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  • Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration
    Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration
    1. Lian Zhao1,,,
    2. Matthew K Zabel1,,,
    3. Xu Wang1,,
    4. Wenxin Ma1,,
    5. Parth Shah1,,
    6. Robert N Fariss2,,
    7. Haohua Qian3,,
    8. Christopher N Parkhurst4,
    9. Wen‐Biao Gan4 and
    10. Wai T Wong*,1,
    1. 1Unit on Neuron‐Glia Interactions in Retinal Disease, National Eye institute National Institutes of Health, Bethesda, MD, USA
    2. 2Biological Imaging Core, National Eye institute National Institutes of Health, Bethesda, MD, USA
    3. 3Visual Function Core, National Eye institute National Institutes of Health, Bethesda, MD, USA
    4. 4Department of Neuroscience and Physiology, Skirball Institute New York University School of Medicine, New York, NY, USA
    1. *Corresponding author. Tel: +1 301 496 1758; Fax: +1 301 496 1759; E‐mail: wongw{at}nei.nih.gov
    1. This article has been contributed to by US Government employees and their work is in the public domain in the USA

    2. These authors contributed equally to this work

    In Retinitis pigmentosa (RP), retinal microglia are shown to potentiate the rate of rod photoreceptor death via phagocytic and pro‐inflammatory mechanisms. This process may be common to multiple genetic etiologies of RP in mouse models and in human patients.

    Synopsis

    In Retinitis pigmentosa (RP), retinal microglia are shown to potentiate the rate of rod photoreceptor death via phagocytic and pro‐inflammatory mechanisms. This process may be common to multiple genetic etiologies of RP in mouse models and in human patients.

    • Microglial phagocytosis of rod photoreceptors was initiated at the start of rod apoptosis with early infiltration of retinal microglia into the outer retina, upregulation of phagocytic molecules in microglia, and exposure of PS, an “eat‐me” signal, on rod photoreceptors.

    • Microglial phagocytosis of rods included apoptotic cells but also cells that have not yet been committed to apoptosis and are negative for apoptotic markers, indicating microglial clearance of stressed but living rods.

    • Infiltrating microglia demonstrated dynamic interactions with photoreceptors via motile processes that culminate in the overt phagocytosis of non‐apoptotic rods.

    • The contribution of infiltrating microglia to rod demise was demonstrated by structural and functional rescue of photoreceptor degeneration.

    • Microglia‐directed interventions may be of potential utility in prolonging the survival of photoreceptors and deferring irreversible vision loss associated with RP of different genetic etiologies.

    • apoptosis
    • microglia
    • phagocytosis
    • retinal degeneration
    • retinitis pigmentosa
    • Received March 30, 2015.
    • Revision received May 28, 2015.
    • Accepted June 1, 2015.

    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.

    Lian Zhao, Matthew K Zabel, Xu Wang, Wenxin Ma, Parth Shah, Robert N Fariss, Haohua Qian, Christopher N Parkhurst, Wen‐Biao Gan, Wai T Wong
  • TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse
    <div xmlns="http://www.w3.org/1999/xhtml"><em>TEX11</em> is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse</div>
    1. Fang Yang1,
    2. Sherman Silber2,
    3. N Adrian Leu1,
    4. Robert D Oates3,
    5. Janet D Marszalek4,
    6. Helen Skaletsky4,
    7. Laura G Brown4,
    8. Steve Rozen4,5,
    9. David C Page4,6 and
    10. P Jeremy Wang*,1
    1. 1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
    2. 2Infertility Center of St. Louis, St. Luke's Hospital, St. Louis, MO, USA
    3. 3Department of Urology, Boston University Medical Center, Boston, MA, USA
    4. 4Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA
    5. 5Duke‐Nus Graduate Medical School Singapore, Singapore City, Singapore
    6. 6Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
    1. *Corresponding author. Tel: +1 2157460160; E‐mail: pwang{at}vet.upenn.edu

    Mutations were identified in the X chromosome‐linked germ cell‐specific gene TEX11 in infertile men with non‐obstructive azoospermia. Functional studies of TEX11 protein in mice revealed an unexpected role in the regulation of genome‐wide recombination rates.

    Synopsis

    Mutations were identified in the X chromosome‐linked germ cell‐specific gene TEX11 in infertile men with non‐obstructive azoospermia. Functional studies of TEX11 protein in mice revealed an unexpected role in the regulation of genome‐wide recombination rates.

    • Sequencing screening of human infertile patients reveals mutations in the TEX11 gene in 1% of non‐obstructive azoospermic men.

    • Infertile men with mutations in TEX11 exhibit meiotic arrest.

    • Experimentally retrotransposed Tex11 on an autosome rescues the fertility of male mice deleted for the X‐linked Tex11 gene.

    • Genetic studies of mice with different Tex11 gene dosages demonstrate a threshold level of TEX11 protein for spermatogenesis.

    • Analysis of crossover formation shows that TEX11 regulates genome‐wide recombination rates in both males and females in a dosage‐dependent manner.

    • chromosomal synapsis
    • infertility
    • meiosis
    • recombination
    • X chromosome
    • Received December 16, 2014.
    • Revision received June 3, 2015.
    • Accepted June 5, 2015.

    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.

    Fang Yang, Sherman Silber, N Adrian Leu, Robert D Oates, Janet D Marszalek, Helen Skaletsky, Laura G Brown, Steve Rozen, David C Page, P Jeremy Wang
  • Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts
    Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts
    1. Kristel Kemper1,,
    2. Oscar Krijgsman1,,
    3. Paulien Cornelissen‐Steijger1,
    4. Aida Shahrabi1,
    5. Fleur Weeber1,
    6. Ji‐Ying Song2,
    7. Thomas Kuilman1,
    8. Daniel J Vis3,
    9. Lodewyk F Wessels3,
    10. Emile E Voest1,
    11. Ton NM Schumacher4,
    12. Christian U Blank4,
    13. David J Adams5,
    14. John B Haanen4 and
    15. Daniel S Peeper*,1
    1. 1Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    2. 2Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    3. 3Computational Cancer Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    4. 4Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    5. 5Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK
    1. *Corresponding author. Tel: +31 205 122 099; Fax: +31 206 691 383; E‐mail: d.peeper{at}nki.nl
    1. These authors contributed equally to this work

    Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies.

    Synopsis

    Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies.

    • Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.

    • A new 3‐bp insertion in the MEK1 gene (MEK1T55delinsRT) confers resistance to vemurafenib.

    • The MEK1T55delinsRT mutation can be traced back to a fraction of the pre‐treatment tumor.

    • Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts.

    • Melanoma
    • drug resistance
    • tumor heterogeneity
    • patient‐derived xenografts
    • Received December 4, 2014.
    • Revision received May 13, 2015.
    • Accepted May 22, 2015.

    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.

    Kristel Kemper, Oscar Krijgsman, Paulien Cornelissen‐Steijger, Aida Shahrabi, Fleur Weeber, Ji‐Ying Song, Thomas Kuilman, Daniel J Vis, Lodewyk F Wessels, Emile E Voest, Ton NM Schumacher, Christian U Blank, David J Adams, John B Haanen, Daniel S Peeper
  • H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis
    H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis
    1. Sanaz Ghazal1,
    2. Brett McKinnon2,
    3. Jichun Zhou1,3,
    4. Martin Mueller1,2,
    5. Yi Men1,4,
    6. Lihua Yang1,5,
    7. Michael Mueller2,
    8. Clare Flannery1,
    9. Yingqun Huang*,1 and
    10. Hugh S Taylor*,1
    1. 1Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
    2. 2Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland
    3. 3Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital Zhejiang University School of Medicine, Hangzhou Zhejiang, China
    4. 4Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases West China Hospital of Stomatology Sichuan University, Chengdu Sichuan, China
    5. 5Obstetrics and Gynecology Department, Tangshan Gongren Hospital, Tangshan Hebei, China
    1. * Corresponding author. Tel: +1 203 737 2578; Fax: +1 203 737 3560; E‐mail: yingqun.huang{at}yale.edu

      Corresponding author. Tel: +1 203 785 4001; Fax: +1 203 785 4713; E‐mail: hugh.taylor{at}yale.edu

    Endometriosis is associated with infertility in reproductive aged women, but the molecular mechanism is unknown. H19 is a long noncoding RNA that is normally expressed in eutopic endometrium and shown here to play a role in endometrial stromal cell growth via the microRNA let‐7 and its downstream target IGF1R.

    Synopsis

    Endometriosis is associated with infertility in reproductive aged women, but the molecular mechanism is unknown. H19 is a long noncoding RNA that is normally expressed in eutopic endometrium and shown here to play a role in endometrial stromal cell growth via the microRNA let‐7 and its downstream target IGF1R.

    • H19 expression is decreased in the eutopic endometrium of women with endometriosis compared to women without endometriosis.

    • Decreased H19 expression leads to increased activity of let‐7, which inhibits IGF1R expression at the post‐transcriptional level.

    • Reduced IGF1R activity leads to impaired endometrial stromal cell proliferation and may impact endometrial receptivity for pregnancy.

    • Aberrations in this H19/let‐7/IGF1R regulatory pathway in women with endometriosis may represent one potential mechanism for infertility in this patient population.

    • endometrium
    • H19
    • IGF
    • let‐7
    • long noncoding RNA
    • Received March 11, 2015.
    • Revision received May 27, 2015.
    • Accepted May 28, 2015.

    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.

    Sanaz Ghazal, Brett McKinnon, Jichun Zhou, Martin Mueller, Yi Men, Lihua Yang, Michael Mueller, Clare Flannery, Yingqun Huang, Hugh S Taylor
  • Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange‐Nielsen deafness syndrome
    <div xmlns="http://www.w3.org/1999/xhtml">Virally mediated <em>Kcnq1</em> gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange‐Nielsen deafness syndrome</div>
    1. Qing Chang1,,
    2. Jianjun Wang1,,
    3. Qi Li1,2,
    4. Yeunjung Kim1,
    5. Binfei Zhou1,
    6. Yunfeng Wang3,
    7. Huawei Li*,3 and
    8. Xi Lin*,3
    1. 1Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA
    2. 2Department of Otolaryngology‐Head and Neck Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
    3. 3Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
    1. * Corresponding author. Tel: +86 18016485727; Fax: +86 21 64377134; hwli{at}shmu.edu.cn

      Corresponding author. Tel: +86 404 727 3723; Fax: +86 404 7276256; xlin2{at}emory.edu

    1. These authors contributed equally

    First gene replacement therapy proof of principle for a deafness gene defect (Kcnq1) affecting the stria vascularis, a major site affected by genetic mutations in inherited hearing loss cases.

    Synopsis

    First gene replacement therapy proof of principle for a deafness gene defect (Kcnq1) affecting the stria vascularis, a major site affected by genetic mutations in inherited hearing loss cases.

    • Gene therapy to preserve hearing was tested in a mouse model of Jervell and Lange‐Nielsen syndrome (Kcnq1−/− mice).

    • Extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions.

    • Cochlear morphological data, normal endocochlear potential, and significant hearing preservation after treatment demonstrated phenotypic correction.

    • gene therapy
    • hearing restoration
    • Jervell and Lange‐Nielsen syndrome
    • Kcnq1 null mice
    • virus
    • Received December 4, 2014.
    • Revision received May 17, 2015.
    • Accepted May 21, 2015.

    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.

    Qing Chang, Jianjun Wang, Qi Li, Yeunjung Kim, Binfei Zhou, Yunfeng Wang, Huawei Li, Xi Lin
  • Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy
    Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy
    1. Bryan W Miller1,,
    2. Jennifer P Morton1,,
    3. Mark Pinese2,,
    4. Grazia Saturno3,,
    5. Nigel B Jamieson4,
    6. Ewan McGhee1,
    7. Paul Timpson2,
    8. Joshua Leach1,
    9. Lynn McGarry1,
    10. Emma Shanks1,
    11. Peter Bailey5,
    12. David Chang5,
    13. Karin Oien5,
    14. Saadia Karim1,
    15. Amy Au1,
    16. Colin Steele1,
    17. Christopher Ross Carter4,
    18. Colin McKay4,
    19. Kurt Anderson1,
    20. Thomas R Jeffry Evans1,5,
    21. Richard Marais3,
    22. Caroline Springer6,,
    23. Andrew Biankin5,,
    24. Janine T Erler*,7, and
    25. Owen J Sansom*,1,
    1. 1Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK
    2. 2The Garvan Institute of Medical Research, Sydney, NSW, Australia
    3. 3Cancer Research UK Manchester Institute, Withington Manchester, UK
    4. 4West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
    5. 5Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK
    6. 6Institute of Cancer Research, London, UK
    7. 7Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen (UCPH), Denmark
    1. * Corresponding author. Tel: +45 3532 5666; Fax: +45 3532 5669; E‐mail: janine.erler{at}bric.ku.dk

      Corresponding author. Tel: +44 141 330 3656; Fax: +44 141 942 6521; E‐mail: o.sansom{at}beatson.gla.ac.uk

    1. These authors contributed equally to this work

    Lysyl oxidase (LOX) is identified as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). Inhibition of LOX resulted in increased drug efficacy and stromal changes and reduction in metastasis.

    Synopsis

    Lysyl oxidase (LOX) is identified as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). Inhibition of LOX resulted in increased drug efficacy and stromal changes and reduction in metastasis.

    • A signature of hazardous and protective genes in PDAC was defined. High expression of hypoxia‐associated genes, including LOX, was associated with poor patient prognosis.

    • Using transgenic mouse models of PDAC, LOX was found to be overexpressed in metastatic disease and its expression was required for PDAC cell invasion.

    • Inhibition of LOX in transgenic mice inhibited metastasis, while combination therapy with LOX inhibition and gemcitabine induced stromal alterations, immune cell infiltration and tumor necrosis and improved survival.

    • animal models of cancer
    • collagen cross‐linking
    • lysyl oxidase
    • pancreatic cancer
    • Received November 9, 2014.
    • Revision received May 12, 2015.
    • Accepted May 21, 2015.

    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.

    Bryan W Miller, Jennifer P Morton, Mark Pinese, Grazia Saturno, Nigel B Jamieson, Ewan McGhee, Paul Timpson, Joshua Leach, Lynn McGarry, Emma Shanks, Peter Bailey, David Chang, Karin Oien, Saadia Karim, Amy Au, Colin Steele, Christopher Ross Carter, Colin McKay, Kurt Anderson, Thomas R Jeffry Evans, Richard Marais, Caroline Springer, Andrew Biankin, Janine T Erler, Owen J Sansom
  • Glucocorticoids and antibiotics, how do they get together?
    Glucocorticoids and antibiotics, how do they get together?
    1. Joachim Reidl (joachim.reidl{at}uni-graz.at)1 and
    2. Eduard Monsó2,3
    1. 1Institute of Molecular Biosciences, University of Graz, Graz, Austria
    2. 2Servei de Pneumologia, Hospital Universitari Parc Taulí, Sabadell, Barcelona, Spain
    3. 3Ciber de Enfermedades Respiratorias – Ciberes Universitat Autònoma de Barcelona, Cerdanyola, Barcelona, Spain

    Antibiotic therapy in patients currently treated with corticosteroids is common in chronic respiratory diseases when exacerbation symptoms attributable to infection appear. Among them, obstructive diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major health issues affecting hundreds of million people worldwide that are frequently treated with inhaled corticosteroids. Systemic corticosteroids are also used for idiopathic pulmonary fibrosis, a less prevalent chronic respiratory disease. In this issue of EMBO Molecular Medicine, Earl et al (2015) report a potentially baleful relationship between steroid and antibiotic treatment in chronic respiratory diseases, affecting colonization persistence and antibiotic tolerance for Haemophilus influenzae, one of the leading potentially pathogenic microorganisms (PPMs) of the respiratory system.

    See also: CS Earl et al

    Earl et al report in this issue of EMBO Molecular Medicine that steroid and antibiotic treatment is a mean combination in the treatment of chronic respiratory diseases mediating bacteria biofilm conversion and antibiotic tolerance.

    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.

    Joachim Reidl, Eduard Monsó