental factors in the development and progression of cardiovascular disease

Cardiac Gene Therapy

Cardiac Gene Therapy
Author: Kiyotake Ishikawa
Publsiher: Humana Press
Total Pages: 355
Release: 2016-12-02
ISBN 10: 9781493965861
ISBN 13: 1493965867
Language: EN, FR, DE, ES & NL

Cardiac Gene Therapy Book Review:

This detailed book provides methodological information on cardiac gene delivery, from classic to state-of-the-art technologies and techniques. Efficient, cardiac-specific, and safe vectors, as well as refined vector delivery methods, are key for successful cardiac gene transfer and eventually for improving patients’ outcomes. Newer vectors and more efficient vector delivery methods have the potential to dramatically improve gene transduction efficacy, while novel gene manipulation techniques enforce the therapeutic power and broaden disease targets. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Cardiac Gene Therapy: Methods and Protocols serves as a valuable tool for molecular biologists and physiologists in the cardiology field conducting cardiac gene transfer research, which will ultimately lead to further advancements in the vital field.

Regenerating the Heart

Regenerating the Heart
Author: Ira S. Cohen,Glenn R. Gaudette
Publsiher: Springer Science & Business Media
Total Pages: 558
Release: 2011-03-23
ISBN 10: 1617790214
ISBN 13: 9781617790218
Language: EN, FR, DE, ES & NL

Regenerating the Heart Book Review:

Medical research made huge strides in treating heart disease in the 20th century, from drug-eluding stents to automatic internal defibrillators. Public awareness of the dangers of heart disease has never been more pervasive. Now, though, ten years into a new millennium, scientists are gearing up for the next great challenges in tackling this pervasive condition. Cell therapy is going to be a key weapon in the fight against heart disease. It has the potential to address many cardiovascular conditions. From heart failure to atrioventricular nodal dysfunction, the young but promising field of cell therapy is set to play a significant role in developing the cures that the upcoming decades of hard work will yield. Regenerating the Heart: Stem Cells and the Cardiovascular System organizes the field into a digestible body of knowledge. Its four sections cover mechanical regeneration, electrical regeneration, cardiac tissues and in vivo stem cell therapies. An array of talented researchers share the fruits of their labors, with chapters covering such crucial issues as the cardiogenic potential of varying stem cell types, the ways in which they might be used to tackle arrhythmias, their possible application to biological replacements for cardiac tissues such as valves, and the varying approaches used in the in vivo evaluation of stem cell therapies, including methods of delivering stem cells to the myocardium. This comprehensive survey of an area of research with such exciting potential is an invaluable resource both for veteran stem cell researchers who need to monitor fresh developments, and for newly minted investigators seeking inspirational examples.

It s Complicated

It s Complicated
Author: Jeff Hsu
Publsiher: Unknown
Total Pages: 121
Release: 2013
ISBN 10: 1928374650XXX
ISBN 13: OCLC:1164806430
Language: EN, FR, DE, ES & NL

It s Complicated Book Review:

Coronary artery disease (CAD) and atrial fibrillation (AF) are two common complex diseases of the heart that both have strong genetic components. Although genome wide association studies in humans and genetic mapping studies in mouse models have identified genomic loci associated with these diseases, the functional genetic variants and the mechanisms by which they alter disease susceptibility are largely unknown. In this thesis we use mouse models and human atrial tissues to perform functional genomic studies to gain insight into these disease associated loci, with the central hypothesis that many disease associated variants function by regulating the expression of nearby genes. The major methods used in these studies are transcriptome profiling by expression microarrays and RNA sequencing followed by rigorous statistical analysis. Transcript expression can be considered as an intermediate phenotype to disease susceptibility; and, the identification of genetic variants that alter transcript expression may lead to the mechanism of disease association. In the first study we performed an intercross between AKR and DBA/2 inbred mouse lines to identify and replicate atherosclerosis modifier genes. Quantitative trait loci (QTL) for atherosclerosis on chromosome 2, 15, and 17 were replicated between studies. We quantified whole-genome expression of bone marrow derived macrophages and endothelial cells and found that much of the gene expression was under genetic control, including at the atherosclerosis QTLs, and that this was genetic regulation of gene expression was reproducible between experiments. In the second study we identified genes that are regulated differentially in macrophages from these two mouse strains upon cholesterol loading. We found that the atherosclerosis resistant strain had much higher up regulation of genes in the lysosomal pathway. Combining these two studies, we identified several atherosclerosis candidate modifier genes, such as \textit{Sys1}. In the third study we quantified the differences in gene expression between human left and right atria using RNA sequencing and found many genes differentially expressed at loci associated with AF in genome-wide association studies. In addition we identified a long non-coding RNA adjacent to \textit{PITX2}, at the locus with that has the highest association with AF. In the future these loci can be studied further using reporter assays to identify the causal variant as well as using genomic editing techniques to study the gene regulatory mechanism.

Genome Editing

Genome Editing
Author: Kursad Turksen
Publsiher: Springer
Total Pages: 166
Release: 2016-08-09
ISBN 10: 3319341480
ISBN 13: 9783319341484
Language: EN, FR, DE, ES & NL

Genome Editing Book Review:

This timely volume explores the use of CRISPR-Cas9 for genome editing, presenting cutting-edge techniques and their applications in treatment of disease. The chapters describe latest methods such as use of targetable nucleases, investigation of the non-coding genome, mouse genome editing, increasing of knock-in efficiency in mouse zygotes, and generation of reporter stem cells; the text contextualizes these methods in treatment of cardiovascular disease, diabetes mellitus, retinitis pigmentosa, and others. The final chapters round out the book with a discussion of controversies and future directions. Genome Editing is an essential, of-the-moment contribution to this rapidly growing field. Drawing from a wealth of international perspectives, it presents novel techniques and applications for the engineering of the human genome. This book is essential reading for all clinicians and researchers in stem cells, regenerative medicine, genomics, biochemical and biomedical engineering- especially those interested in learning more about genome editing and applying it in a targeted, specific way.

Genome Editing and Engineering

Genome Editing and Engineering
Author: Krishnarao Appasani
Publsiher: Cambridge University Press
Total Pages: 586
Release: 2018-07-31
ISBN 10: 1107170370
ISBN 13: 9781107170377
Language: EN, FR, DE, ES & NL

Genome Editing and Engineering Book Review:

A complete guide to endonuclease-based genomic engineering, from basic science to application in disease biology and clinical treatment.

Isogenic Human Pluripotent Stem Cell Models of Cardiovascular Disease Associated Genetic Variation

Isogenic Human Pluripotent Stem Cell Models of Cardiovascular Disease Associated Genetic Variation
Author: Derek Tilghman Peters
Publsiher: Unknown
Total Pages: 135
Release: 2016
ISBN 10: 1928374650XXX
ISBN 13: OCLC:995631144
Language: EN, FR, DE, ES & NL

Isogenic Human Pluripotent Stem Cell Models of Cardiovascular Disease Associated Genetic Variation Book Review:

The properties of human pluripotent stem cells (hPSCs) make them uniquely suited to address this challenge - they retain a normal human genome in culture, can be genetically modified, and can be differentiated into multiple cell types. The work presented in this thesis demonstrates the use of hPSCs and genome editing technology to generate human disease models in vitro. We developed a genome editing system optimized for hPSCs that can be used to efficiently generate hPSC lines with targeted genetic modifications. Modified and isogenic control hPSCs are then differentiated into a relevant cell type for phenotypic characterization. We applied this approach to investigate the functional effects of human genetic variation underlying plasma lipid concentrations.

Genome Plasticity in Health and Disease

Genome Plasticity in Health and Disease
Author: Anonim
Publsiher: Academic Press
Total Pages: 288
Release: 2020-04-08
ISBN 10: 0128178205
ISBN 13: 9780128178201
Language: EN, FR, DE, ES & NL

Genome Plasticity in Health and Disease Book Review:

Genome Plasticity in Health and Disease provides a fully up-to-date overview on genome plasticity and its role in human physiology and disease. Following an introduction to the field, a diverse range of chapters cover genomic and epigenomic analysis and the use of model organisms and genomic databases in studies. Specific molecular and biochemical mechanisms of genome plasticity are examined, including somatic variants, De Novo variants, founder variations, isolated populations dynamics, copy-number variations, mobile elements, DNA methylation, histone modifications, transcription factors, non-coding RNAs, telomere dynamics and RNA editing. Later chapters explore disease relevance for cancer, as well as cardiovascular, neuropsychiatric, inflammatory, and endocrine disease, and associated pathways for drug discovery. Examines the role of genome plasticity across a range of disease types, from cardiovascular disease, to cancer and neuropsychiatric disorders Adopts an interdisciplinary approach, with expert contributions across the spectrum of basic science and disease relevance to drug discovery

Cardiovascular Development and Congenital Malformations

Cardiovascular Development and Congenital Malformations
Author: Michael Artman,D. Woodrow Benson,Deepak Srivastava,Makoto Nakazawa
Publsiher: John Wiley & Sons
Total Pages: 320
Release: 2008-04-15
ISBN 10: 1405143916
ISBN 13: 9781405143912
Language: EN, FR, DE, ES & NL

Cardiovascular Development and Congenital Malformations Book Review:

Congenital cardiovascular malformations are the single most common form of birth defect. Therefore a better understanding of the mechanisms involved in both normal cardiac development and the formation of cardiovascular structural defects is of tremendous importance. This book brings together the leading scientists from around the world who are actively engaged in studies of the etiology, morphogenesis and physiology of congenital cardiovascular diseases. A broad variety of approaches, techniques, experimental models and studies of human genetics combine to make this a truly outstanding and unique treatise on this pressing topic. Cardiovascular Development and Congenital Malformations is divided into distinct categories, each focusing on a particular aspect of cardiovascular development. Sections are accompanied by editorial overviews which integrate new findings and place the information into a broader context.

Reprogramming the Genome CRISPR Cas based Human Disease Therapy

Reprogramming the Genome  CRISPR Cas based Human Disease Therapy
Author: Anonim
Publsiher: Academic Press
Total Pages: 390
Release: 2021-06-12
ISBN 10: 0323853242
ISBN 13: 9780323853248
Language: EN, FR, DE, ES & NL

Reprogramming the Genome CRISPR Cas based Human Disease Therapy Book Review:

Reprogramming the Genome: CRISPR-Cas-based Human Disease Therapy, presents the collation of chapters written by eminent scientists worldwide. CRISPR-Cas9 is a key technology for targeted genome editing and regulation in a number of organisms including mammalian cells. It is a rapid, simple, and cost-effective solution. CRISPR-Cas system has recently gained much scientific and public attention. This volume covers CRISPR-Cas9 based mammalian genome editing, creating disease models, cancer therapy, neurological, heredity, blood disorders, defective gene correction, stem cells therapy, epigenetic modifications, patents, ethics, biosafety and regulatory issues challenges and opportunities. This book is a key source of information on mammalian genome editing available in a single volume. This book will be useful for beginners in mammalian genome editing and also students, researchers, scientists, policymakers, clinicians and stakeholders interested in genome editing in several areas. Offers basic understanding and a clear picture of mammalian genome editing through CRISPR-Cas systems Discusses how to create mammalian disease models, stem cell modification, epigenetic modifications, correction of defective gene in blood disorders, heredity, neurological disorders and many more Discusses the application of CRISPR-Cas9 systems in basic sciences, biomedicine, molecular biology, translational sciences, neurobiology, neurology, cancer, stem cells, and many more

Heart Development and Regeneration

Heart Development and Regeneration
Author: Nadia Rosenthal,Richard P. Harvey
Publsiher: Academic Press
Total Pages: 1136
Release: 2010-05-28
ISBN 10: 0123813336
ISBN 13: 9780123813336
Language: EN, FR, DE, ES & NL

Heart Development and Regeneration Book Review:

The development of the cardiovascular system is a rapidly advancing area in biomedical research, now coupled with the burgeoning field of cardiac regenerative medicine. A lucid understanding of these fields is paramount to reducing human cardiovascular diseases of both fetal and adult origin. Significant progress can now be made through a comprehensive investigation of embryonic development and its genetic control circuitry. Heart Development and Regeneration, written by experts in the field, provides essential information on topics ranging from the evolution and lineage origins of the developing cardiovascular system to cardiac regenerative medicine. A reference for clinicians, medical researchers, students, and teachers, this publication offers broad coverage of the most recent advances. Volume One discusses heart evolution, contributing cell lineages; model systems; cardiac growth; morphology and asymmetry; heart patterning; epicardial, vascular, and lymphatic development; and congenital heart diseases. Volume Two includes chapters on transcription factors and transcriptional control circuits in cardiac development and disease; epigenetic modifiers including microRNAs, genome-wide mutagenesis, imaging, and proteomics approaches; and the theory and practice of stem cells and cardiac regeneration. Authored by world experts in heart development and disease New research on epigenetic modifiers in cardiac development Comprehensive coverage of stem cells and prospects for cardiac regeneration Up-to-date research on transcriptional and proteomic circuits in cardiac disease Full-color, detailed illustrations

Patient Specific Induced Pluripotent Stem Cell Models

Patient Specific Induced Pluripotent Stem Cell Models
Author: Andras Nagy,Kursad Turksen
Publsiher: Humana Press
Total Pages: 368
Release: 2015-11-08
ISBN 10: 9781493930333
ISBN 13: 1493930338
Language: EN, FR, DE, ES & NL

Patient Specific Induced Pluripotent Stem Cell Models Book Review:

This volume captures the rapid developments in the field of induced pluripotent stem (iPS) cells, which have provided novel opportunities and approaches both for better understanding a number of human diseases and for developing new platforms for drug development and screening for such diseases. Specifically, representative protocols on various disease models have been collected from labs around the world. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Patient-Specific Induced Pluripotent Stem Cell Models: Generation and Characterization is an ideal reference for scientists working on furthering iPS research.

Clinical and Molecular Aspects of Cardiomyopathies On the road from gene to therapy An Issue of Heart Failure Clinics E Book

Clinical and Molecular Aspects of Cardiomyopathies  On the road from gene to therapy  An Issue of Heart Failure Clinics  E Book
Author: Giuseppe Limongelli
Publsiher: Elsevier Health Sciences
Total Pages: 135
Release: 2018-04-02
ISBN 10: 0323610471
ISBN 13: 9780323610476
Language: EN, FR, DE, ES & NL

Clinical and Molecular Aspects of Cardiomyopathies On the road from gene to therapy An Issue of Heart Failure Clinics E Book Book Review:

This issue of Heart Failure Clinics--edited by Drs. Giuseppe Limongelli, Sharlene Day, and Perry Elliott--will cover Clinical and Molecular Aspects of Cardiomyopathies: On the Road from Gene to Therapy. Topics include, but are not limited to, Epidemiology and Clinical aspects of Genetic Cardiomyopathies, Existing and New therapies, Gene editing and gene-based therapeutics, Controversies surrounding exercise in genetic cardiomyopathies, Genetic infiltrative cardiomyopathies, LV Noncompaction, Clinical presentation and natural history of hypertrophic cardiomyopathy in Rasopathies, and Moelcular basis and new treatments of cardiac diseases in Rasopathies.

Genetics of Hypertension

Genetics of Hypertension
Author: Xi Cheng,Bina Joe
Publsiher: Biota Publishing
Total Pages: 56
Release: 2015-08-01
ISBN 10: 161504695X
ISBN 13: 9781615046959
Language: EN, FR, DE, ES & NL

Genetics of Hypertension Book Review:

Hypertension, or elevated blood pressure, is a major risk factor for various cardiovascular, renal diseases, and stroke. The form of hypertension with no identifiable cause is referred to as Essential Hypertension. Familial studies indicate that Essential Hypertension is heritable and, thereby, classical genetic approaches have been applied on both human and other mammalian models of hypertension to map the locations of the allelic variants within quantitative trait loci for blood pressure. The post genome era has further elevated this area of research into large-scale genome-wide association studies of hypertension in humans. Collectively, these studies have resulted in the prioritization and cataloging of several genomic regions containing allelic variants as candidates linked or associated with essential hypertension. Further, they are providing evidence to suggest that the inheritance of hypertension is rather complex, encompassing multiple variants both within protein-coding and non-coding annotations, each of which may act independently or interactively with other genes and/or environmental factors to differentially regulate blood pressure. This book provides an overview of the various methods employed to study the genetics of hypertension and discuss the progress and prospects of this area of research that may contribute towards individualized clinical management of hypertension in the future.

The Biology of Heart Disease

The Biology of Heart Disease
Author: Margaret Buckingham,Kenneth R. Chien,Christine L. Mummery
Publsiher: Unknown
Total Pages: 232
Release: 2014-11-25
ISBN 10: 9781936113866
ISBN 13: 1936113864
Language: EN, FR, DE, ES & NL

The Biology of Heart Disease Book Review:

"A subject collection from Cold Spring Harbor perspectives in medicine."

In Vivo and Ex Vivo Gene Therapy for Inherited and Non Inherited Disorders

In Vivo and Ex Vivo Gene Therapy for Inherited and Non Inherited Disorders
Author: Houria Bachtarzi
Publsiher: BoD – Books on Demand
Total Pages: 198
Release: 2019-03-13
ISBN 10: 1789857171
ISBN 13: 9781789857177
Language: EN, FR, DE, ES & NL

In Vivo and Ex Vivo Gene Therapy for Inherited and Non Inherited Disorders Book Review:

Ongoing advances in pharmaceutical biotechnology have paved the way to ground-breaking new biological therapeutic modalities, offering the possibility of a durable curative approach for a number of life-threatening diseases, for which the medical need is as yet unmet. Over the past decades, gene therapy has seen a massive transformation from a proof-of-concept approach to a clinical reality culminating in the regulatory approval of state-of-the-art products in the European Union and in the United States. This book captures some of the scientific progresses notably in gene transfer technologies and translational development of in vivo and ex vivo gene therapy interventions in the treatment of a broad range of complex and debilitating non-inherited and inherited disorders such as: human immunodeficiency virus 1 (HIV-1) infection, cancer, cystic fibrosis, hereditary retinopathies, haemophilia B, cardiac diseases, and chronic liver fibrosis.