![regards it as an objection and as a cause of doubt concerning his
real ego.
919.
I should like man to begin by respecting himself: everything else
follows of itself. Naturally a man ceases from being anything to
others in this way: for this is precisely what they are least likely to
forgive. What? a man who respects himself?[4] This is something
quite different from the blind instinct to love one's self. Nothing is
more common in the love of the sexes or in that duality which is
called ego, than a certain contempt for that which is loved the
fatalism of love.
[4] Cf. Disraeli in Tancred: Self-respect, too, is a superstition of
past ages.... It is not suited to these times; it is much too
arrogant, too self-conceited, too egoistical. No one is important
enough to have self-respect nowadays (book iii. chap. v.).—Tr.
920.
I will have this or that; I would that this or that were so; I know
that this or that is so the degrees of power: the man of will, the man
of desire, the man of fate.
921.
The means by which a strong species maintains itself:—
It grants itself the right of exceptional actions, as a test of the power
of self-control and of freedom.
It abandons itself to states in which a man is not allowed to be
anything else than a barbarian.
It tries to acquire strength of will by every kind of asceticism.
It is not expansive, it practises silence; it is cautious in regard to all
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Kidney Research Experimental Protocols 3rd Edition Edition Tim D. Hewitson
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- 5. Kidney Research Experimental Protocols 3rd Edition Edition Tim D. Hewitson Digital Instant Download Author(s): TimD. Hewitson, Nigel D. Toussaint, Edward R. Smith (Editors) ISBN(s): 9781071631782, 1071631780 Edition: 3rd Edition File Details: PDF, 18.72 MB Year: 2023 Language: english
- 6. Kidney Research Tim D. Hewitson Nigel D.Toussaint Edward R. Smith Editors Experimental Protocols ThirdEdition Methods in Molecular Biology 2664
- 7. M E T H O D S I N M O L E C U L A R B I O L O G Y Series Editor John M. Walker School of Life and Medical Sciences University of Hertfordshire Hatfield, Hertfordshire, UK For further volumes: http://www.springer.com/series/7651
- 8. For over 35 years, biological scientists have come to rely on the research protocols and methodologies in the critically acclaimed Methods in Molecular Biology series. The series was the first to introduce the step-by-step protocols approach that has become the standard in all biomedical protocol publishing. Each protocol is provided in readily-reproducible step-by- step fashion, opening with an introductory overview, a list of the materials and reagents needed to complete the experiment, and followed by a detailed procedure that is supported with a helpful notes section offering tips and tricks of the trade as well as troubleshooting advice. These hallmark features were introduced by series editor Dr. John Walker and constitute the key ingredient in each and every volume of the Methods in Molecular Biology series. Tested and trusted, comprehensive and reliable, all protocols from the series are indexed in PubMed.
- 9. Kidney Research Experimental Protocols Third Edition Edited by Tim D. Hewitson, Nigel D. Toussaint, and Edward R. Smith Department of Nephrology, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia, Department of Medicine (RMH), University of Melbourne, Parkville, Melbourne, VIC, Australia
- 10. Editors Tim D. Hewitson Department of Nephrology The Royal Melbourne Hospital Parkville, Melbourne, VIC, Australia Department of Medicine (RMH) University of Melbourne Parkville, Melbourne, VIC, Australia Nigel D. Toussaint Department of Nephrology The Royal Melbourne Hospital Parkville, Melbourne, VIC, Australia Department of Medicine (RMH) University of Melbourne Parkville, Melbourne, VIC, Australia Edward R. Smith Department of Nephrology The Royal Melbourne Hospital Parkville, Melbourne, VIC, Australia Department of Medicine (RMH) University of Melbourne Parkville, Melbourne, VIC, Australia ISSN 1064-3745 ISSN 1940-6029 (electronic) Methods in Molecular Biology ISBN 978-1-0716-3178-2 ISBN 978-1-0716-3179-9 (eBook) https://doi.org/10.1007/978-1-0716-3179-9 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Humana imprint is published by the registered company Springer Science+Business Media, LLC, part of Springer Nature. The registered company address is: 1 New York Plaza, New York, NY 10004, U.S.A.
- 11. Preface The inherent complexity of kidney structure and function often poses unique problems for research in kidney biology and disease. Through necessity therefore, an organ-specific approach has evolved over time where specialist techniques have been developed and adapted. In this third edition of Kidney Research – Experimental Protocols, we include novel techniques as well as improvements and refinements to established protocols. In doing so, our emphasis has been on protocols that address new and emerging research questions in Nephrology. The first section (Part I) addresses various in vitro, in vivo, and ex vivo models of kidney disease. An initial collection of current in vitro kidney cell culture methods is provided (Chapters 1, 2, 3, and 4). While such 2D cell culture models are valuable tools for examining mechanisms in a controlled environment, being based on a single cell type means that they cannot reproduce complex cellular interactions, homeostasis, and microenvironment. Therefore, in companion chapters, authors also provide state-of-the-art protocols for orga- noid generation (Chapters 5 and 6), in vitro microfabrication models (Chapters 7 and 8), and precision cut kidney slices (Chapter 9) to replicate essential components of in vivo kidney physiology in vitro. These protocols emphasize the utility of such approaches in toxicity screening and drug development. Also included is a cell culture model of tubule cyst formation (Chapter 10). Finally, the similarity of the zebrafish genome to that of the human, and its ease of manipulation, makes the zebrafish a useful single nephron model of glomer- ular disease (Chapter 11). In Part II, a variety of new imaging protocols are provided for direct observation of kidney tissue in studies of kidney disease. These include a technique based on magnetic resonance imaging for the measurement of sodium stores in tissue (Chapter 12), a newly recognized and poorly understood phenomena where imaging is particularly useful for assessing the excess sodium accumulation that occurs in people with chronic kidney disease (CKD). Also presented is a new microscopy technique for examining tissue collagen using second harmonic generation (Chapter 13), which is both quantitative and able to provide a high-resolution view of collagen fiber organization previously only available with electron microscopy. Likewise, a high-resolution adaptation of confocal microscopy is provided (Chapter 14), while the use of a ferritin tracer for imaging glomeruli (Chapter 15) completes Part II. The final section, Part III, consists of recent advances in analytical and functional assays. Protocols for in situ hybridization and spatial transcriptome sequencing are provided in Chapters 16 and 17, respectively. Both approaches offer important morphological context to gene expression within intact tissue. Much current interest relates to the role of mito- chondrial function in disease. To address this, Orozco-Ibarra et al. outline imaging and functional protocols for examining and measuring mitochondria activity (Chapter 18). In this section, Mullins et al. also detail a solution to the vexed problem of measuring glomerular filtration rate in mouse experiments (Chapter 19). Mineralization disorders in v
- 12. CKD are common and measurement of calcific calciprotein particles (C RhoGTPase activity (C biology. poorly understood. Therefore, two chapters provide tools for ation propensity (Chapter 20) and the formation of circulating hapter 21). The final chapter describes a protocol for measuring hapter 22), an important element of signal transduction in kidney vi Preface We are indebted to the generosity of the authors in sharing their protocols and insights. Nephrology is a specialty where discovery science has delivered a great deal. We hope that the protocols will help provide the necessary tools for that to continue. Parkville, Melbourne, VIC, Australia Tim D. Hewitson Parkville, Melbourne, VIC, Australia Nigel D. Toussaint Parkville, Melbourne, VIC, Australia Edward R. Smith
- 13. Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi PART I IN VITRO, IN VIVO, AND EX VIVO MODELS OF KIDNEY DISEASE 1 Restoration of Podocyte Phenotype in Culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Eishin Yaoita 2 Propagation, Culture, and Characterization of Renal Fibroblasts. . . . . . . . . . . . . . 13 Tim D. Hewitson and Edward R. Smith 3 Isolation of Rat Glomeruli and Propagation of Mesangial Cells to Study the Kidney in Health and Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Tim D. Hewitson and Edward R. Smith 4 In Vitro Models to Evaluate Molecular Permeability of the Kidney Filtration Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Dan Wang and Nicholas Ferrell 5 Generating Human Glomeruli from Pluripotent Stem Cells for Disease Modelling and Drug Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Lorna J. Hale and Melissa H. Little 6 Large-Scale Production of Kidney Organoids from Human Pluripotent Stem Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Veronika Sander, Aneta Przepiorski, Neil A. Hukriede, and Alan J. Davidson 7 Construction of a Multitubular Perfusable Kidney-on-Chip for the Study of Renal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Brice Lapin, Sarah Myram, Manh-Louis Nguyen, Giacomo Gropplero, Sylvie Coscoy, and Stéphanie Descroix 8 A “Kidney-on-the-Chip” Model Composed of Primary Human Tubular, Endothelial, and White Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Julian A. Marschner, Lucas Martin, Gregor Wilken, Maria Elena Melica, and Hans-Joachim Anders 9 Standardized Protocol for the Preparation of Precision-Cut Kidney Slices: A Translational Model of Renal Fibrosis . . . . . . . . . . . . . . . . . . . . . . 123 Michael Schou Jensen, Camilla Merrild, Rikke Nørregaard, Peter Olinga, and Henricus A. M. Mutsaers 10 Culture of Three-Dimensional Madin–Darby Canine Kidney (MDCK) Cysts for In Vitro Drug Testing in Polycystic Kidney Disease. . . . . . . . . . . . . . . . . 135 Sayanthooran Saravanabavan and Gopala K. Rangan 11 Zebrafish Model to Study Podocyte Function Within the Glomerular Filtration Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Nina Sopel and Janina Müller-Deile vii
- 14. viii Contents PART II IMAGING IN KIDNEY RESEARCH 12 Magnetic Resonance Imaging (MRI) Analysis of Tissue Sodium Concentration in Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Kylie Martin, Vijay Venkatraman, Angela Agostinelli, Braden Thai, Daniel St€ ab, Tim D. Hewitson, Sven-Jean Tan, Nigel D. Toussaint, and Patsy Robertson 13 Determination of Interstitial Collagen Deposition and Related Topography Using the Second Harmonic Generation-Based HistoIndex Platform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Sadman Bhuiyan, Robert E. Widdop, and Chrishan S. Samuel 14 Quantitative Imaging of Podocyte Foot Processes in the Kidney Using Confocal and STED Microscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 David Unnersjö-Jess 15 Synthesis and Expression of a Targeted, Ferritin-Based Tracer for PET Imaging of Kidney Glomeruli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Edwin J. Baldelomar, Kasey C. Emoto, Maria Veronica Clavijo Jordan, Jennifer R. Charlton, David E. Reichert, Neda Parvin, Courtnie Yokono, Bradley D. Hann, and Kevin M. Bennett PART III ANALYTICAL AND FUNCTIONAL MEASUREMENTS IN THE KIDNEY 16 Multiplex In Situ Hybridization in the Study of Acute Kidney Injury. . . . . . . . . . 217 Agnieszka Masztalerz, Alex Gregorieff, Serge Lemay, and Tomoko Takano 17 Spatial Transcriptomics in Kidney Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Arti M. Raghubar, Joanna Crawford, Kahli Jones, Pui Y. Lam, Stacey B. Andersen, Nicholas A. Matigian, Monica S. Y. Ng, Helen Healy, Andrew J. Kassianos, and Andrew J. Mallett 18 Assessment of Kidney Mitochondrial Function by High-Resolution Respirometry, Transmission Electron Microscopy, and Histological Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Marisol Orozco-Ibarra, Omar Emiliano Aparicio-Trejo, Alexis Paulina Jiménez-Uribe, Estefani Yaquelin Hernández-Cruz, Ana Karina Aranda-Rivera, Isabel Amador-Martı́nez, Francisca Fernández-Valverde, and José Pedraza-Chaverri 19 Transdermal Measurement of Glomerular Filtration Rate in Preclinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Thomas P. Mullins, Daniel Schock-Kusch, and Linda A. Gallo 20 The BioHybrid Assay: A Novel Method for Determining Calcification Propensity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 Armand M. G. Jaminon, Asim C. Akbulut, Nikolas Rapp, Chris P. Reutelingsperger, and Leon J. Schurgers
- 15. Contents ix 21 Quantification of Calciprotein Particles (CPPs) in Serum/Plasma Samples Using a Fluorescent Bisphosphonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333 Yutaka Miura, Hiroshi Kurosu, and Makoto Kuro-o 22 Monitoring of Rho GTPase Activity in Podocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . 343 Jun Matsuda and Tomoko Takano Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
- 16. Contributors ANGELA AGOSTINELLI • Department of Radiology, The Royal Melbourne Hospital and The University of Melbourne, Parkville, Melbourne, VIC, Australia ASIM C. AKBULUT • Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands ISABEL AMADOR-MARTÍNEZ • Facultad de Quı́mica, Departamento de Biologı́a, Universidad Nacional Aut onoma de México (UNAM), Mexico City, Mexico; Posgrado en Ciencias Biol ogicas, Universidad Nacional Aut onoma de México (UNAM), Ciudad Universitaria, Mexico City, Mexico HANS-JOACHIM ANDERS • Renal Division, Department of Medicine IV, Hospital of the Ludwig Maximilians University, Munich, Germany STACEY B. ANDERSEN • Genome Innovation Hub, University of Queensland, Brisbane, QLD, Australia; UQ Sequencing Facility, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia OMAR EMILIANO APARICIO-TREJO • Departamento de Fisiopatologı́a Cardio-Renal, Instituto Nacional de Cardiologı́a Ignacio Chávez, Mexico City, Mexico ANA KARINA ARANDA-RIVERA • Facultad de Quı́mica, Departamento de Biologı́a, Universidad Nacional Aut onoma de México (UNAM), Mexico City, Mexico; Posgrado en Ciencias Biol ogicas, Universidad Nacional Aut onoma de México (UNAM), Ciudad Universitaria, Mexico City, Mexico EDWIN J. BALDELOMAR • Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, USA KEVIN M. BENNETT • Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, USA SADMAN BHUIYAN • Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Melbourne, VIC, Australia JENNIFER R. CHARLTON • Department of Pediatrics, Division of Nephrology, University of Virginia, Charlottesville, VA, USA SYLVIE COSCOY • Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, Paris, France JOANNA CRAWFORD • Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia ALAN J. DAVIDSON • Department of Molecular Medicine Pathology, University of Auckland, Auckland, New Zealand STÉPHANIE DESCROIX • Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, Paris, France KASEY C. EMOTO • Department of Biology, University of Hawaii at Manoa, Honolulu, HI, USA FRANCISCA FERNÁNDEZ-VALVERDE • Laboratorio de Patologı́a Experimental, Instituto Nacional de Neurologı́a y Neurocirugı́a Manuel Velasco Suárez, Mexico City, Mexico NICHOLAS FERRELL • Department of Internal Medicine, Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, USA xi
- 17. xii Contributors LINDA A. GALLO • School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, Australia ALEX GREGORIEFF • Research Institute, McGill University Health Centre, Montreal, QC, Canada; Department of Pathology, McGill University Health Centre, Montreal, QC, Canada GIACOMO GROPPLERO • Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, Paris, France LORNA J. HALE • Murdoch Children’s Research Institute, Parkville, VIC, Australia; UCB Pharma Ltd, Slough, UK BRADLEY D. HANN • Department of Biology, University of Hawaii at Manoa, Honolulu, HI, USA HELEN HEALY • Kidney Health Service, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia; Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia ESTEFANI YAQUELIN HERNÁNDEZ-CRUZ • Facultad de Quı́mica, Departamento de Biologı́a, Universidad Nacional Aut onoma de México (UNAM), Mexico City, Mexico; Posgrado en Ciencias Biol ogicas, Universidad Nacional Aut onoma de México (UNAM), Ciudad Universitaria, Mexico City, Mexico TIM D. HEWITSON • Department of Nephrology, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia NEIL A. HUKRIEDE • Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA ARMAND M. G. JAMINON • Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands MICHAEL SCHOU JENSEN • Department of Clinical Medicine, Aarhus University, Aarhus, Denmark ALEXIS PAULINA JIMÉNEZ-URIBE • Facultad de Quı́mica, Departamento de Biologı́a, Universidad Nacional Aut onoma de México (UNAM), Mexico City, Mexico KAHLI JONES • Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia MARIA VERONICA CLAVIJO JORDAN • Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA ANDREW J. KASSIANOS • Kidney Health Service, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia; Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia MAKOTO KURO-O • Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan HIROSHI KUROSU • Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan PUI Y. LAM • Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
- 18. Contributors xiii BRICE LAPIN • Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, Paris, France SERGE LEMAY • Research Institute, McGill University Health Centre, Montreal, QC, Canada; Department of Medicine, Division of Nephrology, McGill University Health Centre, Montreal, QC, Canada MELISSA H. LITTLE • Murdoch Children’s Research Institute, Parkville, VIC, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia ANDREW J. MALLETT • Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; College of Medicine Dentistry, James Cook University, Townsville, QLD, Australia; Department of Renal Medicine, Townsville University Hospital, Townsville, QLD, Australia JULIAN A. MARSCHNER • Renal Division, Department of Medicine IV, Hospital of the Ludwig Maximilians University, Munich, Germany; Department of Pharmacy, Ludwig Maximilians University, Munich, Germany KYLIE MARTIN • Department of Nephrology, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Department of Medicine (RMH), University of Melbourne, Melbourne, VIC, Australia LUCAS MARTIN • Renal Division, Department of Medicine IV, Hospital of the Ludwig Maximilians University, Munich, Germany AGNIESZKA MASZTALERZ • Research Institute, McGill University Health Centre, Montreal, QC, Canada NICHOLAS A. MATIGIAN • QCIF Facility for Advanced Bioinformatics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia JUN MATSUDA • Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan MARIA ELENA MELICA • Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy CAMILLA MERRILD • Department of Clinical Medicine, Aarhus University, Aarhus, Denmark YUTAKA MIURA • Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan JANINA MÜLLER-DEILE • Friedrich-Alexander Universi€ at Erlangen-Nuremberg, Erlangen, Germany THOMAS P. MULLINS • School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, Australia HENRICUS A. M. MUTSAERS • Department of Clinical Medicine, Aarhus University, Aarhus, Denmark SARAH MYRAM • Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, Paris, France MONICA S. Y. NG • Kidney Health Service, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; Nephrology Department, Princess Alexandra Hospital, Woolloongabba, QLD, Australia MANH-LOUIS NGUYEN • Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, Paris, France
- 19. xiv Contributors RIKKE NØRREGAARD • Department of Clinical Medicine, Aarhus University, Aarhus, Denmark PETER OLINGA • Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands MARISOL OROZCO-IBARRA • Departamento de Bioquı́mica, Instituto Nacional de Cardiologı́a Ignacio Chávez, Mexico City, Mexico NEDA PARVIN • Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, USA JOSÉ PEDRAZA-CHAVERRI • Facultad de Quı́mica, Departamento de Biologı́a, Universidad Nacional Aut onoma de México (UNAM), Mexico City, Mexico ANETA PRZEPIORSKI • Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA ARTI M. RAGHUBAR • Kidney Health Service, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia; Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; Anatomical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia GOPALA K. RANGAN • Michael Stern Laboratory for Polycystic Kidney Disease, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia; Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Westmead, NSW, Australia; Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia NIKOLAS RAPP • Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands DAVID E. REICHERT • Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, USA CHRIS P. REUTELINGSPERGER • Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands PATSY ROBERTSON • Department of Radiology, The Royal Melbourne Hospital and The University of Melbourne, Parkville, Melbourne, VIC, Australia CHRISHAN S. SAMUEL • Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Melbourne, VIC, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC, Australia VERONIKA SANDER • Department of Molecular Medicine Pathology, University of Auckland, Auckland, New Zealand SAYANTHOORAN SARAVANABAVAN • Michael Stern Laboratory for Polycystic Kidney Disease, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia; Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Westmead, NSW, Australia DANIEL SCHOCK-KUSCH • Institute of Process Control and Innovative Energy Conversion, Mannheim University of Applied Sciences, Mannheim, Germany LEON J. SCHURGERS • Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands
- 20. Contributors xv EDWARD R. SMITH • Department of Nephrology, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia NINA SOPEL • Department of Medicine 4 – Nephrology and Hypertension, Universit€ atsklinikum Erlangen, Erlangen, Germany; Friedrich-Alexander Universi€ at Erlangen-Nuremberg, Erlangen, Germany DANIEL ST€ AB • MR Research Collaborations, Siemens Healthcare Pty Limited, Melbourne, VIC, Australia TOMOKO TAKANO • Research Institute, McGill University Health Centre, Montreal, QC, Canada; Department of Medicine, Division of Nephrology, McGill University Health Centre, Montreal, QC, Canada SVEN-JEAN TAN • Department of Nephrology, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Department of Medicine (RMH), University of Melbourne, Melbourne, VIC, Australia BRADEN THAI • Department of Radiology, The Royal Melbourne Hospital and The University of Melbourne, Parkville, Melbourne, VIC, Australia NIGEL D. TOUSSAINT • Department of Nephrology, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Department of Medicine (RMH), University of Melbourne, Parkville, Melbourne, VIC, Australia DAVID UNNERSJÖ-JESS • Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; MedTechLabs, Karolinska University Hospital, Solna, Sweden VIJAY VENKATRAMAN • Department of Radiology, The Royal Melbourne Hospital and The University of Melbourne, Parkville, Melbourne, VIC, Australia DAN WANG • Department of Internal Medicine, Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, USA ROBERT E. WIDDOP • Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Melbourne, VIC, Australia GREGOR WILKEN • Renal Division, Department of Medicine IV, Hospital of the Ludwig Maximilians University, Munich, Germany EISHIN YAOITA • Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan COURTNIE YOKONO • Department of Biology, University of Hawaii at Manoa, Honolulu, HI, USA
- 21. Exploring the Variety of Random Documents with Different Content
- 22. The things which have become spoilt through having been abused by the Church:— (1) Asceticism.—People have scarcely got the courage yet to bring to light the natural utility and necessity of asceticism for the purpose of the education of the will. Our ridiculous world of education, before whose eyes the useful State official hovers as an ideal to be striven for, believes that it has completed its duty when it has instructed or trained the brain; it never even suspects that something else is first of all necessary —the education of will-power; tests are devised for everything except for the most important thing of all: whether a man can will, whether he can promise; the young man completes his education without a question or an inquiry having been made concerning the problem of the highest value of his nature. (2) Fasting:—In every sense—even as a means of maintaining the capacity for taking pleasure in all good things (for instance, to give up reading for a while, to hear no music for a while, to cease from being amiable for a while: one ought also to have fast days for one's virtues). (3) The monastery.—Temporary isolation with severe seclusion from all letters, for instance; a kind of profound introspection and self- recovery, which does not go out of the way of temptations, but out of the way of duties; a stepping out of the daily round of one's environment; a detachment from the tyranny of stimuli and external influences, which condemns us to expend our power only in reactions, and does not allow it to gather volume until it bursts into spontaneous activity (let anybody examine our scholars closely: they only think reflexively, i.e. they must first read before they can think). (4) Feasts.—A man must be very coarse in order not to feel the presence of Christians and Christian values as oppressive, so oppressive as to send all festive moods to the devil. By feasts we understand: pride, high-spirits, exuberance; scorn of all kinds of seriousness and Philistinism; a divine saying of Yea to one's self, as the result of physical plenitude and perfection—all states to which
- 23. the Christian cannot honestly say Yea. A feast is a pagan thing par excellence. (5) The courage of ones own nature: dressing-up in morality,—To be able to call one's passions good without the help of a moral formula: this is the standard which measures the extent to which a man is able to say Yea to his own nature, namely, how much or how little he has to have recourse to morality. (6) Death.—The foolish physiological fact must be converted into a moral necessity. One should live in such a way that one may have the will to die at the right time! 917. To feel ones self stronger or, expressed otherwise: happiness always presupposes a comparison (not necessarily with others, but with one's self, in the midst of a state of growth, and without being conscious that one is comparing). Artificial accentuation: whether by means of exciting chemicals or exciting errors (hallucinations.) Take, for instance, the Christian's feeling of security; he feels himself strong in his confidence, in his patience, and his resignation: this artificial accentuation he owes to the fancy that he is protected by a God. Take the feeling of superiority, for instance: as when the Caliph of Morocco sees only globes on which his three united kingdoms cover four-fifths of the space. Take the feeling of uniqueness, for instance: as when the European imagines that culture belongs to Europe alone, and when he regards himself as a sort of abridged cosmic process; or, as when the Christian makes all existence revolve round the Salvation of man. The question is, where does one begin to feel the pressure of constraint: it is thus that different degrees are ascertained. A philosopher for instance, in the midst of the coolest and most transmontane feats of abstraction feels like a fish that enters its
- 24. element: while colours and tones oppress him; not to speak of those dumb desires—of that which others call the ideal. 918. A healthy and vigorous little boy will look up sarcastically if he be asked: Wilt thou become virtuous?—but he immediately becomes eager if he be asked: Wilt thou become stronger than thy comrades? *** How does one become stronger?—By deciding slowly; and by holding firmly to the decision once it is made. Everything else follows of itself. Spontaneous and changeable natures: both species of the weak. We must not confound ourselves with them; we must feel distance—betimes! Beware of good-natured people!. Dealings with them make one torpid. All environment is good which makes one exercise those defensive and; aggressive powers which are instinctive in man. All one's inventiveness should apply itself to putting one's power of will to the test.... Here the determining factor must be recognised as something which is not knowledge, astuteness, or wit. One must learn to command betimes,—likewise to obey. A man must learn modesty and tact in modesty: he must learn to distinguish and to honour where modesty is displayed; he must likewise distinguish and honour wherever he bestows his confidence. What does one repent most? One's modesty; the fact that one has not lent an ear to one's most individual needs; the fact that one has mistaken one's self; the fact that one has esteemed one's self low; the fact that one has lost all delicacy of hearing in regard to one's instincts.—This want of reverence in regard to one's self is avenged by all sorts of losses: in health, friendship, well-being, pride, cheerfulness, freedom, determination, courage. A man never forgives himself, later on, for this want of genuine egoism: he
- 25. regards it as an objection and as a cause of doubt concerning his real ego. 919. I should like man to begin by respecting himself: everything else follows of itself. Naturally a man ceases from being anything to others in this way: for this is precisely what they are least likely to forgive. What? a man who respects himself?[4] This is something quite different from the blind instinct to love one's self. Nothing is more common in the love of the sexes or in that duality which is called ego, than a certain contempt for that which is loved the fatalism of love. [4] Cf. Disraeli in Tancred: Self-respect, too, is a superstition of past ages.... It is not suited to these times; it is much too arrogant, too self-conceited, too egoistical. No one is important enough to have self-respect nowadays (book iii. chap. v.).—Tr. 920. I will have this or that; I would that this or that were so; I know that this or that is so the degrees of power: the man of will, the man of desire, the man of fate. 921. The means by which a strong species maintains itself:— It grants itself the right of exceptional actions, as a test of the power of self-control and of freedom. It abandons itself to states in which a man is not allowed to be anything else than a barbarian. It tries to acquire strength of will by every kind of asceticism. It is not expansive, it practises silence; it is cautious in regard to all charms.
- 26. It learns to obey in such a way that obedience provides a test of self-maintenance. Casuistry is carried to its highest pitch in regard to points of honour. It never argues, What is sauce for the goose is sauce for the gander,—but conversely! it regards reward, and the ability to repay, as a privilege, as a distinction. It does not covet other people's virtues. 922. The way in which one has to treat raw savages and the impossibility of dispensing with barbarous methods, becomes obvious, in practice, when one is transplanted, with all one's European pampering, to a spot such as the Congo, or anywhere else where it is necessary to maintain one's mastery over barbarians. 923. Warlike and peaceful people.—Art thou a man who has the instincts of a warrior in thy blood? If this be so, another question must be put. Do thy instincts impel thee to attack or to defend? The rest of mankind, all those whose instincts are not warlike, desire peace, concord, freedom, equal rights: these things are but names and steps for one and the same thing. Such men only wish to go where it is not necessary for them to defend themselves,—such men become discontented with themselves when they are obliged to offer resistance: they would fain create circumstances in which war is no longer necessary. If the worst came to the worst, they would resign themselves, obey, and submit: all these things are better than waging war—thus does the Christian's instinct, for instance, whisper to him. In the born warrior's character there is something of armour, likewise in the choice of his circumstances and in the development of every one of his qualities, weapons are best evolved by the latter type, shields are best devised by the former.
- 27. What expedients and what virtues do the unarmed and the undefended require in order to survive—and even to conquer? 924. What will become of a man who no longer has any reasons for either defence or attack? What will remain of his passions when he has lost those which form his defence and his weapons? 925. A marginal note to a niaiserie anglaise: Do not to others that which you would not that they should do unto you. This stands for wisdom; this stands for prudence; this stands as the very basis of morality as a golden maxim. John Stuart Mill believes in it (and what Englishman does not?).... But the maxim does not bear investigation. The argument, Do not as you would not be done by, forbids action which produce harmful results; the thought behind always is that an action is invariably requited. What if some one came forward with the Principe in his hands, and said: We must do those actions alone which enable us to steal a march on others,— and which deprive others of the power of doing the same to us?— On the other hand, let us remember the Corsican who pledges his honour to vendetta. He too does not desire to have a bullet through him; but the prospect of one, the probability of getting one, does not deter him from vindicating his honour.... And in all really decent actions are we not intentionally indifferent as to what result they will bring? To avoid an action which might have harmful results,—that would be tantamount to forbidding all decent actions in general. Apart from this, the above maxim is valuable because it betrays a certain type of man: it is the instinct of the herd which formulates itself through him,—we are equal, we regard each other as equal: as I am to thee so art thou to me.—In this community equivalence of actions is really believed in—an equivalence which never under any circumstances manifests itself in real conditions. It is impossible to
- 28. requite every action: among real individuals equal actions do not exist, consequently there can be no such thing as requital. ... When I do anything, I am very far from thinking that any man is able to do anything at all like it: the action belongs to me.... Nobody can pay me back for anything I do; the most that can be done is to make me the victim of another action. 926. Against John Stuart Mill.—I abhor the man's vulgarity when he says: What is right for one man is right for another; Do not to others that which you would not that they should do unto you. Such principles would fain establish the whole of human traffic upon mutual services, so that every action would appear to be a cash payment for something done to us. The hypothesis here is ignoble to the last degree: it is taken for granted that there is some sort of equivalence in value between my actions and thine; the most personal value Of an action is simply cancelled in this manner (that part of an action which has no equivalent and which cannot be remunerated). Reciprocity is a piece of egregious vulgarity; the mere fact that what I do cannot and may not be done by another, that there is no such thing as equivalence (except in those very select circles where one actually has one's equal, inter pares), that in a really profound sense a man never requites because he is something unique in himself and can only do unique things,—this fundamental conviction contains the cause of aristocratic aloofness from the mob, because the latter believes in equality, and consequently in the feasibility of equivalence and reciprocity. 927. The suburban Philistinism of moral valuations and of its concepts useful and harmful is well founded; it is the necessary point of view of a community which is only able to see and survey immediate and proximate consequences. The State and the political man are
- 29. already in need of a more super-moral attitude of mind: because they have to calculate concerning a much more complicated tissue of consequences. An economic policy for the whole world should be possible which could look at things in such broad perspective that all its isolated demands would seem for the moment not only unjust, but arbitrary. 928. Should one follow one's feelings?—To set one's life at stake on the impulse of the moment, and actuated by a generous feeling, has little worth, and does not even distinguish one. Everybody is alike in being capable of this—and in behaving in this way with determination, the criminal, the bandit, and the Corsican certainly outstrip the honest man. A higher degree of excellence would be to overcome this impulse, and to refrain from performing an heroic deed at its bidding—and to remain cold, raisonnable, free from the tempestuous surging of concomitant sensations of delight.... The same holds good of pity: it must first be sifted through reason; without this it becomes just as dangerous as any other passion. The blind yielding to a passion, whether it be generosity, pity, or hostility, is the cause of the greatest evil. Greatness of character does not consist in not possessing these passions—on the contrary, a man should possess them to a terrible degree: but he should lead them by the bridle.. and even this he should not do out of love of control, but merely because.... 929. To give up one's life for a cause—very effective. But there are many things for which one gives up one's life: the passions, one and all, will be gratified. Whether one's life be pledged to pity, to anger, or to revenge—it matters not from the point of view of value. How
- 30. many have not sacrificed their lives for pretty girls—and even what is worse, their health! When one has temperament, one instinctively chooses the most dangerous things: if one is a philosopher, for instance, one chooses the adventures of speculation; if one is virtuous, one chooses immorality. One kind of man will risk nothing, another kind will risk everything. Are we despisers of life? On the contrary, what we seek is life raised to a higher power, life in danger.... But, let me repeat, we do not, on that account, wish to be more virtuous than others, Pascal, for instance, wished to risk nothing, and remained a Christian. That perhaps was virtuous.——A man always sacrifices something. 930. How many advantages does not a man sacrifice! To how small an extent does he seek his own profit! All his emotions and passions wish to assert their rights, and how remote a passion is From that cautious utility which consists in personal profit! A man does not strive after happiness; one must be an Englishman to be able to believe that a man is always seeking his own advantage. Our desires long to violate things with passion—their overflowing strength seeks obstacles. 931. All passions are generally useful, some directly, others indirectly; in regard to utility it is absolutely impossible to fix upon any gradation of values,—however certainly the forces of nature in general may be regarded as good (i.e. useful), from an economic point of view, they are still the sources of much that is terrible and much that is fatally irrevocable. The most one might say would be, that the mightiest passions are the most valuable: seeing that no stronger sources of power exist.
- 31. 932. All well-meaning, helpful, good-natured attitudes of mind have not come to be honoured on account of their usefulness: but because they are the conditions peculiar to rich souls who are able to bestow and whose value consists in their vital exuberance. Look into the eyes of the benevolent man! In them you will see the exact reverse of self-denial, of hatred of self, of Pascalism. 933. In short, what we require is to dominate the passions and not to weaken or to extirpate them!—The greater the dominating power of the will, the greater the freedom that may be given to the passions. The great man is so, owing to the free scope which he gives to his desires, and to the still greater power which knows how to enlist these magnificent monsters into its service. The good man in every stage of civilisation is at one and the same time the least dangerous and the most useful: a sort of medium; the idea formed of such a man by the common mind is that he is some one whom one has no reason to fear, but whom one must not therefore despise. Education: essentially a means of ruining exceptions in favour of the rule. Culture: essentially the means of directing taste against the exceptions in favour of the mediocre. Only when a culture can dispose of an overflow of force, is it capable of being a hothouse for the luxurious culture of the exception, of the experiment, of the danger, of the nuance: this is the tendency of every aristocratic culture. 934. All questions of strength: to what extent ought one to try and prevail against the preservative measures of society and the latter's
- 32. prejudices?—to what extent ought one to unfetter one's terrible qualities, through which so many go to the dogs?—to what extent ought one to run counter to truth, and take up sides with its most questionable aspects?—to what extent ought one to oppose suffering, self-contempt, pity, disease, vice, when it is always open to question whether one can ever master them (what does not kill us makes us stronger....)?—and, finally, to what extent ought one to acknowledge the rights of the rule, of the common-place, of the petty, of the good, of the upright, in fact of the average man, without thereby allowing one's self to become vulgar? ... The strongest test of character is to resist being ruined by the seductiveness of goodness. Goodness must be regarded as a luxury, as a refinement, as a vice. 3. The Noble Man. 935. Type. real goodness, nobility, greatness of soul, as the result of vital wealth: which does not give in order to receive—and which has no desire to elevate itself by being good, squandering is typical of genuine goodness, vital personal wealth is its prerequisite. 936. Aristocracy.—Gregarious ideals at present culminating in the highest standard of value for society. It has been attempted to give them a cosmic, yea, and even a metaphysical, value.—I defend aristocracy against them. Any society which would of itself preserve a feeling of respect and délicatesse in regard to freedom, must consider itself as an
- 33. exception, and have a force against it from which it distinguishes itself, and upon which it looks down with hostility. The more rights I surrender and the more I level myself down to others, the more deeply do I sink into the average and ultimately into the greatest number. The first condition which an aristocratic society must have in order to maintain a high degree of freedom among its members, is that extreme tension which arises from the presence of the most antagonistic instincts in all its units: from their will to dominate.... If ye would fain do away with strong contrasts and differences of rank, ye will also abolish, strong love, lofty attitudes of mind, and the feeling of individuality. *** Concerning the actual psychology of societies based upon freedom and equality.—What is it that tends to diminish in such a society? The will to be responsible for ones self (the loss of this is a sign of the decline of autonomy); the ability to defend and to attack, even in spiritual matters; the power of command; the sense of reverence, of subservience, the ability to be silent, great passion, great achievements, tragedy and cheerfulness. 937. In 1814 Augustin Thierry read what Montlosier had said in his work, De la Monarchie française: he answered with a cry of indignation, and set himself to his task. That emigrant had said: Race d'affranchis, race d'esclaves arrachés de nos mains, peuple tributaire, peuple nouveau, licence vous fut octroyée d'être libres, et non pas à nous d'être nobles; pour nous tout est de droit, pour vous tout est de grâce, nous ne sommes point de votre communauté; nous sommes un tout par nous mêmes.
- 34. 938. How constantly the aristocratic world shears and weakens itself ever more and more! By means of its noble instincts it abandons its privileges, and owing to its refined and excessive culture, it takes an interest in the people, the weak, the poor, and the poetry of the lowly, etc. 939. There is such a thing as a noble and dangerous form of carelessness, which allows of profound conclusions and insight: the carelessness of the self-reliant and over-rich soul, which has never troubled itself about friends, but which knows only hospitality and knows how to practise it; whose heart and house are open to all who will enter—beggar, cripple, or king. This is genuine sociability: he who is capable of it has hundreds of friends, but probably not one friend. 940. The teaching μηδὲν ἄγαν applies to men with overflowing strength, —not to the mediocre, ἐγκράτεια and ἄσκησις are only steps to higher things. Above them stands golden Nature. Thou shalt—unconditional obedience in Stoics, in Christian and Arabian Orders, in Kant's philosophy (it is immaterial whether this obedience is shown to a superior or to a concept). Higher than Thou shalt stands I will (the heroes); higher than I will stands I am (the gods of the Greeks). Barbarian gods express nothing of the pleasure of restraint,—they are neither simple, nor light-hearted, nor moderate. 941.
- 35. The essence of our gardens and palaces (and to the same extent the essence of all yearning after riches) is the desire to rid the eye of disorder and vulgarity, and to build a home for our soul's nobility. The majority of people certainly believe that they will develop higher natures when those beautiful and peaceful things have operated upon them: hence the exodus to Italy, hence all travelling, etc., and all reading and visits to theatres. People want to be formed—that is the kernel of their labours for culture! But the strong, the mighty, would themselves have a hand in the forming, and would fain have nothing strange about them! It is for this reason, too, that men go to open Nature, not to find themselves, but to lose themselves and to forget themselves. The desire to get away from one's self is proper to all weaklings, and to all those who are discontented with themselves. 942. The only nobility is that of birth and blood. (I do not refer here to the prefix Lord and L'almanac de Gotha: this is a parenthesis for donkeys.) Wherever people speak of the aristocracy of intellect, reasons are generally not lacking for concealing something, it is known to be a password among ambitious Jews. Intellect alone does not ennoble; on the contrary, something is always needed to ennoble intellect.—What then is needed?—Blood. 943. What is noble? —External punctiliousness; because this punctiliousness hedges a man about, keeps him at a distance, saves him from being confounded with somebody else. A frivolous appearance in word, clothing, and bearing, with which stoical hardness and self-control protect themselves from all prying inquisitiveness or curiosity.
- 36. —A slow step and a slow glance. There are not too many valuable things on earth: and these come and wish to come of themselves to him who has value. We are not quick to admire. —We know how to bear poverty, want, and even illness. —We avoid small honours owing to our mistrust of all who are over- ready to praise: for the man who praises believes he understands what he praises: but to understand—Balzac, that typical man of ambition, betrayed the fact comprendre c'est égaler. —Our doubt concerning the communicativeness of our hearts goes very deep; to us, loneliness is not a matter of choice, it is imposed upon us. —We are convinced that we only have duties to our equals, to others we do as we think best: we know that justice is only to be expected among equals (alas! this will not be realised for some time to come), —We are ironical towards the gifted; we hold the belief that no morality is possible without good birth. —We always feel as if we were those who had to dispense honours: while he is not found too frequently who would be worthy of honouring us. —We are always disguised: the higher a man's nature the more is he in need of remaining incognito. If there be a God, then out of sheer decency He ought only to show Himself on earth in the form of a man. —We are capable of otium, of the unconditional conviction that although a handicraft does not shame one in any sense, it certainly reduces one's rank. However much we may respect industry, and know how to give it its due, we do not appreciate it in a bourgeois sense, or after the manner of those insatiable and cackling artists who, like hens, cackle and lay eggs, and cackle again. —We protect artists and poets and any one who happens to be a master in something; but as creatures of a higher order than those,
- 37. who only know how to do something, who are only productive men, we do not confound ourselves with them. —We find joy in all forms and ceremonies; we would fain foster everything formal, and we are convinced that courtesy is one of the greatest virtues; we feel suspicious of every kind of laisser aller, including the freedom of the press and of thought; because, under such conditions, the intellect grows easy-going and coarse, and stretches its limbs. —We take pleasure in women as in a perhaps daintier, more delicate, and more ethereal kind of creature. What a treat it is to meet creatures who have only dancing and nonsense and finery in their minds! They have always been the delight of every tense and profound male soul, whose life is burdened with heavy responsibilities. —We take pleasure in princes and in priests, because in big things, as in small, they actually uphold the belief in the difference of human values, even in the estimation of the past, and at least symbolically. —We are able to keep silence i but we do not breathe a word of this in the presence of listeners. —We are able to endure long enmities: we lack the power of easy reconciliations. —We have a loathing of demagogism, of enlightenment, of amiability, and plebeian familiarity. —We collect precious things, the needs of higher and fastidious souls; we wish to possess nothing in common. We want to have our own books, our own landscapes. —We protest against evil and fine experiences, and take care not to generalise too quickly. The individual case: how ironically we regard it when it has the bad taste to put on the airs of a rule! —We love that which is naïf, and naïf people, but as spectators and higher creatures; we think Faust is just as simple as his Margaret.
- 38. —We have a low estimation of good people, because they are gregarious animals: we know how often an invaluable golden drop of goodness lies concealed beneath the most evil, the most malicious, and the hardest exterior, and that this single grain outweighs all the mere goody-goodiness of milk-and-watery souls. —We don't regard a man of our kind as refuted by his vices, nor by his tomfooleries. We are well aware that we are not recognised with ease, and that we have every reason to make our foreground very prominent. 944. What is noble?—The fact that one is constantly forced to be playing a part. That one is constantly searching for situations in which one is forced to put on airs. That one leaves happiness to the greatest number: the happiness which consists of inner peacefulness, of virtue, of comfort, and of Anglo-angelic-back-parlour-smugness, à la Spencer. That one instinctively seeks for heavy responsibilities. That one knows how to create enemies everywhere, at a pinch even in one's self. That one contradicts the greatest number, not in words at all, but by continually behaving differently from them. 945. Virtue (for instance, truthfulness) is our most noble and most dangerous luxury. We must not decline the disadvantages which it brings in its train. 946. We refuse to be praised: we do what serves our purpose, what gives us pleasure, or what we are obliged to do. 947.
- 39. What is chastity in a man? It means that his taste in sex has remained noble; that in eroticis he likes neither the brutal, the morbid, nor the clever. 948. The concept of honour is founded upon the belief in select society, in knightly excellences, in the obligation of having continually to play a part. In essentials it means that one does not take one's life too seriously, that one adheres unconditionally to the most dignified manners in one's dealings with everybody (at least in so far as they do not belong to us); that one is neither familiar, nor good- natured, nor hearty, nor modest, except inter pares; that one is always playing a part. 949. The fact that one sets one's life, one's health, and one's honour at stake, is the result of high spirits and of an overflowing and spendthrift will: it is not the result of philanthropy, but of the fact that every danger kindles our curiosity concerning the measure of our strength, and provokes our courage. 950. Eagles swoop down straight nobility of soul is best revealed by the magnificent and proud foolishness with which it makes its attacks. 951. War should be made against all namby-pamby ideas of nobility!—A certain modicum of brutality cannot be dispensed with: no more than we can do without a certain approximation to criminality. Self- satisfaction must not be allowed; a man should look upon himself with an adventurous spirit; he should experiment with himself and
- 40. run risks with himself—no beautiful soul-quackery should be tolerated. I want to give a more robust ideal a chance of prevailing. 952. Paradise is under the shadow of a swordsman—this is also a symbol and a test-word by which souls with noble and warrior-like origin betray and discover themselves. 953. The two paths.—There comes a period when man has a surplus amount of power at his disposal. Science aims at establishing the slavery of nature. Then man acquires the leisure in which to develop himself into something new and more lofty. A new aristocracy. It is then that a large number of virtues which are now conditions of existence are superseded.—Qualities which are no longer needed are on that account lost. We no longer need virtues: consequently we are losing them (likewise the morality of one thing is needful, of the salvation of the soul, and of immortality: these were means wherewith to make man capable of enormous self-tyranny, through the emotion of great fear!!!). The different kinds of needs by means of whose discipline man is formed: need teaches work, thought, and self-control. *** Physiological purification and strengthening. The new aristocracy is in need of an opposing body which it may combat: it must be driven to extremities in order to maintain itself. The two futures of mankind: (1) the consequence of a levelling- down to mediocrity, (2) conscious aloofness and self-development. A doctrine which would cleave a gulf: it maintains the highest and the lowest species (it destroys the intermediate).
- 41. The aristocracies, both spiritual and temporal, which have existed hitherto prove nothing against the necessity of a new aristocracy. 4. The Lords of the Earth. 954. A certain question constantly recurs to us; it is perhaps a seductive and evil question; may it be whispered into the ears of those who have a right to such doubtful problems—those strong souls of to-day whose dominion over themselves is unswerving: is it not high time, now that the type gregarious animal is developing ever more and more in Europe, to set about rearing, thoroughly, artificially, and consciously, an opposite type, and to attempt to establish the latter's virtues? And would not the democratic movement itself find for the first time a sort of goal, salvation, and justification, if some one appeared who availed himself of it—so that at last, beside its new and sublime product, slavery (for this must be the end of European democracy), that higher species of ruling and Cæsarian spirits might also be produced, which would stand upon it, hold to it, and would elevate themselves through it? This new race would climb aloft to new and hitherto impossible things, to a broader vision, and to its task on earth. 955. The aspect of the European of to-day makes me very hopeful. A daring and ruling race is here building itself up upon the foundation of an extremely intelligent, gregarious mass. It is obvious that the educational movements for the latter are not alone prominent nowadays. 956. The same conditions which go to develop the gregarious animal also force the development of the leaders.
- 42. 957. The question, and at the same time the task, is approaching with hesitation, terrible as Fate, but nevertheless inevitable: how shall the earth as a whole be ruled? And to what end shall man as a whole— no longer as a people or as a race—be reared and trained? Legislative moralities are the principal means by which one can form mankind, according to the fancy of a creative and profound will: provided, of course, that such an artistic will of the first order gets the power into its own hands, and can make its creative will prevail over long periods in the form of legislation, religions, and morals. At present, and probably for some time to come, one will seek such colossally creative men, such really great men, as I understand them, in vain: they will be lacking, until, after many disappointments, we are forced to begin to understand why it is they are lacking, and that nothing bars with greater hostility their rise and development, at present and for some time to come, than that which is now called the morality in Europe. Just as if there were no other kind of morality, and could be no other kind, than the one we have already characterised as herd-morality. It is this morality which is now striving with all its power to attain to that green-meadow happiness on earth, which consists in security, absence of danger, ease, facilities for livelihood, and, last but not least, if all goes well, even hopes to dispense with all kinds of shepherds and bell-wethers. The two doctrines which it preaches most universally are equality of rights and pity for all sufferers—and it even regards suffering itself as something which must be got rid of absolutely. That such ideas may be modern leads one to think very poorly of modernity. He, however, who has reflected deeply concerning the question, how and where the plant man has hitherto grown most vigorously, is forced to believe that this has always taken place under the opposite conditions; that to this end the danger of the situation has to increase enormously, his inventive faculty and dissembling powers have to fight their way up under long oppression and compulsion, and his will to life has to be increased to the unconditioned will to power, to over-power: he believes that danger, severity, violence,
- 43. peril in the street and in the heart, inequality of rights, secrecy, stoicism, seductive art, and devilry of every kind—in short, the opposite of all gregarious desiderata—are necessary for the elevation of man. Such a morality with opposite designs, which would rear man upwards instead of to comfort and mediocrity; such a morality, with the intention of producing a ruling caste—the future lords of the earth—must, in order to be taught at all, introduce itself as if it were in some way correlated to the prevailing moral law, and must come forward under the cover of the latter's words and forms. But seeing that, to this end, a host of transitionary and deceptive measures must be discovered, and that the life of a single individual stands for almost nothing in view of the accomplishment of such lengthy tasks and aims, the first thing that must be done is to rear a new kind of man in whom the duration of the necessary will and the necessary instincts is guaranteed for many generations. This must be a new kind of ruling species and caste—this ought to be quite as clear as the somewhat lengthy and not easily expressed consequences of this thought. The aim should be to prepare a transvaluation of values for a particularly strong kind of man, most highly gifted in intellect and will, and, to this end, slowly and cautiously to liberate in him a whole host of slandered instincts hitherto held in check: whoever meditates about this problem belongs to us, the free spirits—certainly not to that kind of free spirit which has existed hitherto: for these desired practically the reverse. To this order, it seems to me, belong, above all, the pessimists of Europe, the poets and thinkers of a revolted idealism, in so far as their discontent with existence in general must consistently at least have led them to be dissatisfied with the man of the present; the same applies to certain insatiably ambitious artists who courageously and unconditionally fight against the gregarious animal for the special rights of higher men, and subdue all herd- instincts and precautions of more exceptional minds by their seductive art. Thirdly and lastly, we should include in this group all those critics and historians by whom the discovery of the Old World, which has begun so happily—this was the work of the new Columbus, of German intellect—will be courageously continued (for we still stand in the very first stages of this conquest). For in the Old
- 44. World, as a matter of fact, a different and more lordly morality ruled than that of to-day; and the man of antiquity, under the educational ban of his morality, was a stronger and deeper man than the man of to-day—up to the present he has been the only well-constituted man. The temptation, however, which from antiquity to the present day has always exercised its power on such lucky strokes of Nature, i.e. on strong and enterprising souls, is, even at the present day, the most subtle and most effective of anti-democratic and anti-Christian powers, just as it was in the time of the Renaissance. 958. I am writing for a race of men which does not yet exist: for the lords of the earth. In Plato's Theages the following passage will be found: Every one of us would like if possible to be master of mankind; if possible, a God! This attitude of mind must be reinstated in our midst. Englishmen, Americans, and Russians. 959. That primeval forest-plant Man always appears where the struggle for power has been waged longest. Great men. Primeval forest creatures, the Romans. 960. From now henceforward there will be such favourable first conditions for greater ruling powers as have never yet been found on earth. And this is by no means the most important point. The establishment has been made possible of international race unions which will set themselves the task of rearing a ruling race, the future lords of the earth—a new, vast aristocracy based upon the most severe self-discipline, in which the will of philosophical men of power
- 45. and artist-tyrants will be stamped upon thousands of years: a higher species of men which, thanks to their preponderance of will, knowledge, riches, and influence, will avail themselves of democratic Europe as the most suitable and supple instrument they can have for taking the fate of the earth into their own hands, and working as artists upon man himself. Enough! The time is coming for us to transform all our views on politics. 5. The Great Man. 961. I will endeavour to see at which periods in history great men arise. The significance of despotic moralities that have lasted a long time: they strain the bow, provided they do not break it. 962. A great man,—a man whom Nature has built up and invented in a grand style,—What is such a man? First, in his general course of action his consistency is so broad that owing to its very breadth it can be surveyed only with difficulty, and consequently misleads; he possesses the capacity of extending his will over great stretches of his life, and of despising and rejecting all small things, whatever most beautiful and divine things of the world there may be among them. Secondly, he is colder, harder, less cautious and more free from the fear of public opinion; he does not possess the virtues which are compatible with respectability and with being respected, nor any of those things which are counted among the virtues of the herd. If he is unable to lead, he walks alone; he may then perchance grunt at many things which he meets on his way. Thirdly, he asks for no compassionate heart, but servants, instruments; in his dealings with men his one aim is to make something out of them.
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