Per Artursson is a professor in Dosage Form Design at the Department of Pharmacy, Uppsala University, Sweden where he heads the Drug Delivery research team. He is also Director for the Uppsala University drug optimization and pharmaceutical profiling platform within Science for Life Laboratories. His research aims at understanding drug absorption, distribution, metabolism and elimination (ADME) at the molecular and cellular level in order to deliver drugs more effectively via the oral route. He also investigates the effects of drug transporting proteins on drug disposition and drug interactions. He has published over 200 research articles and reviews, is highly cited and has received several international awards for his research.
Professor Bolger is Chief Scientist at Simulations Plus, Inc. in Lancaster, CA.
His formal education has been in Biology, Chemistry, Pharmaceutical Sciences, and Pharmacology at UC San Diego and UC San Francisco. He was a professor of Pharmaceutical Sciences for 23 years at the University of Southern California School of Pharmacy and retired from USC in 2004. During this period he developed an interest in the computational aspects of drug design and drug development.
From 1987-1993 he was a founder and Director of Medicinal Chemistry at CoCensys Inc. There, he studied the chemistry and use of novel neuroactive steroids for treatment of anxiety, epilepsy, and sleep disorders. Drug candidates emanating from seven of Dr. Bolger's patents have been tested in Phase I and II clinical trials for petite mal epilepsy, sleep disorders, and migraine.
Dr. Bolger programmed the first version of GastroPlus in 1997 and for the last 20 years has worked with a team of scientist / programmers at Simulations Plus, Inc. (Lancaster, CA) in the development of software programs for estimation of biopharmaceutical properties and simulations of absorption and bioavailability. He was elected to the rank of Fellow of the American Association for the Advancement of Science in 1996.
Matthew is a Senior Scientist in Translational DMPK at Simcyp Ltd. Matthew obtained his Bachelor's and Master's degrees in Physiology and Human Nutrition from The University of Sheffield (2000) and PhD (gut transporter proteomics & IVIVE-PBPK) from The University of Manchester (2015). His first PK research involvement was at Hope Hospital, Manchester, sponsored by Pfizer in 2003, using ex vivo intestinal tissue to understand region-specific intestinal drug permeability/transporters. Matthew joined Simcyp Ltd in 2007 and is principally involved (including as project lead) in the development of human & preclinical PBPK models with specialisms in drug transport and metabolism. He has 15 peer reviewed publications and has been a session moderator and invited speaker at the AAPS.
Narendra Chirmule, PhD is Senior Vice President, and Head of R&D at Biocon Research Labs, Bangalore, India. He has responsible for the development of the pipeline of novel biologics and biosimilars. The role includes oversight of early and late translational sciences, regulatory strategies and intellectual property. He has held senior leadership positions at Amgen (Thousand Oaks, CA) and Merck (Philadelphia, PA) in the departments of Clinical Immunology overseeing drug development in regulated laboratories. His expertise is in the area of immune responses to biologics and vaccines. In Biologics, he has published extensively on the topics of immunogenicity prediction and assessment, predictive toxicology and quality-by-design. In vaccines, his experience spans development of assays for various viruses and bacteria to supporting operations of very large clinical trials. He was involved in the immunogenicity assessment of HPV responses for Gardasil. He has a PhD from University of Mumbai, post-doctoral training at Cornell University Medical College, and teaching and research experience as Assistant Professor in the Human Gene Therapy Group of University of Pennsylvania. He is an advisor to the Filovirus consortium and a reviewer on the HIV vaccine study section for the National Institutes of Health.
In culture, he has a keen interest in Indian Classical music that extends to all genres. In this respect, he has learned and played the tabla from many gurus, including Debasish Chaudhuri of Lucknow Gharana. He has performed with a wide range of amateur and professional artists ranging from Hindustani and Carnatic classical, Bollywood, Jazz, Latin, and Fusion. He is on the board of Rupak School of World Music, Los Angeles. In Bangalore, he volunteers his time towards the promotion of music to underprivileged children.
Dr. Goutam Chowdhury is an Assistant Professor and Ramalingaswami Fellow of chemistry at Shiv Nadar University in Uttar Pradesh, India. He did his PhD from Dr. Kent Gates' lab at University of Missouri-Columbia and postdoc from Dr. F. Peter Guengerich's lab in the field of cytochrome P450 and molecular toxicology. He worked as a research instructor at the Vanderbilt University Medical Center before joining Covance Laboratories Inc. in Madison, WI, USA as a staff Scientist. During his career, he has published more than 30 papers in international journals.
Dr. Chowdhury lab specializes in molecular toxicology and drug metabolism. His research spans from the study of DNA and protein damage to P450, drug metabolism, and mass spectrometry. At present, his lab is interested in understanding the mechanism of toxicity of various drugs and molecules including thalidomide, YM155, withanone and 8-nitroguanine. Another area of research in his lab is the development of possible predictive biomarkers of reactive intermediates formed from various drugs.
Dr. F. Peter Guengerich is the Tadashi Inagami Professor of Biochemistry at Vanderbilt University School of Medicine. He received his Ph.D. in Biochemistry from Vanderbilt in 1973 in the area of alkaloid biosynthesis (H. Broquist), was a research fellow at the University of Michigan (M. J. Coon), and joined the faculty at Vanderbilt in 1975 (Professor since 1983). His research deals with the chemical and biological mechanisms by which drugs and cancer-causing chemicals are processed and the relevance to drug development, toxicity, and disease. A major area of interest is the cytochrome P450 enzymes, which are the major catalysts involved in the metabolism of drugs, carcinogens, and steroids. Studies with the recombinant human P450 enzymes involve the molecular basis for substrate and reaction discrimination. He is an author/co-author of 695 original research articles, 220 invited reviews, and 136 proceedings chapters. He is an associate editor of both The Journal of Biological Chemistry (also Deputy Editor) and Chemical Research in Toxicology. Prof. Guengerich is currently a member of the Expert Panel of the Flavor and Extract Manufacturers' Association. In 1992 he received the B. B. Brodie Award from the American Society for Pharmacology and Experimental Therapeutics and in 2011 he received the Founders' Award from the Chemical Toxicology Division of the American Chemical Society and in 2013 he received the Merit Award of the Society of Toxicology. He has also received the Scott Award from Toxicology Forum and the CIIT Founders' Award. In 2010 he received the ISSX R. T. Williams Distinguished Scientific Achievement Award. Prof. Guengerich has trained 20 graduate students and 134 postdoctoral fellows/visiting scientists and received two Vanderbilt mentoring awards for his work with postdoctoral fellows, one of which is now named for him.
Kathie Knights held the position of Professor in Clinical Pharmacology at Flinders University, Adelaide, Australia from 2008-2014 and is currently a Professor Emeritus and a member of the Flinders College of Distinguished Educators. Her main research interests are the metabolism of carboxylic acids, renal drug metabolism and the interplay between renal drug and endobiotic metabolism. She has published >160 research outputs, 6 book chapters and is co-author of the highly successful text Pharmacology for Health Professionals (Elsevier). She is currently a member of the editorial board of Drug Metabolism Reviews (2012-2018) and the BJCP International Editorial Board (2012-2019).
In 2007 she was awarded an Australian Carrick Citation for outstanding contribution to student learning and in 2010 the Australasian Society of Clinical and Experimental Pharmacologists (ASCEPT) Teaching Excellence Award. Kathie served as ASCEPT President (2008-2009), ISSX Councillor (2008-2011) and is currently an Internal Auditor of IUPHAR (2015-2018).
Rukmini Kumar is Principal Scientist and co-founder at Vantage Research. She started working on modeling during her Ph.D at University of Pittsburgh, during which she built a systems model of sepsis, collaborating with researchers from University of Pittsburgh Medical Center. Her work contributed to scientific publications and to the initial model developed at Immunetrics. She worked at Entelos, a pioneer in physiological modeling for 8 years, leading several pharma R&D projects in diverse disease areas, as well as engineering efforts in developing new models for the epidermis and liver toxicity. Rukmini then co-founded Vantage Research, a Modeling & Simulation (M&S) company that focuses on Quantitative Systems Pharmacology. Vantage Research works with Pharma R&D clients in therapeutic areas such as diabetes, auto-immune diseases, hypertension and immuno-oncology.
Hiroyuki Kusuhara received his BSc, MSc and PhD (Pharmaceutical Sciences) from the University of Tokyo (Japan).
Hiroyuki started his carrier as an academic scientist in The University of Tokyo as Assistant Professor of Pharmaceutical Sciences (1998). He was promoted to Associate Professor (2004) and Professor (2012) of Graduate School of Pharmaceutical Sciences, The University of Tokyo. He is currently professor and chair of Laboratory of Molecular Pharmacokinetics at Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Hiroyuki's major research interest encompass interindividual variability in human drug Disposition, specifically: identification of drug transporters in the tissue distribution, and clearance; pharmacokinetics; modeling and simulation; in vitro-in vivo extrapolation; PK imaging; drug-drug interactions; and metabolomics. He is the author of 180 research papers in these areas.
Member of ISSX since 2013. Most recent ISSX activities include Scientific Affairs Committee (2014-2016), and Nominations Committee (2014-2016). Hiroyuki has experience as Council and Director in Japanese societies; JSSX Council (2004-present), Director (2014-2017); APSTJ Council (2010-present), Director (2017-present). Editorial Board membership: Drug Metabolism & Disposition; Journal of Pharmaceutical Sciences; Biopharmaceutics and Drug Disposition. Society membership: ISSX, ASCPT, and Japanese Societies; JSSX, JSCPT, APSTJ, JPS and JSDDS.
John Miners holds BSc, MSc, PhD and DSc degrees. He is a Fellow of the Australian Academy of Science (FAA) and an Honorary Fellow of the Royal Society of New Zealand (HonFRSNZ). He is currently a Matthew Flinders Distinguished Professor in the Flinders University School of Medicine, having served previously as Professor and Head of the Department of Clinical Pharmacology. His broad research interest is drug and chemical metabolism in humans, particularly sources of variability in drug elimination and its pharmacokinetic and therapeutic consequences. Current projects include: (i) structure-function relationships and genetic polymorphisms of human UDP-glucuronosyltransferases and cytochromes P450; (ii) in vitro and computational models for the prediction of drug and chemical metabolism parameters in vivo; (iii) drug-drug interactions; and (iv) metabolomics. He has published over 300 research papers and reviews across these areas and has an ISI h-index of 62. John Miners has served as President of numerous societies, including the Australasian Society of Experimental Pharmacologists and Toxicologists (ASCEPT), the International Society for the Study of Xenobiotics (ISSX) and the Asia Pacific Federation of Pharmacology, as well as being a member of the Executive Committee of the International Union of Basic and Clinical Pharmacology (IUPHAR). He is a current or past member of the Editorial Boards of ten international journals.
Mr. Chandrasekhar (Nat) Natarajan is the Chief Scientific Officer at ViNa Pharma Consulting, LLC. He is also an Adjunct Faculty at Tufts School of Medicine teaching “Translational Medicine”. At Sanofi he was an Associate Vice President in Drug Disposition division and a Strategic Scientific Advisor for Oncology programs providing critical input on translational pharmacology, ADME and PK/PD in discovery and development. Earlier he was the Deputy Global Head of Discovery MPK providing Discovery Support at Sanofi-Aventis overseeing effective chemical optimization and druggability of new compounds for desirable ADME & pharmacokinetic properties
Nat received his B.Pharm and his MSc in Pharmacology from the University of Madras, India. His MS in Pharmacotherapeutics was from Long Island University, New York and his clinical pharmacy training was at Down State Medical Center in New York.
Nat is an invited speaker at PERI, Harvard, Tufts CSDD, CSIR-Institute of Genomics & Integrative Biology (CSIR-IGIB), and Gulf Medical University. Nat is an active member of AAPS, ACCP, SITC and DIA.
Dr. Sheila Annie Peters heads the Translational Quantitative Pharmacology group at Merck Darmstadt. Her areas of expertise in DMPK include Physiologically-based pharmacokinetic (PBPK)-Phamacodynamics (PD) modeling, and PK/PD and drug-drug interactions. Prior to this, she worked at AstraZeneca, Mölndal, where she developed a generic whole-body PBPK model in MATLAB® which she used to support several drug discovery and early development projects across different R&D sites with innovative approaches to identifying potential limitations to drug disposition. She successfully implemented Model-based drug discovery (MBDDx) strategy in Respiratory Inflammation and Autoimmunity iMed through cross-functional collaboration. She won the 2013 IMED (Innovative Medicines) Science Award at AstraZeneca for the “Design and Development of LungSim Simulation tool for Inhalation PK Modelling”. She has published several papers in high impact journals as well as a book on PBPK. As part of the IQ Consortium, she co-authored a White Paper on PBPK along with other experts in industry and continues to work with them on various topics of interest in PBPK.
Dr. Bhagwat Prasad is an assistant professor in the Department of Pharmaceutics, University of Washington (UW), Seattle, WA. He also serves as a co-director of the UW research affiliate program on transporters (UWRAPT). Before joining faculty position, Dr. Prasad worked as a postdoc and a lead scientist, UWRAPT. Dr. Prasad obtained his MS in 2006 and Ph.D. in 2010 in Pharmaceutical Analysis from NIPER, Mohali, India. In his role as a PI or co-inv. in various NIH, US-FDA and industry funded grants, Dr. Prasad has been establishing and applying targeted proteomic assays to quantify population variability in drug transporters and metabolizing enzymes. Dr. Prasad has published >60 peer-reviewed articles and >70 conference abstracts and delivered >35 invited talks.
Utpal Tatu is a Professor at Indian Institute of Science, Bangalore, India. His research focuses on neglected diseases causing organisms with an emphasis on developing better methods of diagnosis and treatment. Prof. Tatu's research in the fields of genomics, proteomics and Metabolomics is internationally recognized. His research work has made it to the editorials of top scientific magazines including Science and Nature Medicine. Prof. Tatu is a member of the United States Pharmacopoeia Expert panel for Biologics. Prof. Tatu has headed several multi-institutional projects with bilateral collaborations with international research laboratories and industries in UK, Switzerland, Denmark, Brazil, France and USA. Prof. Tatu's lab is funded by national and international funding agencies. He is a recipient of several national and international awards such as Ranbaxy Research Award, Birla Science Prize to mention a few. He is endowed with Adjunct professorship to several institutions and health organizations and is on the advisory board of industries in India and abroad. Prof. Tatu is an elected fellow of the National Academy of Sciences and President elect of the Proteomic Society of India. He serves on the editorial board of Cambridge Press journal 'Parasitology' and is one of the few scientists from India to be invited to present his work on Ted Talk.
Allan Rettie is a Professor in the Department of Medicinal Chemistry at the University of Washington (UW). He obtained a Ph.D. in Pharmaceutical Sciences in 1983 from the University of Newcastle-upon-Tyne, England, before moving to Seattle to post-doc with Drs. Mont Juchau and Dr. Bill Trager in the areas of extrahepatic drug metabolism and metabolic drug-drug interactions, respectively. He joined the faculty of the UW School of Pharmacy in 1987 and was Departmental Chair from 2000-14. His primary research areas of interest for almost 30 years have been the elucidation of the chemical, enzymatic and genetic basis for adverse drug reactions, especially those involving CYP2 and CYP4 family enzymes. Dr. Rettie serves or has served on the editorial boards of Drug Metabolism and Disposition, Drug Metabolism Reviews, Journal of Pharmacology and Therapeutics, Current Drug Metabolism, Chemico-Biological Interactions and Chemical Research in Toxicology as well as numerous NIH grant review panels. He is past Chair (2010-14) of the IUPHAR (International Union of Basic and Applied Pharmacology) Section of Drug Metabolism and Transport and past Chair (2013-15) of the Scientific Affairs Committee of International Society for the Study of Xenobiotics (ISSX). Dr. Rettie is a Fellow of the Japanese Society for the Study of Xenobiotics (2016) and received the North American Scientific Achievement Award (2005) from ISSX for his work on elucidating metabolic and genetic mechanisms of adverse drug reactions involving the anticoagulant drug, warfarin.
Kalyanasundaram Subramanian (Kas) is the Head of Bioinformatics at Syngene International. For the past two decades he has been working on modeling chemical and biological systems using a variety of techniques ranging from machine learning to dynamical systems analysis. At Syngene, he leads a team that primarily works with biological and chemical data from various sources, integrates them; derive patterns and themes to provide decision support. Prior to Syngene, he was Chief Scientific Officer at Strand Life Sciences Pvt. Ltd where he led the groups involved in the development of the Virtual Liver and the interpretation platforms for NGS-based diagnostics. He headed the Collaborative R&D group for immunology products at Entelos, a systems biology company and has also worked at Genetic Therapy Inc (Novartis) where he helped found a group to perform research in synthetic and hybrid vectors for gene delivery. He has a B.Tech. in chemical engineering from the Indian Institute of Technology, Bombay, India and an MS from SUNY at Buffalo. His Ph.D. is in Biomedical Engineering from the Johns Hopkins University, School of Medicine.
Raju Subramanian is currently a Director and head of the Pharmacokinetics group in the Department of Drug Metabolism and Pharmacokinetics (DMPK), Gilead Sciences. Raju has over 16 years of experience in DMPK supporting small molecule, peptide and large molecule modalities spanning the discovery and development continuum. He obtained his B. Sc. (Honors), Chemistry, St. Stephen's College, University of Delhi, India 1989; Ph. D., Physical Chemistry, SUNY at Stony Brook, NY 1994; and from 1994-1999 completed post-doctoral training at College of William and Mary (Physics) and University of Illinois at Urbana-Champaign, IL (Electrical and Computer Engineering). Following his post-doctoral training he joined Merck from 1999-2005 where he led a structure elucidation laboratory. He moved to Amgen and over this phase of his career (2005-June 2016), he led a biotransformation/ADME chemistry group and managed broader aspects of ADME science with molecules in discovery through regulatory filing and approval. Externally, Raju has +60 publications, participated in industry consortia and as a speaker, organizer and organizing committees for conferences.
Philip Tagari is currently Vice President of Research (Therapeutic Discovery) at Amgen Inc, the world's largest biotechnology company. His laboratories are responsible for biologics discovery, scaffold engineering, optimization and early manufacturability assessment; medicinal, oligonucleotide and peptide chemistry; protein conjugates (ADC, peptibodies) and reagents; assay development, screening, enzymological and pharmacological characterization and profiling (in vitro), as well as structural biology, biophysics, computational and analytical chemistry, materials logistics and automation. Prior to joining Amgen in 1998, Philip was a Research Fellow at Merck Frosst (Canada) Inc, where he contributed to several programs in eicosanoid and inflammatory biology, culminating in the discovery of odanacatib and rofecoxib, as well as the clinically active leukotriene D4 receptor antagonist MK-571 and the leukotriene biosynthesis inhibitor MK-591. In addition to the elucidation of leukotriene metabolism in several species, Philip established one of the first robotic screening laboratories at Merck, building on work performed at McGill and Oxford Universities on automated image analysis, quantitative immunohistochemistry and neurotransmitter measurements in neurodegeneration and cerebrovascular research. Philip is a graduate of Gonville & Caius College, Cambridge University (UK).
Larry C. Wienkers received his Ph.D. in Medicinal Chemistry from University of Washington in 1993 under the direction of Dr William F. Trager. He did postdoctoral work in the department of Drug Metabolism at the Upjohn Company and subsequently joined the company as a Research Scientist 1995. In 1998, Larry became Director of Drug Metabolism Enabling Technologies at Pharmacia & Upjohn and in 2002 became Executive Director of Pharmacokinetics, Dynamics and Metabolism at Pfizer. In 2004 Larry moved to Amgen and is currently Vice President of the department of Pharmacokinetics and Drug Metabolism. Larry's current research interests are focused on exploring bioactivation pathways associated with small molecule drug metabolism in order to explain the untoward side effects encountered with these compounds. In addition, he continues to investigate the application of novel in vitro metabolism techniques to understand the enzymatic basis for biotransformation of potential therapeutic agents and the prospective application of this information to predict clinically relevant drug-drug interactions. To this end, his group uses a multidisciplinary approach applying organic chemistry, biochemistry, biophysics, enzymology, analytical chemistry, and cell biology research techniques to study cytochrome P450 mechanism based inhibition of novel therapeutics.
Griff Humphreys is currently the Executive Director of the Biotransformation Department at Bristol-Myers Squibb. He received his graduate training at the University of Virginia in chemistry and completed a post-doctoral fellowship at Vanderbilt University in the Center in Molecular Toxicology. He then joined Bristol-Myers Squibb and has been with the company for 23 years. He oversees a group responsible for drug metabolism, disposition and metabolite identification studies during the candidate optimization and drug development phases. His interests include the consequences of reactive metabolite formation, development of new analytical methodologies for metabolite detection, reaction phenotyping of CYP and UGT catalyzed biotransformations, predictive metabolism and toxicology models, in vitro-in vivo correlations, and strategies for candidate optimization.
Amita Joshi, PhD, is an Executive Leader with 27 years experience in Clinical Drug Development and Clinical Pharmacology. In her role as Vice President and Head of Clinical Pharmacology at Genentech, Amita is responsible for the strategic and scientific direction of Clinical Pharmacology and Pharmacometric aspects of all Genentech programs from Early Clinical Research through post-approval. The scientific staff of Clinical Pharmacology is responsible for ensuring that they identify and deliver the right dose, by the right route and by the right regimen to patients. In her role, Amita has overseen successful development strategies and tactics for first product approvals and/or product extensions for Small molecules, Monoclonal Antibodies and Antibody Drug Conjugates. These include Cotellic, Tecentriq, Kadcyla, Lucentis, Rituxan, Erivedge, Perjeta, Herceptin, Avastin, Xolair and Nutropin. Amita has published more than 40 manuscripts and book chapters and presented at national and international conferences.
Amita is also recognized by her peers in the Biotech industry for her contributions in understanding the Clinical Pharmacology of therapeutic monoclonal antibodies, has been a member of the AAPS and ASCPT scientific leadership and has chaired AAPS's National Biotechnology Conference in 2010. Amita received the Professional Businesswoman "Industry Leader" award in 2015 and received the San Francisco Business Times "100 Most Influential Women in Business" award in 2016.
Michael W. Sinz, Ph.D. is a Director at Biocon-Bristol-Myers Squibb Department of Metabolism and Pharmacokinetics in Bangalore, India where he manages ADME lead optimization of drug discovery assets (2001-present). Dr. Sinz previously held the position of Section Director-Pharmacokinetics and Drug Metabolism for Parke-Davis/Pfizer Global Research and Development (Ann Arbor, MI, 1991-2001). He received two B.S. degrees, one in Chemistry (ACS) and one in Biology from the University of Wisconsin-Eau Claire, and a Ph.D. in Pharmacognosy/Medicinal Chemistry from the University of Minnesota. Dr. Sinz is an active member of the International Society for the Study of Xenobiotics, IQ Consortium (Drug Metabolism), and American Chemical Society. He is also on the organizing committee for the Land O'Lakes conference on Drug Metabolism and Pharmacokinetics (2004-present), as well as the 2018 Asia Pacific ISSX meeting. He is editor in chief of Current Drug Metabolism, an associate editor of Drug Metabolism Letters, and on the editorial advisory boards of Current Pharmacology Reports and Drug Metabolism and Disposition. His areas of research include in vitro and in vivo drug metabolism, clearance predictions, reaction phenotyping, and predicting drug-drug interactions. Dr. Sinz's resume includes an extensive number of peer reviewed publications, book chapters, and external presentations.
Dr Macwan is currently Senior Scientist at Simulations Plus, Inc. in Lancaster, CA. She earned B.S. and M.S. degrees in Pharmaceutical Sciences at Sardar Patel University, Gujarat, India. She also served as the lecturer for a year at Sat Kaival College of Pharmacy, Gujarat, India.
Dr Macwan was enrolled in University of Rhode Island, RI, USA as the graduate assistant to pursue her research interest in clinical pharmacokinetics in August 2007. She was honored with graduate student research excellence award in 2012. Dr Macwan earned PhD in pharmaceutical sciences specializing in clinical pharmacokinetic in May 2013. The major focus of her PhD research was to characterize the effect of diseases on pharmacokinetic properties of a lipid-lowering class of drugs through model-based approaches. She used GastroPlusTM software for one of her research projects and during that period she developed the keen interest in physiologically-based pharmacokinetic (PBPK) modeling. Dr Macwan joined Simulations Plus, Inc. as scientist II in July 2013 to further nourish her interest in mechanistic modeling. She has been working on several contract studies in simulation studies team for guiding teams of pharmaceutical scientists to improve decision making-process during drug discovery and various stages of drug development. This work is mainly facilitated by mechanistic absorption and PBPK modeling approach using GastroPlus, which is the company's leading modeling and simulation software.
Dr Macwan demonstrated her proficiency in this field by presenting work at various regional and international conferences either through poster or oral presentations.