Web Desc
Autophagy: Fundamentals to Disease
Organizer(s): Christina H. Eng, Daniel J. Klionsky, Guido Kroemer and Li Yu
Date: May 23 - 28, 2014
Location: Hyatt Regency Austin, Austin, TX, USA
Sponsored by AbbVie Inc., Cell Research and Shire Human Genetic Therapies
Summary of Meeting:
Autophagy is a fundamental cellular process that orchestrates the degradation of proteins, lipids and organelles during both basal and cellular or environmental stress conditions. Once thought to occur only during times of nutrient limitation, autophagy clearly plays major roles in both developmental and pathological situations. As the importance of autophagy in a variety of diseases is emerging, an in-depth knowledge of primary and alternative autophagic pathways is required to fully understand and effectively modulate it. The forefront of autophagy research will be highlighted at this meeting, from basic mechanistic insights and signaling to the role autophagy plays in multiple disease areas and prospects for therapeutic targeting. Key areas of discussion will include the source of the autophagosomal membrane, new mechanistic insights into both macroautophagy and mitophagy, and the critical roles of autophagy in normal and disease situations such as cancer, neurodegenerative diseases, Crohn’s disease, lysosomal storage diseases, cardiomyopathy and aging. Examining the role of autophagy in disease will enable us to understand in contexts in which modulation of autophagy may be beneficial, and identifying the core processes that control autophagy will enable us to identify tools to modulate the pathway. This meeting will bring together a variety of investigators exploring different facets of autophagy, and their interactions will expand our knowledge of fundamental autophagic mechanisms in different contexts and their critical functions in physiological and pathological settings.
Scholarship Deadline: January 23 2014
Discounted Abstract Deadline: January 23 2014
Abstract Deadline: February 27 2014
Discounted Registration Deadline: March 24 2014
Keystone Symposia thanks our Sponsor(s) for generously supporting this meeting:
AbbVie Inc.Cell ResearchShire Human Genetic Therapies
We gratefully acknowledge additional support for this conference from:
Cell Signaling Technology, Inc.Promega Corporation
We gratefully acknowledge additional in-kind support for this conference from those foregoing speaker expense reimbursements:

Novartis Pharma AG

Pfizer Oncology
We appreciate the organizations that provide Keystone Symposia with additional support, such as marketing and advertising:
EMBO (European Molecular Biology Organization)
We gratefully acknowledge the generous grant for this conference provided by:

National Cancer Institute (NCI)
Grant No. 1R13CA183034-01
The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
We appreciate the organizations that provide Keystone Symposia with additional support, such as marketing and advertising:

Click here to view more of these organizations
Special thanks to the following for their support of Keystone Symposia initiatives to increase participation at this meeting by scientists from underrepresented backgrounds:

Click here to view more of these organizations

Program

Friday, May 23 | 4:00PM - 8:00PM
Arrival and Registration
Room: Texas Foyer


Friday, May 23 | 6:00PM - 8:00PM
Mixer
Room: Texas Foyer


Saturday, May 24 | 7:30AM - 8:30AM
Breakfast
Room: Texas Ballroom


Saturday, May 24 | 8:00AM - 8:30AM
Poster Setup
Room: Texas Ballroom


Saturday, May 24 | 8:30AM - 7:30PM
Poster Viewing
Room: Texas Ballroom


Saturday, May 24 | 8:30AM - 9:30AM
Keynote Address
Room: Texas Ballroom

Speaker 1 of 2
* Christina H. Eng, Pfizer, USA

Saturday, May 24 | 8:30AM - 9:30AM
Keynote Address
Room: Texas Ballroom

Speaker 2 of 2
Noboru Mizushima, University of Tokyo, Japan
Novel Insights into Autophagy Function

Saturday, May 24 | 9:30AM - 11:45AM
Autophagosome Biogenesis and Trafficking
Room: Texas Ballroom

Speaker 1 of 5
* Li Yu, Tsinghua University, China

Saturday, May 24 | 9:30AM - 11:45AM
Autophagosome Biogenesis and Trafficking
Room: Texas Ballroom

Speaker 2 of 5
Zvulun Elazar, Weizmann Institute of Science, Israel
Atg8 in Health and Disease

Saturday, May 24 | 9:30AM - 11:45AM
Autophagosome Biogenesis and Trafficking
Room: Texas Ballroom

Speaker 3 of 5
Fulvio Reggiori, University Medical Centre Groningen, Netherlands
Roles of phosphatidylinositol-3-phosphate in autophagy

Saturday, May 24 | 9:30AM - 11:45AM
Autophagosome Biogenesis and Trafficking
Room: Texas Ballroom

Speaker 4 of 5
Sharon A. Tooze, Francis Crick Institute, UK
The Role of PI3P and WIPI2 in Autophagy

Saturday, May 24 | 9:30AM - 11:45AM
Autophagosome Biogenesis and Trafficking
Room: Texas Ballroom

Speaker 5 of 5
Liang Ge, Tsinghua University, China
Short Talk: A Functional Approach Identifies the ER-Golgi Intermediate Compartment as a Key Membrane Source for Autophagosome Biogenesis

Saturday, May 24 | 10:10AM - 10:30AM
Coffee Break
Room: Texas Foyer


Saturday, May 24 | 11:45AM - 12:45PM
Lunch
Room: Texas Ballroom


Saturday, May 24 | 12:45PM - 3:00PM
Poster Session 1
Room: Texas Ballroom


Saturday, May 24 | 3:00PM - 5:00PM
Workshop 1: Autophagy at the Single Cell and Molecular Level
Room: Texas Ballroom

Speaker 1 of 8
* David C. Rubinsztein, Cambridge Institute for Medical Research, UK

Saturday, May 24 | 3:00PM - 5:00PM
Workshop 1: Autophagy at the Single Cell and Molecular Level
Room: Texas Ballroom

Speaker 2 of 8
* Sharon A. Tooze, Francis Crick Institute, UK

Saturday, May 24 | 3:00PM - 5:00PM
Workshop 1: Autophagy at the Single Cell and Molecular Level
Room: Texas Ballroom

Speaker 3 of 8
Ben Loos, Stellenbosch University, South Africa
Defining and Measuring Autophagic Flux at Single Cell Level

Saturday, May 24 | 3:00PM - 5:00PM
Workshop 1: Autophagy at the Single Cell and Molecular Level
Room: Texas Ballroom

Speaker 4 of 8
Jiajie Diao, Stanford University, USA
Single-Vesicle Analysis of SNARE-Mediated Membrane Fusion Involved in Autophagy

Saturday, May 24 | 3:00PM - 5:00PM
Workshop 1: Autophagy at the Single Cell and Molecular Level
Room: Texas Ballroom

Speaker 5 of 8
Sangita C. Sinha, North Dakota State University, USA
Intrinsically Disordered Regions in Autophagy Proteins

Saturday, May 24 | 3:00PM - 5:00PM
Workshop 1: Autophagy at the Single Cell and Molecular Level
Room: Texas Ballroom

Speaker 6 of 8
Takanori Otomo, The Scripps Research Institute, USA
Structural Basis of ATG3 Recognition by the Autophagic Ubiquitin-Like Protein ATG12

Saturday, May 24 | 3:00PM - 5:00PM
Workshop 1: Autophagy at the Single Cell and Molecular Level
Room: Texas Ballroom

Speaker 7 of 8
Daric J. Wible, University of Texas MD Anderson Science Park, USA
ATG16L1 Interaction with ATG5 Forms a Molecular Switch that Controls the Competing Conjugation Reactions of Ubiquitin and the Ubiquitin-Like (Ubl) Protein, ATG12

Saturday, May 24 | 3:00PM - 5:00PM
Workshop 1: Autophagy at the Single Cell and Molecular Level
Room: Texas Ballroom

Speaker 8 of 8
Calvin Yip, University of British Columbia, Canada
Molecular Architecture of the Saccharomyces cerevisiae Autophagy Regulatory Complex Atg17-Atg31-Atg29

Saturday, May 24 | 5:00PM - 5:30PM
Coffee Available
Room: Texas Foyer


Saturday, May 24 | 5:30PM - 7:30PM
Mitochondrial Autophagy
Room: Texas Ballroom

Speaker 1 of 4
* Richard J. Youle, NINDS, National Institutes of Health, USA
Damage Control - How the Pink1/Parkin Pathway can Regulate Removal of Impaired Mitochondria by Autophagy

Saturday, May 24 | 5:30PM - 7:30PM
Mitochondrial Autophagy
Room: Texas Ballroom

Speaker 2 of 4
Mondira Kundu, St. Jude Children's Hospital, USA
Mitochondrial (Dys)Function and Autophagy - A “Chicken or Egg?” Conundrum

Saturday, May 24 | 5:30PM - 7:30PM
Mitochondrial Autophagy
Room: Texas Ballroom

Speaker 3 of 4
Charleen T. Chu, University of Pittsburgh, USA
Mitophagy and Parkinson’s Disease: Hanging in the Balance

Saturday, May 24 | 5:30PM - 7:30PM
Mitochondrial Autophagy
Room: Texas Ballroom

Speaker 4 of 4
Iain Scott, University of Pittsburgh, USA
Short Talk: GCN5L1 – Holding the Balance between Mitochondrial Biogenesis and Degradation

Saturday, May 24 | 7:30PM - 7:30PM
On Own for Dinner


Sunday, May 25 | 7:30AM - 8:30AM
Breakfast
Room: Texas Ballroom


Sunday, May 25 | 8:30AM - 11:45AM
Mechanisms of Autophagy
Room: Texas Ballroom

Speaker 1 of 7
* Fulvio Reggiori, University Medical Centre Groningen, Netherlands

Sunday, May 25 | 8:30AM - 11:45AM
Mechanisms of Autophagy
Room: Texas Ballroom

Speaker 2 of 7
Meiyan Jin, University of Michigan, USA
Transcriptional Regulation by Pho23 Modulates the Frequency of Autophagosome Formation

Sunday, May 25 | 8:30AM - 11:45AM
Mechanisms of Autophagy
Room: Texas Ballroom

Speaker 3 of 7
Adi Kimchi, Weizmann Institute of Science, Israel
Discovering Novel Protein-Protein Interactions in Autophagy and in its Cross-Talk with Apoptosis

Sunday, May 25 | 8:30AM - 11:45AM
Mechanisms of Autophagy
Room: Texas Ballroom

Speaker 4 of 7
Li Yu, Tsinghua University, China
Regulation of Autophagy by Protein Acetylation

Sunday, May 25 | 8:30AM - 11:45AM
Mechanisms of Autophagy
Room: Texas Ballroom

Speaker 5 of 7
Beat Nyfeler, Novartis Institutes for BioMedical Research, Switzerland
Genetic and Pharmacological Tools to Modulate Autophagy

Sunday, May 25 | 8:30AM - 11:45AM
Mechanisms of Autophagy
Room: Texas Ballroom

Speaker 6 of 7
Virginie M. Betin, University of Bristol, UK
Short Talk: Investigating the Role of Sorting Nexin-4 (SNX4) in Autophagosome Biogenesis

Sunday, May 25 | 8:30AM - 11:45AM
Mechanisms of Autophagy
Room: Texas Ballroom

Speaker 7 of 7
Guang-Chao Chen, Academia Sinica, Taiwan
Short Talk; The Transmembrane Protein Atg9 Coordinates with dTRAF2/TRAF6 in the Regulation of JNK Signaling and Autophagy Under Oxidative Stress Conditions

Sunday, May 25 | 9:50AM - 10:10AM
Coffee Break
Room: Texas Foyer


Sunday, May 25 | 11:45AM - 1:00PM
Poster Setup
Room: Texas Ballroom


Sunday, May 25 | 11:45AM - 5:00PM
On Own for Lunch


Sunday, May 25 | 1:00PM - 10:00PM
Poster Viewing
Room: Texas Ballroom


Sunday, May 25 | 4:30PM - 5:00PM
Coffee Available
Room: Texas Foyer


Sunday, May 25 | 5:00PM - 7:00PM
Role of Autophagy in Neurodegeneration
Room: Texas Ballroom

Speaker 1 of 5
* Charleen T. Chu, University of Pittsburgh, USA

Sunday, May 25 | 5:00PM - 7:00PM
Role of Autophagy in Neurodegeneration
Room: Texas Ballroom

Speaker 2 of 5
Albert R. La Spada, Duke University, USA
Defining a Transcriptional Regulatory Network for Autophagy Activation

Sunday, May 25 | 5:00PM - 7:00PM
Role of Autophagy in Neurodegeneration
Room: Texas Ballroom

Speaker 3 of 5
Patricia Boya, Centro de Investigaciones Biológicas, CSIC, Spain
Lysosome Dysfunction and Neurodegeneration

Sunday, May 25 | 5:00PM - 7:00PM
Role of Autophagy in Neurodegeneration
Room: Texas Ballroom

Speaker 4 of 5
David C. Rubinsztein, Cambridge Institute for Medical Research, UK
ATG16L1 Meets mATG9 in Recycling Endosomes - Additional Roles for the Plasma Membrane and Endocytosis in Autophagosome Biogenesis

Sunday, May 25 | 5:00PM - 7:00PM
Role of Autophagy in Neurodegeneration
Room: Texas Ballroom

Speaker 5 of 5
Veronika Redmann, Washington University, USA
Short Talk: Clec16A Plays a Critical Role in Autophagy and the Survival of Purkinje Cells

Sunday, May 25 | 7:00PM - 8:00PM
Social Hour with Lite Bites
Room: Texas Ballroom


Sunday, May 25 | 7:30PM - 10:00PM
Poster Session 2
Room: Texas Ballroom


Monday, May 26 | 7:30AM - 8:30AM
Breakfast
Room: Texas Ballroom


Monday, May 26 | 8:30AM - 11:45AM
Impact of Autophagy in Cancer
Room: Texas Ballroom

Speaker 1 of 7
* Beth Levine, University of Texas Southwestern Medical Center, USA

Monday, May 26 | 8:30AM - 11:45AM
Impact of Autophagy in Cancer
Room: Texas Ballroom

Speaker 2 of 7
Guido Kroemer, Cordeliers Research Center, France
Autophagy and Anticancer Immune Responses

Monday, May 26 | 8:30AM - 11:45AM
Impact of Autophagy in Cancer
Room: Texas Ballroom

Speaker 3 of 7
Ravi K. Amaravadi, University of Pennsylvania, USA
Targeting Autophagy for Cancer Therapy

Monday, May 26 | 8:30AM - 11:45AM
Impact of Autophagy in Cancer
Room: Texas Ballroom

Speaker 4 of 7
Jayanta Debnath, University of California, San Francisco, USA
Autophagy, Secretion and Cancer

Monday, May 26 | 8:30AM - 11:45AM
Impact of Autophagy in Cancer
Room: Texas Ballroom

Speaker 5 of 7
Eileen P. White, Rutgers Cancer Institute of New Jersey, USA
Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance

Monday, May 26 | 8:30AM - 11:45AM
Impact of Autophagy in Cancer
Room: Texas Ballroom

Speaker 6 of 7
Xian-De Liu, University of Texas MD Anderson Cancer Center, USA
Short Talk: Autophagy Mediates HIF2alpha Degradation and Suppresses Renal Tumorigenesis

Monday, May 26 | 8:30AM - 11:45AM
Impact of Autophagy in Cancer
Room: Texas Ballroom

Speaker 7 of 7
David L. Boone, Indiana University School of Medicine, USA
Short Talk: The Thr300Ala Variant in ATG16L1 Is Associated with Improved Survival in Human Colorectal Cancer and Enhanced Production of Type I Interferon

Monday, May 26 | 9:50AM - 10:10AM
Coffee Break
Room: Texas Foyer


Monday, May 26 | 11:45AM - 1:00PM
Poster Setup
Room: Texas Ballroom


Monday, May 26 | 11:45AM - 5:00PM
On Own for Lunch


Monday, May 26 | 1:00PM - 10:00PM
Poster Viewing
Room: Texas Ballroom


Monday, May 26 | 4:30PM - 5:00PM
Coffee Available
Room: Texas Foyer


Monday, May 26 | 5:00PM - 7:00PM
Pharmacological Manipulation of Autophagy
Room: Texas Ballroom

Speaker 1 of 5
* Ravi K. Amaravadi, University of Pennsylvania, USA

Monday, May 26 | 5:00PM - 7:00PM
Pharmacological Manipulation of Autophagy
Room: Texas Ballroom

Speaker 2 of 5
Christina H. Eng, Pfizer, USA
Are Atgs Good Oncology Drug Targets?

Monday, May 26 | 5:00PM - 7:00PM
Pharmacological Manipulation of Autophagy
Room: Texas Ballroom

Speaker 3 of 5
Natalie D'Amore, Takeda Boston, USA
Targeting Autophagy for Cancer Therapy

Monday, May 26 | 5:00PM - 7:00PM
Pharmacological Manipulation of Autophagy
Room: Texas Ballroom

Speaker 4 of 5
Junying Yuan, Harvard Medical School, USA
Chaperone-Mediated Autophagy Degrades Mutant p5

Monday, May 26 | 5:00PM - 7:00PM
Pharmacological Manipulation of Autophagy
Room: Texas Ballroom

Speaker 5 of 5
Xiaojun Tan, University of Wisconsin-Madison, USA
Short Talk: A Kinase Independent Role for EGF Receptor in Autophagy Initiation

Monday, May 26 | 7:00PM - 8:00PM
Social Hour with Lite Bites
Room: Texas Ballroom


Monday, May 26 | 7:30PM - 10:00PM
Poster Session 3
Room: Texas Ballroom


Tuesday, May 27 | 7:30AM - 8:30AM
Breakfast
Room: Texas Ballroom


Tuesday, May 27 | 8:30AM - 11:45AM
Autophagy and Disease
Room: Texas Ballroom

Speaker 1 of 7
* Junying Yuan, Harvard Medical School, USA

Tuesday, May 27 | 8:30AM - 11:45AM
Autophagy and Disease
Room: Texas Ballroom

Speaker 2 of 7
Beth Levine, University of Texas Southwestern Medical Center, USA
Autophagy and Immunity

Tuesday, May 27 | 8:30AM - 11:45AM
Autophagy and Disease
Room: Texas Ballroom

Speaker 3 of 7
Andrea Ballabio, Telethon Institute of Genetics and Medicine, Italy
The Transcriptional Control of Autophagy in Health and Disease

Tuesday, May 27 | 8:30AM - 11:45AM
Autophagy and Disease
Room: Texas Ballroom

Speaker 4 of 7
Ken H. Cadwell, New York University School of Medicine, USA
Anti-Inflammatory Functions of Autophagy in Crohn’s Disease and Beyond

Tuesday, May 27 | 8:30AM - 11:45AM
Autophagy and Disease
Room: Texas Ballroom

Speaker 5 of 7
Junichi Sadoshima, Rutgers New Jersey Medical School, USA
Autophagy and Cardiomyopathy

Tuesday, May 27 | 8:30AM - 11:45AM
Autophagy and Disease
Room: Texas Ballroom

Speaker 6 of 7
Qingjun Wang, University of Kentucky, USA
Short Talk: Novel Role of Juvenile Neuronal Ceroid Lipofuscinosis (Batten) Disease Gene CLN3 in Autophagy

Tuesday, May 27 | 8:30AM - 11:45AM
Autophagy and Disease
Room: Texas Ballroom

Speaker 7 of 7
Neng-Yu Lin, Friedrich Alexander University, Germany
Short Talk: Inhibition of Autophagy Ameliorates Inflammatory and Non-Inflammatory Bone Loss

Tuesday, May 27 | 9:50AM - 10:10AM
Coffee Break
Room: Texas Foyer


Tuesday, May 27 | 11:45AM - 2:30PM
On Own for Lunch


Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 1 of 10
* Christina H. Eng, Pfizer, USA

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 2 of 10
* Ana Maria Cuervo, Albert Einstein College of Medicine, USA

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 3 of 10
Hong Dou, University of Texas MD Anderson Cancer Center, USA
SUMO-Driven Autophagy Regulates DNA Replication

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 4 of 10
Seungmin (Sam) Hwang, University of Chicago, USA
Vesicle-Like Endomembrane Structures of Pathogens Are Targeted for Disruption by the Ubiquitin-Like Conjugation Systems of Macroautophagy Pathway

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 5 of 10
Wen-Xing Ding, University of Kansas Medical Center, USA
Excess Endoplasmic Reticulum Is Degraded by SQSTM1/p62-Mediated Selective Autophagy in Mammals

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 6 of 10
Taras Nazarko, Georgia State University, USA
Atg37/ACBD5 Is a New Important Component of the Pexophagic Receptor Protein Complex

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 7 of 10
Jon Sin, Heart Institute, Cedars-Sinai Medical Center, USA
Coxsackievirus B3 Escapes the Host Cell via Ejected Autophagosomes

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 8 of 10
Chengyu Liang, University of Southern California, USA
A Coordinator of Golgi-ER Transport and Atg9-Mediated Autophagy Trafficking

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 9 of 10
Michelangelo Campanella, RVC and UCL Consortium for Mitochondrial Research, UK
The 18kDa Translocator Protein Triggers a ROS-Mediated Inhibition of Mitochondrial Autophagy

Tuesday, May 27 | 2:30PM - 4:30PM
Workshop 2: Novel Functions of Autophagy
Room: Texas Ballroom

Speaker 10 of 10
Zaiming Tang, University of Texas Southwestern Medical Center, USA
Autophagy Promotes Primary Ciliogenesis

Tuesday, May 27 | 4:30PM - 5:00PM
Coffee Available
Room: Texas Foyer


Tuesday, May 27 | 5:00PM - 7:00PM
Interplay between Autophagy, Metabolism and Aging
Room: Texas Ballroom

Speaker 1 of 5
* Guido Kroemer, Cordeliers Research Center, France

Tuesday, May 27 | 5:00PM - 7:00PM
Interplay between Autophagy, Metabolism and Aging
Room: Texas Ballroom

Speaker 2 of 5
Ana Maria Cuervo, Albert Einstein College of Medicine, USA
Selective Autophagy and Metabolism in Aging

Tuesday, May 27 | 5:00PM - 7:00PM
Interplay between Autophagy, Metabolism and Aging
Room: Texas Ballroom

Speaker 3 of 5
Frank Madeo, University of Graz, Austria
Spermidine Induced Autophagy for the Avoidance of Age-Associated Diseases

Tuesday, May 27 | 5:00PM - 7:00PM
Interplay between Autophagy, Metabolism and Aging
Room: Texas Ballroom

Speaker 4 of 5
Myung-Shik Lee, Yonsei University College of Medicine, South Korea
Role of Autophagy in Obesity and Diabetes

Tuesday, May 27 | 5:00PM - 7:00PM
Interplay between Autophagy, Metabolism and Aging
Room: Texas Ballroom

Speaker 5 of 5
Louis R. Lapierre, Brown University, USA
Short Talk: HLH-30/TFEB Is a Conserved Regulator of Autophagy and Modulates Longevity in C. elegans

Tuesday, May 27 | 7:00PM - 8:00PM
Social Hour with Lite Bites
Room: Texas Ballroom


Tuesday, May 27 | 8:00PM - 11:00PM
Entertainment
Room: Texas Ballroom


Tuesday, May 27 | 8:00PM - 11:00PM
Cash Bar
Room: Texas Ballroom


Wednesday, May 28 | 10:25AM - 10:25AM
Departure


*Session Chair.