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  • Articles  (12)
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  • Nature Publishing Group (NPG)  (12)
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  • 1
    Publication Date: 2008-10-14
    Description: Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695978/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695978/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cadwell, Ken -- Liu, John Y -- Brown, Sarah L -- Miyoshi, Hiroyuki -- Loh, Joy -- Lennerz, Jochen K -- Kishi, Chieko -- Kc, Wumesh -- Carrero, Javier A -- Hunt, Steven -- Stone, Christian D -- Brunt, Elizabeth M -- Xavier, Ramnik J -- Sleckman, Barry P -- Li, Ellen -- Mizushima, Noboru -- Stappenbeck, Thaddeus S -- Virgin, Herbert W 4th -- AI062773/AI/NIAID NIH HHS/ -- DK43351/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P30 DK043351-18/DK/NIDDK NIH HHS/ -- P30 DK052574-09/DK/NIDDK NIH HHS/ -- P30 DK52574/DK/NIDDK NIH HHS/ -- R01 AI062773/AI/NIAID NIH HHS/ -- R01 AI062773-01A1/AI/NIAID NIH HHS/ -- R01 AI062832/AI/NIAID NIH HHS/ -- R01 AI062832-04/AI/NIAID NIH HHS/ -- T32 AR007279/AR/NIAMS NIH HHS/ -- T32 AR007279-30/AR/NIAMS NIH HHS/ -- T32 AR07279/AR/NIAMS NIH HHS/ -- U54 AI057160/AI/NIAID NIH HHS/ -- U54 AI057160-010005/AI/NIAID NIH HHS/ -- U54 AI057160-05S10018/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Nov 13;456(7219):259-63. doi: 10.1038/nature07416. Epub 2008 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18849966" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Autophagy/*genetics ; Carrier Proteins/genetics/*metabolism ; Cell Line ; Crohn Disease/genetics/pathology ; Exocytosis/genetics ; Homozygote ; Humans ; Mice ; Mice, Inbred C57BL ; Mutation ; Paneth Cells/*metabolism/pathology
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  • 2
    Publication Date: 2009-10-23
    Description: The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767301/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767301/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trimboli, Anthony J -- Cantemir-Stone, Carmen Z -- Li, Fu -- Wallace, Julie A -- Merchant, Anand -- Creasap, Nicholas -- Thompson, John C -- Caserta, Enrico -- Wang, Hui -- Chong, Jean-Leon -- Naidu, Shan -- Wei, Guo -- Sharma, Sudarshana M -- Stephens, Julie A -- Fernandez, Soledad A -- Gurcan, Metin N -- Weinstein, Michael B -- Barsky, Sanford H -- Yee, Lisa -- Rosol, Thomas J -- Stromberg, Paul C -- Robinson, Michael L -- Pepin, Francois -- Hallett, Michael -- Park, Morag -- Ostrowski, Michael C -- Leone, Gustavo -- P01 CA097189/CA/NCI NIH HHS/ -- P01 CA097189-050002/CA/NCI NIH HHS/ -- P01CA097189/CA/NCI NIH HHS/ -- R01 CA053271/CA/NCI NIH HHS/ -- R01 CA085619/CA/NCI NIH HHS/ -- R01 CA085619-05/CA/NCI NIH HHS/ -- R01 CA121275/CA/NCI NIH HHS/ -- R01 CA121275-02/CA/NCI NIH HHS/ -- R01 HD047470/HD/NICHD NIH HHS/ -- R01 HD047470-05/HD/NICHD NIH HHS/ -- R01CA053271/CA/NCI NIH HHS/ -- R01CA85619/CA/NCI NIH HHS/ -- R01HD47470/HD/NICHD NIH HHS/ -- England -- Nature. 2009 Oct 22;461(7267):1084-91. doi: 10.1038/nature08486.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847259" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*metabolism/*pathology ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic ; Extracellular Matrix/metabolism ; Fibroblasts/*metabolism ; Gene Deletion ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity, Innate ; Mammary Neoplasms, Experimental/metabolism/pathology ; Mice ; Mice, Transgenic ; Neoplasms, Glandular and Epithelial/*metabolism/*pathology ; PTEN Phosphohydrolase/deficiency/genetics/*metabolism ; Proto-Oncogene Protein c-ets-2/deficiency/metabolism ; Stromal Cells/*metabolism
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  • 3
    Publication Date: 2010-06-18
    Description: Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900412/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900412/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Surolia, Ira -- Pirnie, Stephan P -- Chellappa, Vasant -- Taylor, Kendra N -- Cariappa, Annaiah -- Moya, Jesse -- Liu, Haoyuan -- Bell, Daphne W -- Driscoll, David R -- Diederichs, Sven -- Haider, Khaleda -- Netravali, Ilka -- Le, Sheila -- Elia, Roberto -- Dow, Ethan -- Lee, Annette -- Freudenberg, Jan -- De Jager, Philip L -- Chretien, Yves -- Varki, Ajit -- MacDonald, Marcy E -- Gillis, Tammy -- Behrens, Timothy W -- Bloch, Donald -- Collier, Deborah -- Korzenik, Joshua -- Podolsky, Daniel K -- Hafler, David -- Murali, Mandakolathur -- Sands, Bruce -- Stone, John H -- Gregersen, Peter K -- Pillai, Shiv -- AI 064930/AI/NIAID NIH HHS/ -- AI 068759/AI/NIAID NIH HHS/ -- AI 076505/AI/NIAID NIH HHS/ -- AR 022263/AR/NIAMS NIH HHS/ -- AR 044422/AR/NIAMS NIH HHS/ -- AR 058481/AR/NIAMS NIH HHS/ -- NS 32765/NS/NINDS NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI064930/AI/NIAID NIH HHS/ -- R01 AI064930-04/AI/NIAID NIH HHS/ -- R01 AI068759/AI/NIAID NIH HHS/ -- R01 AI068759-05/AI/NIAID NIH HHS/ -- R01 AI076505/AI/NIAID NIH HHS/ -- R01 AI076505-02/AI/NIAID NIH HHS/ -- R01 AR044422/AR/NIAMS NIH HHS/ -- R01 AR044422-13/AR/NIAMS NIH HHS/ -- RC1 AR058481/AR/NIAMS NIH HHS/ -- RC1 AR058481-01/AR/NIAMS NIH HHS/ -- England -- Nature. 2010 Jul 8;466(7303):243-7. doi: 10.1038/nature09115. Epub 2010 Jun 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20555325" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Acetylesterase/*genetics/metabolism/secretion ; Alleles ; Animals ; Antibodies, Antinuclear/blood ; Arthritis, Rheumatoid/enzymology/genetics ; Autoimmune Diseases/*enzymology/*genetics ; Autoimmunity/*genetics ; B-Lymphocytes/metabolism ; Biocatalysis ; Carboxylic Ester Hydrolases/*genetics/metabolism/secretion ; Case-Control Studies ; Cell Line ; Diabetes Mellitus, Type 1/enzymology/genetics ; Europe/ethnology ; Exons/genetics ; Genetic Predisposition to Disease/*genetics ; Germ-Line Mutation/*genetics ; Humans ; Mice ; N-Acetylneuraminic Acid/*metabolism ; Odds Ratio ; Polymorphism, Single Nucleotide/genetics ; Sample Size ; Sequence Analysis, DNA
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  • 4
    Publication Date: 2012-07-06
    Description: During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401326/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dutta, Partha -- Courties, Gabriel -- Wei, Ying -- Leuschner, Florian -- Gorbatov, Rostic -- Robbins, Clinton S -- Iwamoto, Yoshiko -- Thompson, Brian -- Carlson, Alicia L -- Heidt, Timo -- Majmudar, Maulik D -- Lasitschka, Felix -- Etzrodt, Martin -- Waterman, Peter -- Waring, Michael T -- Chicoine, Adam T -- van der Laan, Anja M -- Niessen, Hans W M -- Piek, Jan J -- Rubin, Barry B -- Butany, Jagdish -- Stone, James R -- Katus, Hugo A -- Murphy, Sabina A -- Morrow, David A -- Sabatine, Marc S -- Vinegoni, Claudio -- Moskowitz, Michael A -- Pittet, Mikael J -- Libby, Peter -- Lin, Charles P -- Swirski, Filip K -- Weissleder, Ralph -- Nahrendorf, Matthias -- P50-CA086355/CA/NCI NIH HHS/ -- R01 AI084880/AI/NIAID NIH HHS/ -- R01 EB006432/EB/NIBIB NIH HHS/ -- R01 HL095612/HL/NHLBI NIH HHS/ -- R01 HL095629/HL/NHLBI NIH HHS/ -- R01 HL096576/HL/NHLBI NIH HHS/ -- R01-EB006432/EB/NIBIB NIH HHS/ -- R01-HL095629/HL/NHLBI NIH HHS/ -- R01-HL096576/HL/NHLBI NIH HHS/ -- T32 CA079443/CA/NCI NIH HHS/ -- T32-CA79443/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jul 19;487(7407):325-9. doi: 10.1038/nature11260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763456" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apolipoproteins E/genetics ; Atherosclerosis/*etiology/*pathology ; Hematopoietic Stem Cells/cytology ; Inflammation/complications ; Mice ; Mice, Inbred C57BL ; Monocytes/cytology ; Myocardial Infarction/*complications/*pathology ; Spleen/cytology ; Stem Cells/cytology
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  • 5
    Publication Date: 2014-08-21
    Description: Modern strains of Mycobacterium tuberculosis from the Americas are closely related to those from Europe, supporting the assumption that human tuberculosis was introduced post-contact. This notion, however, is incompatible with archaeological evidence of pre-contact tuberculosis in the New World. Comparative genomics of modern isolates suggests that M. tuberculosis attained its worldwide distribution following human dispersals out of Africa during the Pleistocene epoch, although this has yet to be confirmed with ancient calibration points. Here we present three 1,000-year-old mycobacterial genomes from Peruvian human skeletons, revealing that a member of the M. tuberculosis complex caused human disease before contact. The ancient strains are distinct from known human-adapted forms and are most closely related to those adapted to seals and sea lions. Two independent dating approaches suggest a most recent common ancestor for the M. tuberculosis complex less than 6,000 years ago, which supports a Holocene dispersal of the disease. Our results implicate sea mammals as having played a role in transmitting the disease to humans across the ocean.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550673/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550673/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bos, Kirsten I -- Harkins, Kelly M -- Herbig, Alexander -- Coscolla, Mireia -- Weber, Nico -- Comas, Inaki -- Forrest, Stephen A -- Bryant, Josephine M -- Harris, Simon R -- Schuenemann, Verena J -- Campbell, Tessa J -- Majander, Kerttu -- Wilbur, Alicia K -- Guichon, Ricardo A -- Wolfe Steadman, Dawnie L -- Cook, Della Collins -- Niemann, Stefan -- Behr, Marcel A -- Zumarraga, Martin -- Bastida, Ricardo -- Huson, Daniel -- Nieselt, Kay -- Young, Douglas -- Parkhill, Julian -- Buikstra, Jane E -- Gagneux, Sebastien -- Stone, Anne C -- Krause, Johannes -- 098051/Wellcome Trust/United Kingdom -- AI090928/AI/NIAID NIH HHS/ -- MC_U117581288/Medical Research Council/United Kingdom -- R01 AI090928/AI/NIAID NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Oct 23;514(7523):494-7. doi: 10.1038/nature13591. Epub 2014 Aug 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Archaeological Sciences, University of Tubingen, Ruemelinstrasse 23, 72070 Tubingen, Germany [2]. ; 1] School of Human Evolution and Social Change, Arizona State University, PO Box 872402, Tempe, Arizona 85287-2402, USA [2]. ; 1] Department of Archaeological Sciences, University of Tubingen, Ruemelinstrasse 23, 72070 Tubingen, Germany [2] Center for Bioinformatics, University of Tubingen, Sand 14, 72076 Tubingen, Germany [3]. ; 1] Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland [2] University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland [3]. ; Center for Bioinformatics, University of Tubingen, Sand 14, 72076 Tubingen, Germany. ; 1] Genomics and Health Unit, FISABIO-Public Health, Avenida Cataluna 21, 46020 Valencia, Spain [2] CIBER (Centros de Investigacion Biomedica en Red) in Epidemiology and Public Health, Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellon 11, Planta 0, 28029 Madrid, Spain. ; Department of Archaeological Sciences, University of Tubingen, Ruemelinstrasse 23, 72070 Tubingen, Germany. ; Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Department of Archaeology, University of Cape Town, Private Bag X1, Rondebosch, 7701, South Africa. ; School of Human Evolution and Social Change, Arizona State University, PO Box 872402, Tempe, Arizona 85287-2402, USA. ; CONICET, Laboratorio de Ecologia Evolutiva Humana (FACSO, UNCPBA), Departamento de Biologia (FCEyN, UNMDP), Calle 508 No. 881 (7631), Quequen, Argentina. ; Department of Anthropology, University of Tennessee, 250 South Stadium Hall, Knoxville, Tennessee 37996, USA. ; Department of Anthropology, Indiana University, 701 East Kirkwood Avenue, Bloomington, Indiana 47405-7100, USA. ; 1] Molecular Mycobacteriology, Forschungszentrum Borstel, Parkallee 1, 23845 Borstel, Germany [2] German Center for Infection Research, Forschungszentrum Borstel, Parkallee 1, 23845 Borstel, Germany. ; McGill International TB Centre, McGill University, 1650 Cedar Avenue, Montreal H3G 1A4, Canada. ; Biotechnology Institute, CICVyA-INTA Castelar, Dr. Nicolas Repetto y De Los Reseros S/N, (B1686IGC) Hurlingham, Buenos Aires, Argentina. ; Instituto de Investigaciones Marinas y Costeras (CONICET-UNMdP), Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, San Luis 1722, Mar del Plata 7600, Argentina. ; 1] Department of Medicine, Imperial College, London W2 1PG, UK [2] Division of Mycobacterial Research, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. ; 1] Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland [2] University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland. ; 1] Department of Archaeological Sciences, University of Tubingen, Ruemelinstrasse 23, 72070 Tubingen, Germany [2] Senckenberg Centre for Human Evolution and Palaeoenvironment, University of Tubingen, Tubingen 72070, Germany [3] Max Planck Institute for Science and History, Khalaische Strasse 10, 07745 Jena, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25141181" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone and Bones/microbiology ; Europe/ethnology ; Genome, Bacterial/*genetics ; Genomics ; History, Ancient ; Human Migration/history ; Humans ; Mycobacterium tuberculosis/*genetics ; Peru ; Phylogeny ; Pinnipedia/*microbiology ; Tuberculosis/*history/*microbiology/transmission ; Zoonoses/*history/*microbiology/transmission
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  • 6
    Publication Date: 2010-03-17
    Description: The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hagberg, Carolina E -- Falkevall, Annelie -- Wang, Xun -- Larsson, Erik -- Huusko, Jenni -- Nilsson, Ingrid -- van Meeteren, Laurens A -- Samen, Erik -- Lu, Li -- Vanwildemeersch, Maarten -- Klar, Joakim -- Genove, Guillem -- Pietras, Kristian -- Stone-Elander, Sharon -- Claesson-Welsh, Lena -- Yla-Herttuala, Seppo -- Lindahl, Per -- Eriksson, Ulf -- England -- Nature. 2010 Apr 8;464(7290):917-21. doi: 10.1038/nature08945. Epub 2010 Mar 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tissue Biology Group, Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20228789" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/metabolism ; Animals ; Biological Transport ; Cell Line ; Cell Nucleus/genetics ; Cells, Cultured ; Endothelium/cytology/*metabolism ; Fatty Acid Transport Proteins/genetics ; Fatty Acids/*metabolism ; Gene Expression Regulation ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/genetics/metabolism ; Mitochondrial Proteins/genetics/metabolism ; Muscles/metabolism ; Myocardium/metabolism ; Neuropilin-1/genetics/metabolism ; Oligonucleotide Array Sequence Analysis ; Organ Specificity ; Signal Transduction ; Transcription, Genetic ; Vascular Endothelial Growth Factor B/deficiency/genetics/*metabolism ; Vascular Endothelial Growth Factor Receptor-1/metabolism
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  • 7
    Publication Date: 2012-10-02
    Description: The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved beta-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hagberg, Carolina E -- Mehlem, Annika -- Falkevall, Annelie -- Muhl, Lars -- Fam, Barbara C -- Ortsater, Henrik -- Scotney, Pierre -- Nyqvist, Daniel -- Samen, Erik -- Lu, Li -- Stone-Elander, Sharon -- Proietto, Joseph -- Andrikopoulos, Sofianos -- Sjoholm, Ake -- Nash, Andrew -- Eriksson, Ulf -- England -- Nature. 2012 Oct 18;490(7420):426-30. doi: 10.1038/nature11464. Epub 2012 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23023133" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Diabetes Mellitus, Type 2/*drug therapy/*metabolism ; Diet, High-Fat ; Disease Models, Animal ; Dyslipidemias/drug therapy/metabolism ; Endothelium, Vascular/metabolism ; Female ; Glucose/metabolism ; Glucose Tolerance Test ; *Insulin Resistance ; Islets of Langerhans/anatomy & histology/cytology/pathology ; Lipid Metabolism ; Male ; Metabolic Syndrome X/drug therapy/metabolism ; Mice ; Mice, Inbred C57BL ; *Molecular Targeted Therapy ; Muscles/metabolism ; Obesity/metabolism/pathology ; Rats ; Rats, Wistar ; Signal Transduction/drug effects/immunology ; Vascular Endothelial Growth Factor B/*antagonists & ; inhibitors/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Nature Publishing Group (NPG)
    Publication Date: 2011-02-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stone, Lewi -- England -- Nature. 2011 Feb 3;470(7332):47-9. doi: 10.1038/470047a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21293367" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Australia ; Ferns/*growth & development ; Floods ; *Fresh Water ; Introduced Species/statistics & numerical data ; Models, Biological ; Papua New Guinea ; Pest Control, Biological/*statistics & numerical data ; Plant Weeds/*growth & development ; South America/ethnology ; Stochastic Processes ; Weevils/*physiology ; Wilderness
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2012-08-17
    Description: The ocean plays a critical role in supporting human well-being, from providing food, livelihoods and recreational opportunities to regulating the global climate. Sustainable management aimed at maintaining the flow of a broad range of benefits from the ocean requires a comprehensive and quantitative method to measure and monitor the health of coupled human-ocean systems. We created an index comprising ten diverse public goals for a healthy coupled human-ocean system and calculated the index for every coastal country. Globally, the overall index score was 60 out of 100 (range 36-86), with developed countries generally performing better than developing countries, but with notable exceptions. Only 5% of countries scored higher than 70, whereas 32% scored lower than 50. The index provides a powerful tool to raise public awareness, direct resource management, improve policy and prioritize scientific research.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Halpern, Benjamin S -- Longo, Catherine -- Hardy, Darren -- McLeod, Karen L -- Samhouri, Jameal F -- Katona, Steven K -- Kleisner, Kristin -- Lester, Sarah E -- O'Leary, Jennifer -- Ranelletti, Marla -- Rosenberg, Andrew A -- Scarborough, Courtney -- Selig, Elizabeth R -- Best, Benjamin D -- Brumbaugh, Daniel R -- Chapin, F Stuart -- Crowder, Larry B -- Daly, Kendra L -- Doney, Scott C -- Elfes, Cristiane -- Fogarty, Michael J -- Gaines, Steven D -- Jacobsen, Kelsey I -- Karrer, Leah Bunce -- Leslie, Heather M -- Neeley, Elizabeth -- Pauly, Daniel -- Polasky, Stephen -- Ris, Bud -- St Martin, Kevin -- Stone, Gregory S -- Sumaila, U Rashid -- Zeller, Dirk -- England -- Nature. 2012 Aug 30;488(7413):615-20. doi: 10.1038/nature11397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Center for Ecological Analysis and Synthesis, 735 State St Suite 300, Santa Barbara, California 93101, USA. halpern@nceas.ucsb.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22895186" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conservation of Natural Resources/*statistics & numerical data ; *Ecosystem ; Environmental Monitoring/*methods ; Environmental Policy ; Fisheries ; Geography ; Human Activities/standards/statistics & numerical data ; *Internationality ; Marine Biology/*methods ; Oceanography/*methods ; Oceans and Seas ; Recreation ; *Seawater ; Water Pollution/analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2012-02-24
    Description: Fibrous media are functional and versatile materials, as demonstrated by their ubiquity both in natural systems such as feathers and adhesive pads and in engineered systems from nanotextured surfaces to textile products, where they offer benefits in filtration, insulation, wetting and colouring. The elasticity and high aspect ratios of the fibres allow deformation under capillary forces, which cause mechanical damage, matting self-assembly or colour changes, with many industrial and ecological consequences. Attempts to understand these systems have mostly focused on the wetting of rigid fibres or on elastocapillary effects in planar geometries and on a fibre brush withdrawn from an infinite bath. Here we consider the frequently encountered case of a liquid drop deposited on a flexible fibre array and show that flexibility, fibre geometry and drop volume are the crucial parameters that are necessary to understand the various observations referred to above. We identify the conditions required for a drop to remain compact with minimal spreading or to cause a pair of elastic fibres to coalesce. We find that there is a critical volume of liquid, and, hence, a critical drop size, above which this coalescence does not occur. We also identify a drop size that maximizes liquid capture. For both wetting and deformation of the substrates, we present rules that are deduced from the geometric and material properties of the fibres and the volume of the drop. These ideas are applicable to a wide range of fibrous materials, as we illustrate with examples for feathers, beetle tarsi, sprays and microfabricated systems.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duprat, C -- Protiere, S -- Beebe, A Y -- Stone, H A -- England -- Nature. 2012 Feb 23;482(7386):510-3. doi: 10.1038/nature10779.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey 08544, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22358841" target="_blank"〉PubMed〈/a〉
    Keywords: Aerosols ; Animals ; Beetles/anatomy & histology ; Feathers/*chemistry ; Geese ; Glass/chemistry ; *Pliability ; Surface Tension ; Viscosity ; *Wettability
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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