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Frederick Campbell, Frank L Bos, Sandro Sieber, Gabriela Arias-Alpizar, Bjørn E Koch, Jörg Huwyler, Alexander Kros, Jeroen Bussmann
Up to 99% of systemically administered nanoparticles are cleared through the liver. Within the liver, most nanoparticles are thought to be sequestered by macrophages (Kupffer cells), although significant nanoparticle interactions with other hepatic cells have also been observed. To achieve effective cell-specific targeting of drugs through nanoparticle encapsulation, improved mechanistic understanding of nanoparticle-liver interactions is required. Here, we show the caudal vein of the embryonic zebrafish ( Danio rerio) can be used as a model for assessing nanoparticle interactions with mammalian liver sinusoidal (or scavenger) endothelial cells (SECs) and macrophages...
March 27, 2018: ACS Nano
Karen Nuytemans, Thomas L Ortel, Lissette Gomez, Natalia Hofmann, Natalie Alves, Nicole Dueker, Ashley Beecham, Patrice Whitehead, Susan Hahn Estabrooks, Craig S Kitchens, Doruk Erkan, Leonardo R Brandão, Andra H James, Roshni Kulkarni, Marilyn J Manco-Johnson, Margaret A Pericak-Vance, Jeffery M Vance
INTRODUCTION: Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. MATERIAL AND METHODS: We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients...
January 2018: Thrombosis Research
Thomas Leibing, Cyrill Géraud, Iris Augustin, Michael Boutros, Hellmut G Augustin, Jürgen G Okun, Claus-Dieter Langhans, Johanna Zierow, Sebastian A Wohlfeil, Victor Olsavszky, Kai Schledzewski, Sergij Goerdt, Philipp-Sebastian Koch
Postnatal liver development is characterized by hepatocyte growth, proliferation and functional maturation. Notably, canonical Wnt signaling in hepatocytes has been identified as an important regulator of final adult liver size and metabolic liver zonation. The cellular origin of Wnt ligands responsible for homeostatic liver/body weight ratio remained unclear, which was also attributable to a lack of suitable endothelial Cre driver mice. To comprehensively analyze the effects of hepatic angiocrine Wnt signaling on liver development and metabolic functions, we used endothelial subtype-specific Stab2-Cre driver mice to delete Wls from hepatic endothelial cells (HEC)...
October 23, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Paul H Weigel
Exciting discoveries in many diverse fields of hyaluronan (HA) biology over the last 40 years have centered around the ability of HA to bind cell surface HA receptors (e.g., CD44, Layilin, LYVE-1, HARE/Stab2 and RHAMM) and sometimes also to activate intracellular signal transduction pathways, frequently involving ERK1/2. Although perplexing, a major characteristic of HA-mediated signal pathway activation for some receptors has been a dependence on the size of the bound HA. Receptors that directly interact with HA, which may not include TLR2/4, bind very well to any HA molecule >8-20 sugars, depending on the receptor...
September 1, 2017: Glycobiology
Philipp-Sebastian Koch, Victor Olsavszky, Friederike Ulbrich, Carsten Sticht, Alexandra Demory, Thomas Leibing, Thomas Henzler, Mathias Meyer, Johanna Zierow, Sven Schneider, Katja Breitkopf-Heinlein, Haristi Gaitantzi, Bradley Spencer-Dene, Bernd Arnold, Kay Klapproth, Kai Schledzewski, Sergij Goerdt, Cyrill Géraud
Microvascular endothelial cells (ECs) display a high degree of phenotypic and functional heterogeneity among different organs. Organ-specific ECs control their tissue microenvironment by angiocrine factors in health and disease. Liver sinusoidal endothelial cells (LSECs) are uniquely differentiated to fulfill important organ-specific functions in development, under homeostatic conditions, and in regeneration and liver pathology. Recently, Bmp2 has been identified by us as an organ-specific angiokine derived from LSECs...
January 26, 2017: Blood
Wenbin Guan, Yu Yan, Wenguang He, Meng Qiao, Yi Liu, Yanhua Wang, Bo Jiang, Wenwei Yu, Ruifen Wang, Lifeng Wang
Ossifying renal tumor of infancy (ORTI) is a rare benign pediatric renal tumor, which has typical clinical and pathological features. In this article, the histological features, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assay of two cases of ORTI were performed and the literatures were reviewed. Both of the patients presented to hospital with painless gross hematuria without other symptoms. One is 6 months old male, another is 5-month-old. After several diagnostic procedures, they underwent surgery and the histological diagnosis of ORTI was finally made...
November 2016: Pathology, Research and Practice
Xiaohua Sun, Sanhong Liu, Pengfei Chen, Da Fu, Yingyong Hou, Jin Hu, Zhi Liu, Yuhang Jiang, Xinwei Cao, Chunyan Cheng, Xi Chen, Yu Tao, Cuifeng Li, Yiming Hu, Zhanjie Liu, Yu Zhan, Jie Mao, Qi Wang, Yushui Ma, Xianling Cong, Ran Sun, Yufang Shi, Mingliang Wang, Xiaoren Zhang
miR-449a has been reported to act as a tumor suppressor in several cancers, however, it is controversial whether it inhibits tumor growth in colorectal cancer. The mechanisms underlying its expression and functions in colorectal cancers are still largely unknown. SATB2 is a sensitive and specific marker for CRC diagnosis. However, the mechanisms by which the expression and functions of SATB2 are regulated still remain to be clarified. We investigated the expression and functional significance of miR-449a and SATB2 and the mechanisms of their dysregulation in human CRC cells...
July 28, 2016: Oncotarget
Go-Woon Kim, Seung-Yoon Park, In-San Kim
Myoblast fusion is important for skeletal muscle formation. Even though the knowledge of myoblast fusion mechanism has accumulated over the years, the initial signal of fusion is yet to be elucidated. Our study reveals the novel function of a phosphatidylserine (PS) receptor, stabilin-2 (Stab2), in the modulation of myoblast fusion, through the recognition of PS exposed on myoblasts. During differentiation of myoblasts, Stab2 expression is higher than other PS receptors and is controlled by calcineurin/NFAT signaling on myoblasts...
June 2016: BMB Reports
Seung-Yoon Park, Youngeun Yun, Jung-Suk Lim, Mi-Jin Kim, Sang-Yeob Kim, Jung-Eun Kim, In-San Kim
Myoblast fusion is essential for the formation of skeletal muscle myofibres. Studies have shown that phosphatidylserine is necessary for myoblast fusion, but the underlying mechanism is not known. Here we show that the phosphatidylserine receptor stabilin-2 acts as a membrane protein for myoblast fusion during myogenic differentiation and muscle regeneration. Stabilin-2 expression is induced during myogenic differentiation, and is regulated by calcineurin/NFAT signalling in myoblasts. Forced expression of stabilin-2 in myoblasts is associated with increased myotube formation, whereas deficiency of stabilin-2 results in the formation of small, thin myotubes...
2016: Nature Communications
Janine van Loon, Abbas Dehghan, Tang Weihong, Stella Trompet, Wendy L McArdle, Folkert W Asselbergs, Ming-Huei Chen, Lorna M Lopez, Jennifer E Huffman, Frank W G Leebeek, Saonli Basu, David J Stott, Ann Rumley, Ron T Gansevoort, Gail Davies, James J F Wilson, Jacqueline C M Witteman, Xiting Cao, Anton J M de Craen, Stephan J L Bakker, Bruce M Psaty, John M Starr, Albert Hofman, J Wouter Jukema, Ian J Deary, Caroline Hayward, Pim van der Harst, Gordon D O Lowe, Aaron R Folsom, David P Strachan, Nicolas Smith, Moniek P M de Maat, Christopher O'Donnell
Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available...
July 2016: European Journal of Human Genetics: EJHG
Florent Baty, Dirk Klingbiel, Francesco Zappa, Martin Brutsche
Alternative splicing is an important component of tumorigenesis. Recent advent of exon array technology enables the detection of alternative splicing at a genome-wide scale. The analysis of high-throughput alternative splicing is not yet standard and methodological developments are still needed. We propose a novel statistical approach-Dually Constrained Correspondence Analysis-for the detection of splicing changes in exon array data. Using this methodology, we investigated the genome-wide alteration of alternative splicing in patients with non-small cell lung cancer treated by bevacizumab/erlotinib...
December 2015: Journal of Biomedical Informatics
Muhammad Farooq Rai, Eric J Schmidt, Shingo Hashimoto, James M Cheverud, Linda J Sandell
This study reports on genetic susceptibility to ectopic calcification in the LG/J and SM/J advanced intercross mice. Using 347 mice in 98 full-sibships, destabilization of medial meniscus (DMM) was performed to induce joint injury. We found that joint destabilization instigated ectopic calcifications as detected and quantified by micro-CT. We performed quantitative trait locus (QTL) analysis to map ectopic calcification phenotypes to discrete genomic locations. To validate the functional significance of the selected QTL candidate genes, we compared mRNA expression between parental LG/J and SM/J inbred strains...
October 2015: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
Y V Sanders, J G van der Bom, A Isaacs, M H Cnossen, M P M de Maat, B A P Laros-van Gorkom, K Fijnvandraat, K Meijer, C M van Duijn, E P Mauser-Bunschoten, J Eikenboom, F W G Leebeek
BACKGROUND: von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown. OBJECTIVES: To investigate the association between single-nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype. PATIENTS/METHODS: In 364 type 1 VWD and 240 type 2 VWD patients from the nationwide cross-sectional 'Willebrand in The Netherlands' (WiN) study, we studied the association between eight SNPs in STXBP5, SCARA5, ABO, VWF, STAB2, STX2, TC2N, and CLEC4M, and VWF antigen (VWF:Ag), VWF activity (VWF:Act), and bleeding phenotype as assessed with the Tosetto bleeding score...
June 2015: Journal of Thrombosis and Haemostasis: JTH
M Iris Hermanns, Vera Grossmann, Henri M H Spronk, Andreas Schulz, Claus Jünger, Dagmar Laubert-Reh, Johanna Mazur, Tommaso Gori, Tanja Zeller, Norbert Pfeiffer, Manfred Beutel, Stefan Blankenberg, Thomas Münzel, Karl J Lackner, Arina J Ten Cate-Hoek, Hugo Ten Cate, Philipp S Wild
BACKGROUND: Elevated levels of FVIII: c are associated with risk for both venous and arterial thromboembolism. However, no population-based study on the sex-specific distribution and reference ranges of plasma FVIII: c and its cardiovascular determinants is available. METHODS: HASH(0x489cbc0) FVIII: c was analyzed in a randomly selected sample of 2533 males and 2440 females from the Gutenberg Health Study in Germany...
2015: International Journal of Cardiology
Yukako Kayashima, Natalia A Makhanova, Kota Matsuki, Hirofumi Tomita, Brian J Bennett, Nobuyo Maeda
The genetic background of apolipoprotein E (apoE) deficient mice influences atherosclerotic plaque development. We previously reported three quantitative trait loci (QTL), Aath1-Aath3, that affect aortic arch atherosclerosis independently of those in the aortic root in a cross between C57BL6 apoEKO mice (B6-apoE) and 129S6 apoEKO mice (129-apoE). To gain further insight into genetic factors that influence atherosclerosis at different vascular locations, we analyzed 335 F2 mice from an intercross between 129-apoE and apoEKO mice on a DBA/2J genetic background (DBA-apoE)...
2015: PloS One
Amanda K Hare, Edward N Harris
The hyaluronan receptor for endocytosis (HARE), or Stabilin-2, is the mammalian endocytic clearance receptor for HA, heparin, advanced glycation end-products, acetylated and oxidized low-density lipoproteins and collagen N-terminal propeptides. This large 2551 amino acid receptor is encoded by a gene that covers over 180 kbp on human chromosome 12 and is predicted to be composed of 69 exons. Due to the expression profile of this gene and the number of exons it contains, we hypothesized that splice variants of stab2 are encoded in these tissues...
January 2, 2015: Biochemical and Biophysical Research Communications
Hyeon-Min Jang, Gisela F Erf, Kaylee C Rowland, Byung-Whi Kong
BACKGROUND: The Smyth line (SL) chicken is the only animal model for autoimmune vitiligo that spontaneously displays all clinical and biological manifestations of the human disorder. To understand the genetic components underlying the susceptibility to develop SL vitiligo (SLV), whole genome resequencing analysis was performed in SLV chickens compared with non-vitiliginous parental Brown line (BL) chickens, which maintain a very low incidence rate of vitiligo. RESULTS: Illumina sequencing technology and reference based assembly on Red Jungle Fowl genome sequences were used...
2014: BMC Genomics
Madhu S Pandey, Paul H Weigel
The human hyaluronan (HA) receptor for endocytosis (HARE; the 190-kDa C terminus of Stab2) is a major clearance receptor for multiple circulating ligands including HA, heparin (Hep), acetylated LDL (AcLDL), dermatan sulfate (DS), apoptotic debris, and chondroitin sulfate types A, C, D, and E. We previously found that HARE contains an N-glycan in the HA binding Link domain (at Asn(2280)), and cells expressing membrane-bound HARE(N2280A) bind and endocytose HA normally (Harris, E. N., Parry, S., Sutton-Smith, M...
August 8, 2014: Journal of Biological Chemistry
Saem Mul Park, Catherine E Angel, Julie D McIntosh, Claudia J Mansell, Claudia M Mansell, Chun-Jen J Chen, Jonathon Cebon, P Rod Dunbar
The lymphatic sinuses in human lymph nodes (LNs) are crucial to LN function yet their structure remains poorly defined. Much of our current knowledge of lymphatic sinuses derives from rodent models, however human LNs differ substantially in their sinus structure, most notably due to the presence of trabeculae and trabecular lymphatic sinuses that rodent LNs lack. Lymphatic sinuses are bounded and traversed by lymphatic endothelial cells (LECs). A better understanding of LECs in human LNs is likely to improve our understanding of the regulation of cell trafficking within LNs, now an important therapeutic target, as well as disease processes that involve lymphatic sinuses...
2014: PloS One
Megan S Rost, Saulius Sumanas
The hyaluronic acid receptor for endocytosis Stabilin-2/HARE mediates systemic clearance of multiple glycosaminoglycans from the vascular and lymphatic circulations. In addition, recent in vitro studies indicate that Stab2 can participate in signal transduction by interacting with hyaluronic acid (HA), which results in Erk phosphorylation. However, it is not known whether Stab2 function or HA-Stab2 signaling play any role in embryonic development. Here we show that Stab2 functions in a signal transduction pathway regulating arterial-venous differentiation during zebrafish embryogenesis...
2014: PloS One
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