Joyce Jean Lu, Ph.D.
Name Joyce Jean Lu, Ph.D.
Position Associate Professor
所屬單位

stem cell renewal, de-differentiation, reprogramming, differentiation, embryonic stem cells, mesenchymal stem cells, totipotent, retinal progenitor cells. high-throughput functional screen

Ph.D. Institute of Microbiology, National Taiwan University, Taipei, Taiwan. 1995-2000
M.S. Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan. 1992-1994
B.S. Department of Medical Technology, National Taiwan University, Taipei, Taiwan. 1988-1992
名片 In Memory of
Dr. Joyce Jean Lu
研究方向/領域

RESEARCH INTERESTS

Stem cell renewal/de-differentiation/differentiation is important for stem cell biology and regenerative medicine. To efficiently pinpoint factors critical for cell fate determination, systematic functional screens were performed in mouse embryonic stem cells (ESCs), human ESCs, and mesenchymal stem cells (MSCs). We established the first shRNA screen in ESCs. With a shRNA library of kinases and phosphatases containing 4796 shRNAs, we identified 244 genes essential for ESC renewal. Among them, Nme6 and Nme7 are necessary for 8 stemness gene expressions. With 517 shRNA target genes differentially expressed in undifferentiated human ESCs, we performed a shRNA functional screen and found 86 genes essential for human ESC renewal. Two candidate genes, either bridging the oxidation and reduction status of ESCs with stemness signals, or blocking neural stem cell differentiation, are currently being studied in-depth.

To fulfill the unmet need for bone diseases, a gain-of-function screen was performed with an overexpression library containing 12380 genes. 9 candidate genes are found to be essential and sufficient to promote the osteogenesis of human MSCs. By this method, we found soluble factors that can completely treat and prevent osteoporosis.

In addition, we found PODXL/cholesterol pathway can promote human mouse chimerism by up to 57% and published in Advanced Science (impact factor 17.521).  Recently, how to dedifferentiate/reprogram stem cells into totipotency that can differentiate stem cells into all cell types has become an important topic. We develop a novel cocktail that can uniquely trigger the reprogramming of totipotent stem cells.We also differentiate fibroblasts into mesenchymal stem cells, oligodendrocytes, and retinal progenitor cells. We won the 2024 Future Technology Award and the 2023 National Innovation Award. Thus, we found many factors play critical roles in ESC/ MSC/fibroblast renewal, de-differentiation, and differentiation by systematically functional screens. (edited by ChatGPT)


jeanlu1
EDUCATION AND POSITIONS HELD
  • 2018-2025 Adjunct Associate Professor, Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
  • 2016-2025 Adjunct Associate Professor, Department of Life Science, Tzu Chi University, Hualien, Taiwan
  • 2015-2025 Associate Research Fellow, Genomics Research Center, Academia Sinica, Taiwan
  • 2015-2025 Adjunct Associate Professor, Genomics and System Biology Program, College of Life Science, National Taiwan University, Taiwan
  • 2009-2023 Co-PI, National RNAicore Facility Plateform
  • 2007-2015 Assistant Research Fellow, Stem Cell Program, Genomics Research Center, Academia Sinica, Taiwan
  • 2010-2015 Adjunct Assistant Professor, Genomics and System Biology Program, College of Life Science, National Taiwan University, Taiwan
  • 2003-2007 Postdoctoral Fellow/Associate, Molecular, Department of Cellular, and Developmental Biology, Yale University, USA
  • 2001-2003 Postdoctoral Fellow, Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taiwan
  • 1994-1995 Research Assistant, Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taiwan
HONORS
  • 2024 Future Technology Award
  • 2023 National Innovation Award
  • 2017 Keystone symposia scholarship. Regeneration Biology and applications: cell differentiation, tissue organization and biomedical engineering.
  • 2003-2005 Ruth L. Kirschstein National Research Service Award Fellowship, Ruth L. Kirschstein
  • 2002 Outstanding Paper Award (National Taiwan University)
survival., Blood, vol. 128(12), 1578-89, 2016具代表性; 任職中研院著作;
Year Paper Title
2024 Chen WJ, Chao YY, Huang WK, Chang WF, Tzeng CR, Chuang CH, Lai PL, Schuyler SC, Li LY, (Lu J)*, Identification of apelin/APJ signaling dysregulation in a human iPSC-derived granulosa cell model of Turner syndrome., Cell death discovery, vol. 10(1), 468, 2024任職中研院著作;
2024 Tsai YF, Fang MC, Chen CH, Yu IS, Shun CT, Tao MH, Sun CP, (Lu J, Sheu JC, Hsu YC*, Lin SW*, Enhancement of adult liver regeneration in mice through the hepsin-mediated epidermal growth factor receptor signaling pathway., Communications biology, vol. 7(1), 1672, 2024任職中研院著作;
2023 Chen WJ, Huang WK, Pather SR, Chang WF, Sung LY, Wu HC, Liao MY, Lee CC, Wu HH, Wu CY, Liao KS, Lin CY, Yang SC, Lin H, Lai PL, Ng CH, Hu CM, Chen IC, Chuang CH, Lai CY, Lin PY, Lee YC, Schuyler SC, Schambach A, Lu FL, (Lu J*, Podocalyxin-Like Protein 1 Regulates Pluripotency through the Cholesterol Biosynthesis Pathway., Advanced science (Weinheim, Baden-Wurttemberg, Germany), vol. 10(1), e2205451, 2023具代表性; 任職中研院著作;
2022 Yadav A, Ramasamy TS, Lin SC, Chen SH, （Lu J）, Liu YH, Lu FI, Hsueh YY, Lin SP, Wu CC, Autologous Platelet-Rich Growth Factor Reduces M1 Macrophages and Modulates Inflammatory Microenvironments to Promote Sciatic Nerve Regeneration., Biomedicines, vol. 10(8), 1991, 2022具代表性; 任職中研院著作;
2022 Lai PL, Ng CH, Wu CH, Lai CY, Schuyler SC, Wang V, Lin H, Lee YC, Chuang MH, Yang CH, Chen WJ, Huang HC, ( Lu J*, Development of a Chemical Cocktail That Rescues Mouse Brain Demyelination in a Cuprizone-Induced Model., Cells, vol. 11(7), 1091, 2022任職中研院著作;
2021 Lai YP, Kuo LC, Lin BR, Lin HJ, Lin CY, Chen YT, Hsiao PW, Chang HT, Ko PC, Chen HC, Chang HY, Lu J, Ho HN, Wu-Hsieh BA, Kung JT, Chen SC, CD28 engagement inhibits CD73-mediated regulatory activity of CD8(+) T cells., Communications biology, vol. 4(1), 595, 2021任職中研院著作;
2021 Lin PY, Yang D, Chuang CH, Lin H, Chen WJ, Chen CY, Chuang TJ, Lai CY, Li LY, Schuyler SC, Lu FL, Liu YC, (Lu J)*, Comparative analyses of single-cell transcriptomic profiles between In vitro totipotent blastomere-like cells and In vivo early mouse embryonic cells, CELLS, vol. 10(11), 3111, 2021具代表性; 任職中研院著作;
2020 Lai Pei‑Lun, Chen Ting‑Chun, Feng Chun‑Yen, Lin Hsuan, Ng Chi‑Hou, Chen Yun, Hsiao Michael, (Lu Jean)*, Huang Hsiao‑Chun*, Selection of a malignant subpopulation from a colorectal cancer cell line, Oncology Letters, vol. 20(3), 2937-2945, 2020具代表性; 任職中研院著作;
2020 Nguyen Mai-Huong Thi, Lin Chen-Huan, Liu Szu-Mam, Miyashita Azusa, Ihn Hironobu, Lin Hsuan, Ng Chi Hou, Tsai Jen-Chieh, Chen Ming-Hong, Tsai Mu-Shiun, Lin In-Yu, Liu Shu-Chen, Li Long-Yuan, Fukushima Satoshi*, (Lu Jean)*, Ma Nianhan*, miR-524-5p reduces the progression of the BRAF inhibitor-resistant melanoma, Neoplasia, vol. 22(12), 789-799, 2020具代表性; 任職中研院著作;
2020 Cheng Chih-Lun, Yang Shang-Chih, Lai Chien-Ying, Wang Cheng-Kai, Chang Ching-Fang, Lin Chun-Yu, Chen Wei-Ju, Lin Po-Yu, Wu Han-Chung, Ma Nianhan, Lu Frank Leigh*, (Lu Jean)*, CXCL14 Maintains hESC Self-Renewal through Binding to IGF-1R and Activation of the IGF-1R Pathway, Cells, vol. 9(7), 1706, 2020具代表性; 任職中研院著作;
2019 Yang SC, Liu JJ, Wang CK, Lin YT, Tsai SY, Chen WJ, Huang WK, Tu PA, Lin YC, Chang CF, Cheng CL, Lin H, Lai CY, Lin CY, Lee YH, Chiu YC, Hsu CC, Hsu SC, Hsiao M, Schuyler SC, Lu FL＊, （Lu J＊）, Down-regulation of ATF1 leads to early neuroectoderm differentiation of human embryonic stem cells by increasing the expression level of SOX2., FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 33(9), 10577-10592, 2019具代表性; 任職中研院著作;
2019 Kuan II, Lee CC, Chen CH, (Lu J, Kuo YS, Wu HC, The extracellular domain of epithelial cell adhesion molecule (EpCAM) enhances multipotency of mesenchymal stem cells through EGFR-LIN28-LET7 signaling., The Journal of biological chemistry, vol. 294(19), 7769-7786, 2019具代表性; 任職中研院著作;
2018 Liu SM, Lin CH, (Lu J, Lin IY, Tsai MS, Chen MH, Ma N, miR-596 Modulates Melanoma Growth by Regulating Cell Survival and Death., The Journal of investigative dermatology, vol. 138(4), 911-921, 2018具代表性; 任職中研院著作;
2018 Chang HC, Huang PH, Syu FS, Hsieh CH, Chang SL, Lu J*, Chen HC*, Critical involvement of atypical chemokine receptor CXCR7 in allergic airway inflammation., Immunology, vol. 154(2), 274-284, 2018具代表性; 任職中研院著作;
2017 Hsieh MH, Chen YT, Chen YT, Lee YH, (Lu J, Chien CL, Chen HF, Ho HN, Yu CJ, Wang ZQ, Teng SC, PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells., Nucleic acids research, vol. 45(18), 10492-10503, 2017具代表性; 任職中研院著作;
2017 Kuan II, Liang KH, Wang YP, Kuo TW, Meir YJ, Wu SC, Yang SC, (Lu J)*, Wu HC*, EpEX/EpCAM and Oct4 or Klf4 alone are sufficient to generate induced pluripotent stem cells through STAT3 and HIF2alpha., Scientific reports, vol. 7, 41852, 2017具代表性; 任職中研院著作;
2017 Lin YT, Wang CK, Yang SC, Hsu SC, Lin H, Chang FP, Kuo TC, Shen CN, Chiang PM, Hsiao M, Lu FL, (Lu J)*, Elimination of undifferentiated human embryonic stem cells by cardiac glycosides., Scientific reports, vol. 7(1), 5289, 2017具代表性; 任職中研院著作;
2017 Lai PL, Lin H, Chen SF, Yang SC, Hung KH, Chang CF, Chang HY, Lu FL, Lee YH, Liu YC, Huang HC*, (Lu J)*, Efficient Generation of Chemically Induced Mesenchymal Stem Cells from Human Dermal Fibroblasts., Scientific reports, vol. 7, 44534, 2017具代表性; 任職中研院著作;
2017 Wang CK, Yang SC, Hsu SC, Chang FP, Lin YT, Chen SF, Cheng CL, Hsiao M, Lu FL, (Lu J)*, CHAC2 is essential for self-renewal and glutathione maintenance in human embryonic stem cells., Free radical biology & medicine, vol. 113, 439-451, 2017具代表性; 任職中研院著作;
2016 Huang YC, Lin SJ, Lin KM, Chou YC, Lin CW, Yu SC, Chen CL, Shen TL, Chen CK, Lu J, Chen MR, Tsai CH, Regulation of EBV LMP1-triggered EphA4 downregulation in EBV-associated B lymphoma and its impact on patients
2016 Chang WF, Hwu YM, Xu J, Lin CJ, Wang SW, Cheng AS, (Lu J, Lu CH, Sung LY, Derivation of Patient Specific Pluripotent Stem Cells Using Clinically Discarded Cumulus Cells., PloS one, vol. 11(11), e0165715, 2016具代表性; 任職中研院著作;
2015 Wu, C. C., Wu, H.C., Chen, W.J, Wang, C.H, Lin, C.H., Hsu, S.C., Chen, Y.R., Hsiao, M., Schuyler, S.C., Lu, F. L., Ma, N.H., Lu, J.)*., Suppression of Dual leucine zipper-bearing Kinase activity by Akt is required for mouse embryonic stem cell self-renewal, CELL CYCLE, vol. 14(8), 1207-1217, 2015具代表性; 任職中研院著作;
2015 Chua HH, Tsuei DJ, Lee PH, Jeng YM, (Lu J, Wu JF, Su DS, Chen YH, Chien CS, Kao PC, Lee CN, Hu RH, Ni YH, Chang MH, RBMY, a novel inhibitor of glycogen synthase kinase 3beta, increases tumor stemness and predicts poor prognosis of hepatocellular carcinoma., Hepatology, vol. 62(5), 1480-96, 2015具代表性; 任職中研院著作;
2015 Chang JS, Su CY, Yu WH, Lee WJ, Liu YP, Lai TC, Jan YH, Yang YF, Shen CN, Shew JY, (Lu J, Yang CJ, Huang MS, Lu PJ, Lin YF, Kuo ML, Hua KT, Hsiao M, GIT1 promotes lung cancer cell metastasis through modulating Rac1/Cdc42 activity and is associated with poor prognosis., Oncotarget, vol. 6(34), 36278-91, 2015具代表性; 任職中研院著作;
2014 Lin SJ, Lo M, Kuo RL, Shih SR, Ojcius DM, (Lu J, Lee CK, Chen HC, Lin MY, Leu CM, Lin CN, Tsai CH, The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection., Journal of biomedical science, vol. 21, 99-117, 2014任職中研院著作;
2014 Yang YF, Jan YH, Liu YP, Yang CJ, Su CY, Chang YC, Lai TC, Chiou J, Tsai HY, (Lu J, Shen CN, Shew JY, Lu PJ, Lin YF, Huang MS, Hsiao M, Squalene synthase induces tumor necrosis factor receptor 1 enrichment in lipid rafts to promote lung cancer metastasis., American journal of respiratory and critical care medicine, vol. 190(6), 675-687, 2014具代表性; 任職中研院著作;
2014 Liu SM, (Lu J, Lee HC, Chung FH, Ma N, miR-524-5p suppresses the growth of oncogenic BRAF melanoma by targeting BRAF and ERK2., Oncotarget, vol. 5(19), 9444-9459, 2014具代表性; 任職中研院著作;
2014 Liu YC, Kao YT, Huang WK, Lin KY, Wu SC, Hsu SC, Schuyler SC, Li LY, Leigh Lu F, (Lu J*, CCL5/RANTES is important for inducing osteogenesis of human mesenchymal stem cells and is regulated by dexamethasone., Bioscience trends, vol. 8(3), 138-143, 2014具代表性; 任職中研院著作;
2014 Huang HN, Chen SY, Hwang SM, Su MW, Mai W, Wang HW, Cheng WC, Schuyler SC, Ma N, Lu FL, (Lu, J.)*, miR-200c and GATA binding protein 4 regulate human embryonic stem cell renewal and differentiation, Stem Cell Research, vol. 12(2), 338-353, 2014具代表性; 任職中研院著作;
2014 Chang, C.F., Hsu, K.H., Shen, C.N., Li, C.L.*, Lu, J.)*, Enrichment and characterization of two subgroups of committed osteogenic cells in the mouse endosteal bone marrow with expression levels of CD24, Journal of Bone Research, vol. 2, 144, 2014具代表性; 任職中研院著作;
2013 Lu FL, Yu CC, Chiu HH, Liu HE, Chen SY, Lin S, Goh TY, Hsu HC, Chien CH, Wu HC, Chen MS, Schuyler SC, Hsieh WS, Wu MH, (Lu J)*, Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-alpha, or interferons., Investigational New Drugs, vol. 31(4), 823-832, 2013具代表性; 任職中研院著作;
2013 Chen HW, Chen HY, Wang LT, Wang FH, Fang LW, Lai HY, Chen HH, (Lu J, Hung MS, Cheng Y, Chen MY, Liu SJ, Chong P, Lee OK, Hsu SC, Mesenchymal stem cells tune the development of monocyte-derived dendritic cells toward a myeloid-derived suppressive phenotype through growth-regulated oncogene chemokines., Journal of Immunology, vol. 190(10), 5065-5077, 2013具代表性; 任職中研院著作;
2013 Liu YP, Yang CJ, Huang MS, Yeh CT, Wu AT, Lee YC, Lai TC, Lee CH, Hsiao YW, (Lu J, Shen CN, Lu PJ, Hsiao M, Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling., Cancer Research, vol. 73(1), 406-416, 2013具代表性; 任職中研院著作;
2013 Wang CH, Ma N, Lin YT, Wu CC, Wu HJ, Yu CC, Hsiao M, Lu FL, Schuyler SC, （Lu J＊）, Array-based high-throughput screening in mouse embryonic stem cells with shRNAs., Current protocols in stem cell biology, vol. 26, 5C.3.1-5C.3.19, 2013具代表性; 任職中研院著作;
2012 Chan CC, Cheng LY, (Lu J, Huang YH, Chiou SH, Tsai PH, Huo TI, Lin HC, Lee FY, The Role of Interferon-gamma Inducible Protein-10 in a Mouse Model of Acute Liver Injury Post Induced Pluripotent Stem Cells Transplantation., PLoS One, vol. 7(12), e50577, 2012具代表性; 任職中研院著作;
2012 Chou YC, Chen CL, Yeh TH, Lin SJ, Chen MR, Doong SL, (Lu J, Tsai CH, Involvement of recepteur d'origine nantais receptor tyrosine kinase in Epstein-Barr virus-associated nasopharyngeal carcinoma and its metastasis., The American Journal of Pathology, vol. 181(5), 1773-1781, 2012具代表性; 任職中研院著作;
2012 Wang, C. H., Ma, N. H., Lin, Y.T., Wu, C.C., Hsiao M., Lu, F. L., Yu, C.C., Chen, S.Y., Lu, J.)*, A shRNA functional screening in embryonic stem cells reveals Nme6 and Nme7 signaling are crucial for stem cell renewal, Stem Cells, vol. 30(10), 2199-2211, 2012具代表性; 任職中研院著作;
2011 Chou YC, Lin SJ, Lu J, Yeh TH, Chen CL, Weng PL, Lin JH, Yao M, Tsai CH, Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation, BLOOD, vol. 118(5), 1340-1349, 2011具代表性; 任職中研院著作;
2006 Chang Y, Lee HH, Chen YT, (Lu J, Wu SY, Chen CW, Takada K, Tsai CH, Induction of the early growth response 1 gene by Epstein-Barr virus lytic transactivator Zta, J Virol, vol. 80, 7748-7755, 2006具代表性;
2006 Lu J, Lin WS, Chen SY, Longnecker R, Tsai CH, Epstein-Barr virus latent membrane protein 2A enhances cell mobility in epithelial cells through syk kinase, J Biol Chem, vol. 281, 8806-8814, 2006具代表性;
2006 Lu J, Hou R, Booth C J, Yang SH, Snyder M, Defined culture conditions of human embryonic stem cells, Proceedings of the national academy of sciences of the united states of america, vol. 103, 5688-5693, 2006具代表性;
2003 Lu J, Chua HH, Chen SY, Chen JY, Tsai CH, Regulation of matrix metalloproteinase-1 by Epstein-Barr virus proteins, Cancer Res, vol. 63, 256-262, 2003具代表性;
2002 ChenSY, (Lu J, Shih YC, Tsai CH, Epstein-Barr virus latent membrane protein 2A regulates c-Jun protein through extracellular signal-regulated kinase, J Virol, vol. 76, 9556-9561, 2002具代表性;
2000 Lu J, Chen SY, Chua HH, Liu YS, Huang YT, Chang Y, Chen JY, Sheen TS, Tsai CH, Upregulation of tyrosine kinase TKT by the Epstein-Barr virus transactivator Zta, J Virol, vol. 74, 7391-7399, 2000具代表性;
1999 Chang Y, Tung CH, Huang YT, (Lu J, Chen JY, Tsai CH, Requirement for cell-to-cell contact in Epstein-Barr virus infection of nasopharyngeal carcinoma cells and keratinocytes, J Virol, vol. 73, 8857-8866, 1999具代表性;
1999 Huang YT, Sheen TS, Chen CL, ( Lu J, Chang Y, Chen JY, Tsai CH, Profile of cytokine expression in nasopharyngeal carcinomas: a distinct expression of interleukin 1 in tumor and CD4+ T cells, Cancer Res, vol. 59, 1599-1605, 1999具代表性;
1998 Chang Y, Sheen TS, (Lu J, Huang YT, Chen JY, Yang CS, Tsai CH, Detection of transcripts initiated from two viral promoters (Cp and Wp) in Epstein-Barr virus-infected nasopharyngeal carcinoma cells and biopsies, Lab Invest, vol. 78, 715-726, 1998具代表性;
1997 Tsai CH, Liu MT, Chen MR, Lu J, Yang HL, Chen JY, Yang CS, Characterization of monoclonal antibodies to the Zta and DNase proteins of Epstein-Barr virus, J Biomed Sci, vol. 4, 69-77, 1997具代表性;
jeanlu5
Podocalyxin-Like Protein 1 Regulates Pluripotency via the Cholesterol Biosynthesis Pathway – Advanced Science, Impact Factor: 17.521

We uncovered Podocalyxin-like protein 1 (PODXL) /cholesterol signals critical for maintaining the extended pluripotent stem cell (EPSC) pluripotent state, which is essential for understanding early embryonic development. Altering PODXL expression levels affects self-renewal capacity, protein expression of c-MYC/ telomerase, and colony formation efficiency of induced pluripotent stem cells (iPSCs) and EPSCs.

We are the first group to report that PODXL functions as a membrane protein regulator of cholesterol biosynthesis. Human pluripotent stem cells (hPSCs) exhibit greater sensitivity to cholesterol depletion compared to fibroblasts. The addition of exogenous cholesterol fully rescued the loss of pluripotency caused by PODXL gene silencing. PODXL influences lipid raft dynamics by modulating intracellular cholesterol levels. Specifically, PODXL regulates the recruitment of the RAC1/CDC42 network to control the maturation of SREBP1 and SREBP2, thereby affecting lipid raft dynamics.

Single-cell RNA sequencing further revealed that PODXL overexpression, along with cholesterol supplementation, markedly enhanced the contribution of human cells within human-mouse chimeric embryos, achieving a chimerism rate of 57%. These findings underscore the pivotal role of PODXL-mediated cholesterol signaling in regulating pluripotency in ESCs and EPSCs.


jeanlu6

Direct Reprogramming of Human Fibroblasts into Retinal Progenitor Cells Using Small Molecules for Photoreceptor Degeneration Therapy

We successfully reprogrammed human fibroblasts into retinal progenitor cells (RPCs) using a small-molecule-based approach, avoiding traditional gene editing or viral transduction techniques. This innovative method has demonstrated outstanding therapeutic efficacy in animal models without the risk of tumorigenesis.

The reprogramming protocol is straightforward, cost-effective, and exhibits high conversion efficiency, offering new hope for patients suffering from vision loss. The breakthrough work on RPCs highlights their potential in regenerative ophthalmology. 

Looking ahead, the team aims to establish partnerships with medical institutions and pharmaceutical companies to accelerate the clinical translation of RPC-based cell therapies. This significant advancement marks a promising step toward restoring sight and improving the quality of life for individuals affected by photoreceptor degeneration like retinitis pigmentosa (orphan drug), macular degeneration, diabetic retinopathy.
jeanlu2

jeanlu3

jeanlu4