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  • Article
    Pseudouridines in U2 snRNA stimulate the ATPase activity of Prp5 during spliceosome assembly
    Pseudouridines in U2 snRNA stimulate the ATPase activity of Prp5 during spliceosome assembly
    1. Guowei Wu14,
    2. Hironori Adachi1,
    3. Junhui Ge2,
    4. David Stephenson1,
    5. Charles C Query3 and
    6. Yi‐Tao Yu*,1
    1. 1Department of Biochemistry and Biophysics, Center for RNA Biology, The Rochester Aging Research (RoAR) Center, University of Rochester Medical Center, Rochester, NY, USA
    2. 2Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai, China
    3. 3Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
    4. 4Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA
    1. *Corresponding author. Tel: +1 585 275 1271; Fax: +1 585 275 6007; E‐mail: yitao_yu{at}urmc.rochester.edu

    Activation of the DEAD‐box helicase Prp5 requires pseudouridine formation, shedding light on the regulatory potential of such increasingly recognized RNA modifications.

    Synopsis

    Activation of the DEAD‐box helicase Prp5 requires pseudouridine formation, shedding light on the regulatory potential of such increasingly recognized RNA modifications.

    • Pseudouridines (Ψ35, Ψ42, and Ψ44) in the U2 branch site recognition region are important for spliceosome assembly, pre‐mRNA splicing, and cell growth.

    • Ψ42 and Ψ44 interact genetically with Prp5 and promote direct interaction of U2 with Prp5.

    • U2 pseudouridylation also stimulates Prp5's RNA‐dependent ATPase activity.

    • Pseudouridylation alters the U2 local structure, thereby contributing to Prp5 binding.

    • Prp5 ATPase
    • pseudouridylation
    • spliceosome assembly
    • splicing
    • U2 snRNA
    • Received September 21, 2015.
    • Revision received December 19, 2015.
    • Accepted January 4, 2016.
    Guowei Wu, Hironori Adachi, Junhui Ge, David Stephenson, Charles C Query, Yi‐Tao Yu
  • Article
    Molecular basis of ion permeability in a voltage‐gated sodium channel
    Molecular basis of ion permeability in a voltage‐gated sodium channel
    1. Claire E Naylor1,,
    2. Claire Bagnéris1,,
    3. Paul G DeCaen2,3,
    4. Altin Sula1,
    5. Antonella Scaglione2,34,
    6. David E Clapham2,3 and
    7. B A Wallace*,1
    1. 1Institute of Structural and Molecular Biology, Birkbeck College University of London, London, UK
    2. 2Department of Cardiology, Howard Hughes Medical Institute Boston Children's Hospital, Boston, MA, USA
    3. 3Department of Neurobiology, Harvard Medical School, Boston, MA, USA
    4. 4Department of Biochemical Sciences, Institute of Molecular Biology and Pathology of CNR Sapienza University of Rome, Rome, Italy
    1. *Corresponding author. Tel: +44 207 6316800; E‐mail: b.wallace{at}mail.cryst.bbk.ac.uk
    1. These authors contributed equally to this work

    Structural localisation of sodium ions passing through the prokaryotic NavM channel selectivity filter explains this channel's strong sodium preference over other cations in electrochemical signalling across cell membranes.

    Synopsis

    Structural localisation of sodium ions passing through the prokaryotic NavM channel selectivity filter explains this channel's strong sodium preference over other cations in electrochemical signalling across cell membranes.

    • Crystal structures of the NavMs prokaryotic sodium channel indicate the locations of sodium ions in its selectivity filter.

    • Electrostatic calculations based on the structure are consistent with the relative cation permeability ratios measured for these channels.

    • An E178D selectivity filter mutant constructed to validate the structure/function relationships has altered ion preference, and the sodium ion binding site nearest the extracellular side is missing.

    • The sodium ions appear to be hydrated and are associated with side chains of the filter residues.

    • crystal structure
    • electrophysiology
    • ion permeability
    • sodium channel
    • Received October 15, 2015.
    • Revision received January 16, 2016.
    • Accepted January 18, 2016.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Claire E Naylor, Claire Bagnéris, Paul G DeCaen, Altin Sula, Antonella Scaglione, David E Clapham, B A Wallace
  • Article
    ALS‐linked protein disulfide isomerase variants cause motor dysfunction
    ALS‐linked protein disulfide isomerase variants cause motor dysfunction
    1. Ute Woehlbier1,2,3,
    2. Alicia Colombo4,5,
    3. Mirva J Saaranen6,
    4. Viviana Pérez7,
    5. Jorge Ojeda7,
    6. Fernando J Bustos8,
    7. Catherine I Andreu1,2,
    8. Mauricio Torres1,2,
    9. Vicente Valenzuela1,2,9,
    10. Danilo B Medinas1,2,9,
    11. Pablo Rozas1,2,
    12. Rene L Vidal1,9,10,
    13. Rodrigo Lopez‐Gonzalez11,
    14. Johnny Salameh11,
    15. Sara Fernandez‐Collemann12,
    16. Natalia Muñoz1,9,10,
    17. Soledad Matus1,9,10,
    18. Ricardo Armisen2,
    19. Alfredo Sagredo2,
    20. Karina Palma1,2,
    21. Thergiory Irrazabal1,2,
    22. Sandra Almeida11,
    23. Paloma Gonzalez‐Perez11,
    24. Mario Campero13,14,
    25. Fen‐Biao Gao11,
    26. Pablo Henny12,
    27. Brigitte van Zundert8,
    28. Lloyd W Ruddock6,
    29. Miguel L Concha1,4,9,
    30. Juan P Henriquez7,
    31. Robert H Brown*,11 and
    32. Claudio Hetz*,1,2,9,15
    1. 1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
    2. 2Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
    3. 3Center for Genomics and Bioinformatics, Universidad Mayor, Santiago, Chile
    4. 4Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
    5. 5Department of Pathological Anatomy, Hospital Clínico, University of Chile, Santiago, Chile
    6. 6Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
    7. 7Department of Cell Biology, Faculty of Biological Sciences, Millennium Nucleus of Regenerative Biology, Center for Advanced Microscopy (CMA Bio‐Bio), Universidad de Concepción, Concepción, Chile
    8. 8Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile
    9. 9Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
    10. 10Neurounion Biomedical Foundation, CENPAR, Santiago, Chile
    11. 11Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA
    12. 12Department of Anatomy, Medical School, Universidad Católica de Chile, Santiago, Chile
    13. 13Department of Neurology and Neurosurgery, Faculty of Medicine, University of Chile, Santiago, Chile
    14. 14Faculty of Medicine, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
    15. 15Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
    1. * Corresponding author. Tel: +1 508 334 1271; E‐mail: robert.brown{at}umassmed.edu
      Corresponding author. Tel: +56 2 978 6506; E‐mails: clahetz{at}med.uchile.cl chetz{at}hsph.harvard.edu

    Disease phenotypes associated with expression of mutant PDIA1 and ERp57 show how impaired ER proteostasis can drive initial stages of amyotrophic lateral sclerosis pathology.

    Synopsis

    The degeneration of motoneurons in ALS is associated with a chronic endoplasmic reticulum (ER) stress response. Here we report the consequences of mutations of two major ER foldases in ALS known as PDIA1 and ERp57. Expression of these ALS‐linked mutants trigger some cardinal features of ALS, including the disruption of motoneuron connectivity and function, highlighting ER proteostasis imbalance as a driver of the initial stages of the disease.

    • ALS‐linked mutations in PDIA1 and ERp57 adversely affect PDI structure and function.

    • PDI mutants cause abnormal motoneuron morphology and functionality.

    • Targeting of ERp57 in the CNS results in premature death and impaired motor control.

    • ERp57 deficiency causes alterations of neuromuscular junctions.

    • amyotrophic lateral sclerosis
    • ERp57
    • PDIA1
    • protein disulfide isomerase
    • Received June 6, 2015.
    • Revision received December 27, 2015.
    • Accepted January 5, 2016.
    Ute Woehlbier, Alicia Colombo, Mirva J Saaranen, Viviana Pérez, Jorge Ojeda, Fernando J Bustos, Catherine I Andreu, Mauricio Torres, Vicente Valenzuela, Danilo B Medinas, Pablo Rozas, Rene L Vidal, Rodrigo Lopez‐Gonzalez, Johnny Salameh, Sara Fernandez‐Collemann, Natalia Muñoz, Soledad Matus, Ricardo Armisen, Alfredo Sagredo, Karina Palma, Thergiory Irrazabal, Sandra Almeida, Paloma Gonzalez‐Perez, Mario Campero, Fen‐Biao Gao, Pablo Henny, Brigitte van Zundert, Lloyd W Ruddock, Miguel L Concha, Juan P Henriquez, Robert H Brown, Claudio Hetz
  • Article
    Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis
    Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis
    1. Christian Lange1,2,
    2. Miguel Turrero Garcia3,
    3. Ilaria Decimo1,2,
    4. Francesco Bifari1,2,
    5. Guy Eelen1,2,
    6. Annelies Quaegebeur1,2,
    7. Ruben Boon1,2,
    8. Hui Zhao4,5,
    9. Bram Boeckx4,5,
    10. Junlei Chang6,
    11. Christine Wu6,
    12. Ferdinand Le Noble7,8,
    13. Diether Lambrechts4,5,
    14. Mieke Dewerchin1,2,
    15. Calvin J Kuo6,
    16. Wieland B Huttner3 and
    17. Peter Carmeliet*,1,2
    1. 1Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium
    2. 2Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium
    3. 3Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    4. 4Laboratory of Translational Genetics, Vesalius Research Center, VIB, Leuven, Belgium
    5. 5Laboratory of Translational Genetics, Department of Oncology, KU Leuven Leuven, Belgium
    6. 6Department of Medicine, Hematology Division Stanford University, Stanford, CA, USA
    7. 7Angiogenesis and Cardiovascular Pathology, Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany
    8. 8Department of Cell and Developmental Biology, KIT, Karlsruhe, Germany
    1. *Corresponding author. Tel: +32 16 37 32 02; Fax: +32 16 37 25 85; E‐mail: peter.carmeliet{at}vib-kuleuven.be

    Blood vessel formation in mammalian brain development promotes neural stem cell differentiation by triggering a cascade of tissue oxygenation, reduced activity of HIF‐1α and blunted glycolytic metabolism that favors the switch towards neurogenesis.

    Synopsis

    Blood vessel formation in mammalian brain development promotes neural stem cell differentiation by triggering a cascade of tissue oxygenation, reduced activity of HIF‐1α and blunted glycolytic metabolism that favors the switch towards neurogenesis. An animated version of this synopsis is available online at: http://embopress.org/video_EMBOJ-2015-92372.

    • Absence of blood vessels reduces neural stem cell (NSC) differentiation in development.

    • Restoring oxygenation rescues NSC differentiation in the absence of normal vessels.

    • HIF‐1α levels regulate the switch of NSC expansion to differentiation in the cortex.

    • The glycolytic regulator and HIF target gene Pfkfb3 is critically required for normal NSC expansion and upon HIF‐1α stabilization.

    • hypoxia
    • neural stem cell
    • neurogenesis
    • stem cell metabolism
    • vascular niche
    • Received June 23, 2015.
    • Revision received December 22, 2015.
    • Accepted January 5, 2016.
    Christian Lange, Miguel Turrero Garcia, Ilaria Decimo, Francesco Bifari, Guy Eelen, Annelies Quaegebeur, Ruben Boon, Hui Zhao, Bram Boeckx, Junlei Chang, Christine Wu, Ferdinand Le Noble, Diether Lambrechts, Mieke Dewerchin, Calvin J Kuo, Wieland B Huttner, Peter Carmeliet
  • Article
    Mitochondria are required for pro‐ageing features of the senescent phenotype
    Mitochondria are required for pro‐ageing features of the senescent phenotype
    1. Clara Correia‐Melo1,2,
    2. Francisco DM Marques1,
    3. Rhys Anderson1,
    4. Graeme Hewitt1,
    5. Rachael Hewitt3,
    6. John Cole3,
    7. Bernadette M Carroll1,
    8. Satomi Miwa1,
    9. Jodie Birch1,
    10. Alina Merz1,
    11. Michael D Rushton1,
    12. Michelle Charles1,
    13. Diana Jurk1,
    14. Stephen WG Tait3,
    15. Rafal Czapiewski1,
    16. Laura Greaves4,
    17. Glyn Nelson1,
    18. Mohammad Bohlooly‐Y5,
    19. Sergio Rodriguez‐Cuenca6,
    20. Antonio Vidal‐Puig6,
    21. Derek Mann7,
    22. Gabriele Saretzki1,
    23. Giovanni Quarato8,
    24. Douglas R Green8,
    25. Peter D Adams3,
    26. Thomas von Zglinicki1,
    27. Viktor I Korolchuk1 and
    28. João F Passos*,1
    1. 1Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK
    2. 2GABBA Program, Abel Salazar Biomedical Sciences Institute University of Porto, Porto, Portugal
    3. 3Institute of Cancer Sciences, CR‐UK Beatson Institute, University of Glasgow, Glasgow, UK
    4. 4Wellcome Trust Centre for Mitochondrial Research, Newcastle University Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK
    5. 5Transgenic RAD, Discovery Sciences, AstraZeneca, Mölndal, Sweden
    6. 6Metabolic Research Laboratories, Wellcome Trust‐MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
    7. 7Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    8. 8Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
    1. *Corresponding author. Tel: +44 191 248 1222; Fax: +44 191 248 1101; E‐mail: joao.passos{at}ncl.ac.uk

    Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.

    Synopsis

    Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.

    • Mitochondria are required for the development of the pro‐oxidant and pro‐inflammatory features of senescence.

    • ATM, Akt, mTOR and PGC‐1β‐mediated mitochondrial biogenesis are involved in a novel senescence signalling pathway.

    • Mitochondrial biogenesis stabilizes senescence via a positive feedback loop involving ROS and the DDR.

    • ageing
    • inflammation
    • mitochondria
    • mTOR
    • senescence
    • Received August 19, 2015.
    • Revision received January 9, 2016.
    • Accepted January 12, 2016.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Clara Correia‐Melo, Francisco DM Marques, Rhys Anderson, Graeme Hewitt, Rachael Hewitt, John Cole, Bernadette M Carroll, Satomi Miwa, Jodie Birch, Alina Merz, Michael D Rushton, Michelle Charles, Diana Jurk, Stephen WG Tait, Rafal Czapiewski, Laura Greaves, Glyn Nelson, Mohammad Bohlooly‐Y, Sergio Rodriguez‐Cuenca, Antonio Vidal‐Puig, Derek Mann, Gabriele Saretzki, Giovanni Quarato, Douglas R Green, Peter D Adams, Thomas von Zglinicki, Viktor I Korolchuk, João F Passos
  • Article
    p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration
    p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration
    1. Bárbara González‐Terán1,,
    2. Nuria Matesanz1,,
    3. Ivana Nikolic1,,
    4. María Angeles Verdugo1,2,
    5. Vinatha Sreeramkumar1,
    6. Lourdes Hernández‐Cosido3,4,
    7. Alfonso Mora1,
    8. Georgiana Crainiciuc1,
    9. María Laura Sáiz1,
    10. Edgar Bernardo1,
    11. Luis Leiva‐Vega1,
    12. Elena Rodríguez1,
    13. Victor Bondía1,
    14. Jorge L Torres5,6,
    15. Sonia Perez‐Sieira7,8,
    16. Luis Ortega3,4,
    17. Ana Cuenda2,
    18. Francisco Sanchez‐Madrid1,
    19. Rubén Nogueiras7,8,
    20. Andrés Hidalgo1,
    21. Miguel Marcos5,6 and
    22. Guadalupe Sabio*,1
    1. 1Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
    2. 2Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    3. 3Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain
    4. 4Department of Surgery, University of Salamanca, Salamanca, Spain
    5. 5Department of Internal Medicine, University Hospital of Salamanca‐IBSAL, Salamanca, Spain
    6. 6Department of Medicine, University of Salamanca, Salamanca, Spain
    7. 7Department of Physiology, CIMUS, University of Santiago de Compostela‐Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
    8. 8CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
    1. *Corresponding author. Tel: +34 91453 12 00; E‐mail: guadalupe.sabio{at}cnic.es
    1. These authors contributed equally to this work

    Mice lacking p38γ/δ in myeloid cells are protected against diet‐induced fatty liver. This effect is due to defective migration of p38γ/δ‐deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes.

    Synopsis

    Mice lacking p38γ/δ in myeloid cells are protected against diet‐induced fatty liver. This effect is due to defective migration of p38γ/δ‐deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes.

    • Expression of p38δ and p38γ is elevated in the liver from patients with non‐alcoholic fatty liver disease (NAFLD).

    • p38γ/δ KO and myeloid‐specific p38γ/δ cKO mice are resistant to hepatic steatosis induced by high‐fat diet or methionine‐choline‐deficient diet.

    • p38γ/δ control neutrophil migration to the damaged liver.

    • Migration of neutrophils to the liver is necessary for the development of steatosis.

    • diabetes
    • inflammation
    • obesity
    • steatosis
    • stress kinases
    • Received April 20, 2015.
    • Revision received December 18, 2015.
    • Accepted December 22, 2015.
    Bárbara González‐Terán, Nuria Matesanz, Ivana Nikolic, María Angeles Verdugo, Vinatha Sreeramkumar, Lourdes Hernández‐Cosido, Alfonso Mora, Georgiana Crainiciuc, María Laura Sáiz, Edgar Bernardo, Luis Leiva‐Vega, Elena Rodríguez, Victor Bondía, Jorge L Torres, Sonia Perez‐Sieira, Luis Ortega, Ana Cuenda, Francisco Sanchez‐Madrid, Rubén Nogueiras, Andrés Hidalgo, Miguel Marcos, Guadalupe Sabio
  • Article
    PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L‐associated PI3K activity
    PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L‐associated PI3K activity
    1. Da‐Qian Xu1,
    2. Zheng Wang1,
    3. Chen‐Yao Wang1,
    4. De‐Yi Zhang1,
    5. Hui‐Da Wan2,
    6. Zi‐Long Zhao1,
    7. Jin Gu1,
    8. Yong‐Xian Zhang1,
    9. Zhi‐Gang Li1,
    10. Kai‐Yang Man1,3,
    11. Yi Pan1,
    12. Zhi‐Fei Wang4,
    13. Zun‐Ji Ke4,
    14. Zhi‐Xue Liu1,
    15. Lu‐Jian Liao2 and
    16. Yan Chen*,1,3
    1. 1Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
    2. 2Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China
    3. 3School of Life Sciences and Technology, Shanghai Tech University, Shanghai, China
    4. 4School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
    1. *Corresponding author. Tel: +86 21 54920916; E‐mail: ychen3{at}sibs.ac.cn

    Golgi‐resident protein PAQR3 facilitates formation of the autophagy‐initiating ATG14L–VPS34 complex. Upon glucose starvation, AMPK phosphorylates PAQR3 to enhance this function, thus integrating nutrient sensing with VPS34 activity.

    Synopsis

    Golgi‐resident protein PAQR3 facilitates formation of the autophagy‐initiating ATG14L–VPS34 complex. Upon glucose starvation, AMPK phosphorylates PAQR3 to enhance this function, thus integrating nutrient sensing with VPS34 activity.

    • PAQR3 enhances autophagosome formation and ATG14L‐linked class III PI3K activity without altering AMPK or mTOR activity.

    • PAQR3 facilitates the formation of the ATG14L‐linked VPS34 complex, but not the UVRAG‐associated VPS34 complex.

    • PAQR3 T32 is phosphorylated by AMPK upon glucose starvation in an ATG14L‐dependent manner.

    • PAQR3 T32 phosphorylation is required for ATG14L‐linked class III PI3K activation and autophagy initiation upon glucose starvation.

    • PAQR3‐deleted mice display deficiencies in exercise‐induced autophagy as well as behavioral disorders.

    • AMPK
    • autophagy
    • class III PI3K
    • glucose starvation
    • PAQR3
    • Received August 18, 2015.
    • Revision received December 24, 2015.
    • Accepted January 4, 2016.

    This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

    Da‐Qian Xu, Zheng Wang, Chen‐Yao Wang, De‐Yi Zhang, Hui‐Da Wan, Zi‐Long Zhao, Jin Gu, Yong‐Xian Zhang, Zhi‐Gang Li, Kai‐Yang Man, Yi Pan, Zhi‐Fei Wang, Zun‐Ji Ke, Zhi‐Xue Liu, Lu‐Jian Liao, Yan Chen