24 results on '"Dorothy Zhang"'
Search Results
2. Induced Gnas R201H expression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/β-catenin signaling
- Author
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Khan, Sanjoy Kumar, Yadav, Prem Swaroop, Elliott, Gene, Hu, Dorothy Zhang, Xu, Ruoshi, and Yang, Yingzi
- Published
- 2018
3. A Systematic Literature Review of Group Contingencies Within General Education Classrooms
- Author
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Brittany N. Beaver, Tyler C. Ré, Annette K. Griffith, Dorothy Zhang, and Mary A. Schoener
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General Medicine - Published
- 2023
4. Synthetic Data: A New Regulatory Tool
- Author
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John C. Hull, Jay Cao, Jacky Chen, Zissis Poulos, and dorothy zhang
- Published
- 2021
5. MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice
- Author
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Zou, Weiguo, Greenblatt, Matthew B., Shim, Jae-Hyuck, Kant, Shashi, Zhai, Bo, Lotinun, Sutada, Brady, Nicholas, Hu, Dorothy Zhang, Gygi, Steven P., Baron, Roland, Davis, Roger J., Jones, Dallas, and Glimcher, Laurie H.
- Published
- 2011
- Full Text
- View/download PDF
6. Letter to Editor: The Synergistic Effect of Albumin on Terlipressin in Acute-on-Chronic Liver Failure With Acute Kidney Injury
- Author
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Shengtao Lin, Bing Hou, Yuan Gao, Da Dorothy Zhang, and Yueke Zhu
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Albumin ,Acute kidney injury ,Acute-On-Chronic Liver Failure ,Lypressin ,Acute Kidney Injury ,medicine.disease ,Gastroenterology ,Norepinephrine (medication) ,Norepinephrine ,Text mining ,Internal medicine ,Albumins ,medicine ,Humans ,Acute on chronic liver failure ,Terlipressin ,business ,medicine.drug - Published
- 2019
7. Developing composite nanofibre fabrics using electrospinning, ultrasonic sewing, and laser cutting technologies
- Author
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Dorothy Zhang, Margaret W. Frey, Nidia K. Trejo, Catherine G. Reyes, and Vanessa Sanchez
- Subjects
Nanofabrics ,010407 polymers ,Engineering drawing ,Materials science ,Visual Arts and Performing Arts ,Laser cutting ,Composite number ,02 engineering and technology ,Yarn ,021001 nanoscience & nanotechnology ,01 natural sciences ,Industrial and Manufacturing Engineering ,Electrospinning ,0104 chemical sciences ,Education ,Stress (mechanics) ,chemistry.chemical_compound ,Nylon 6 ,chemistry ,visual_art ,visual_art.visual_art_medium ,Ultrasonic sensor ,Composite material ,0210 nano-technology - Abstract
In this study, we combine Nylon 6 nanomembranes with tulle and organza fashion fabrics to construct a full-scale, flying kite. For the first time, this work demonstrates the processing of electrospun nanofabrics using laser cut and ultrasonic technologies. The composite fabrics were analysed for their morphological and mechanical properties. Micrographs show the nanofibres are about 129 nm in diameter and the fashion fabrics have yarn diameters greater than 40 µm. The nanofibres were at least 300 times smaller than the individual fibres in the fashion fabrics and successfully joined with non-puncturing ultrasonic seaming. The fracture strain of the nanomembrane–tulle composites increased 58–171% compared to the control samples due to nanofibre entanglements on the open weave structure of tulle. The ultrasonic sewn fabric regions endured 169% greater applied stress with the addition of the organza fabric and the seaming process compared to the nanomembrane–tulle composite. The burst strength of the...
- Published
- 2016
8. Induced
- Author
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Sanjoy Kumar, Khan, Prem Swaroop, Yadav, Gene, Elliott, Dorothy Zhang, Hu, Ruoshi, Xu, and Yingzi, Yang
- Subjects
Osteoblasts ,Cell Differentiation ,Mesenchymal Stem Cells ,Fibrous Dysplasia of Bone ,Up-Regulation ,Wnt Proteins ,Gene Expression Regulation ,PNAS Plus ,Mutation ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,Humans ,beta Catenin ,Signal Transduction - Abstract
Understanding molecular and cellular mechanisms of rare genetic diseases provides invaluable insights into the human biology and pathology of both rare and related common diseases. Fibrous dysplasia (FD) is a mosaic disease resulting from postzygotic activating mutations of GNAS. The mouse models we created allowed us to precisely model FD by expressing the FD Gαs mutation under the control of its endogenous genetic locus. We found in our FD mouse models that up-regulated Wnt/β-catenin signaling resulted in impaired differentiation and proliferation of bone marrow stem cells, which in turn caused marrow fibrosis. Our work provides a solid new foundation for therapeutic development of FD and understanding the principles whereby Gαs signaling governs bone formation and maintenance and bone marrow stromal cell differentiation.
- Published
- 2017
9. Addressing the Needs of Students with Autism and Other Disabilities in China: Perspectives from the Field
- Author
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Dorothy Zhang and Vicky G. Spencer
- Subjects
Semi-structured interview ,Health (social science) ,Teaching method ,education ,Psychological intervention ,Special education ,medicine.disease ,Health Professions (miscellaneous) ,Teacher education ,Education ,Pedagogy ,Developmental and Educational Psychology ,medicine ,Autism ,Psychology ,Curriculum ,Qualitative research - Abstract
Autism is a developmental disability that has gained increasing attention during the past several decades in China. The two case studies presented in this article examined the perspectives of two school leaders on educating students with autism in China. Two school principals, one from a public school and one from a private school, were interviewed during this study using 10 open-ended questions. Responses generated the following areas of discussion: teacher recruitment and training, curriculum and teaching methodology, parental involvement, and factors that contribute to success and present challenges. This study provides the readers with an update from the perspectives of two school leaders on the school system in China for children with disabilities, particularly for students with autism. Implications of the study and further suggestions for future research are also discussed.
- Published
- 2015
10. Induced GnasR201Hexpression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/β-catenin signaling
- Author
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Khan, Sanjoy Kumar, primary, Yadav, Prem Swaroop, additional, Elliott, Gene, additional, Hu, Dorothy Zhang, additional, Xu, Ruoshi, additional, and Yang, Yingzi, additional
- Published
- 2017
- Full Text
- View/download PDF
11. Colitis-Associated Colorectal Cancer Driven by T-bet Deficiency in Dendritic Cells
- Author
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Graham M. Lord, Carey Ann Gallini, Dorothy Zhang, Laurie H. Glimcher, Kirsten Sigrist, Jonathan N. Glickman, Wendy S. Garrett, Monia Michaud, and Shivesh Punit
- Subjects
Cancer Research ,Colon ,Colorectal cancer ,chemical and pharmacologic phenomena ,Inflammation ,CELLCYCLE ,Article ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Rectal Adenocarcinoma ,Animals ,Humans ,Colitis ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Innate immune system ,business.industry ,hemic and immune systems ,Dendritic Cells ,Cell Biology ,Cell cycle ,medicine.disease ,Immunohistochemistry ,Ulcerative colitis ,digestive system diseases ,3. Good health ,DNA-Binding Proteins ,Disease Models, Animal ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Colitis, Ulcerative ,medicine.symptom ,Colorectal Neoplasms ,T-Box Domain Proteins ,business - Abstract
SummaryWe previously described a mouse model of ulcerative colitis linked to T-bet deficiency in the innate immune system. Here, we report that the majority of T-bet−/−RAG2−/− ulcerative colitis (TRUC) mice spontaneously progress to colonic dysplasia and rectal adenocarcinoma solely as a consequence of MyD88-independent intestinal inflammation. Dendritic cells (DCs) are necessary cellular effectors for a proinflammatory program that is carcinogenic. Whereas these malignancies arise in the setting of a complex inflammatory environment, restoration of T-bet selectively in DCs was sufficient to reduce colonic inflammation and prevent the development of neoplasia. TRUC colitis-associated colorectal cancer resembles the human disease and provides ample opportunity to probe how inflammation drives colorectal cancer development and to test preventative and therapeutic strategies preclinically.
- Published
- 2009
12. Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice
- Author
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Michael J. Grusby, Andrea L. Wurster, Tom Van Belle, Andrew P. R. Sutherland, Monia Michaud, Dorothy Zhang, Matthias von Herrath, and Akira Suto
- Subjects
Insulin Antibodies ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Nod ,Biology ,Islets of Langerhans ,Mice ,Interleukin 21 ,Mice, Inbred NOD ,Insulin Secretion ,Internal Medicine ,medicine ,Animals ,Insulin ,Pancreas ,NOD mice ,Mice, Knockout ,Type 1 diabetes ,Reverse Transcriptase Polymerase Chain Reaction ,Interleukins ,Receptors, Interleukin-1 ,medicine.disease ,Mice, Inbred C57BL ,Diabetes Mellitus, Type 1 ,Cytokine ,Interleukin-21 receptor ,Immunology ,RNA ,Original Article ,Immunology and Transplantation ,Insulitis ,Spleen ,Signal Transduction - Abstract
OBJECTIVE Interleukin (IL)-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes via the unique biology of the nonobese diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in type 1 diabetes. RESEARCH DESIGN AND METHODS We generated IL-21R–deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic β-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in type 1 diabetes. RESULTS Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies, and onset of type 1 diabetes. The lymphoid compartment in IL-21R−/− NOD is normal and does not contain an increased regulatory T-cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T-cells in IL-21R−/− NOD by transfer experiments. Conversely, overexpression of IL-21 in pancreatic β-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-γ, monocyte chemoattractant protein (MCP)-1, MCP-2, and interferon-inducible protein-10 in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of β-cells and spontaneous type 1 diabetes in the normally diabetes-resistant C57Bl/6 and NOD × C57Bl/6 backgrounds. CONCLUSIONS This work provides demonstration of the essential prodiabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human type 1 diabetes.
- Published
- 2009
13. Developing composite nanofibre fabrics using electrospinning, ultrasonic sewing, and laser cutting technologies
- Author
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Nidia K. Trejo, Catherine G. Reyes, Vanessa Sanchez, Dorothy Zhang, Margaret W. Frey, Nidia K. Trejo, Catherine G. Reyes, Vanessa Sanchez, Dorothy Zhang, and Margaret W. Frey
- Published
- 2016
- Full Text
- View/download PDF
14. Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system
- Author
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Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, and Laurie H. Glimcher
- Subjects
General Medicine - Published
- 2004
15. Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron
- Author
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Ansermet, Camille, primary, Moor, Matthias B., additional, Centeno, Gabriel, additional, Auberson, Muriel, additional, Hu, Dorothy Zhang, additional, Baron, Roland, additional, Nikolaeva, Svetlana, additional, Haenzi, Barbara, additional, Katanaeva, Natalya, additional, Gautschi, Ivan, additional, Katanaev, Vladimir, additional, Rotman, Samuel, additional, Koesters, Robert, additional, Schild, Laurent, additional, Pradervand, Sylvain, additional, Bonny, Olivier, additional, and Firsov, Dmitri, additional
- Published
- 2016
- Full Text
- View/download PDF
16. Molecular Cloning, Characterization, and Promoter Analysis of the Mouse Crp2/SmLim Gene
- Author
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Mark A. Perrella, Masao Yoshizumi, Shaw-Fang Yet, Mu-En Lee, Koji Maemura, Michael T. Chin, Pooja B. Marria, Sara C. Folta, Chung-Ming Hsieh, Mukesh K. Jain, Matthew D. Layne, and Dorothy Zhang
- Subjects
Regulation of gene expression ,Rapid amplification of cDNA ends ,Transcription (biology) ,Complementary DNA ,E-box ,Electrophoretic mobility shift assay ,Cell Biology ,Biology ,Molecular cloning ,Molecular Biology ,Biochemistry ,Gene ,Molecular biology - Abstract
Several members of the LIM protein family have important roles in development and differentiation. We recently isolated a rat cDNA encoding a new member of this family, CRP2/SmLIM, that contains two LIM domains and is expressed preferentially in vascular smooth muscle cells (VSMC). To study the molecular mechanisms that regulate VSMC-specific transcription of the Crp2/SmLim gene, we cloned the cDNA and gene of mouse Crp2/SmLim. Mouse Crp2/SmLim is a single copy gene of six exons and five introns spanning approximately 20 kilobases of genomic DNA. By 5'-rapid amplification of cDNA ends and S1 nuclease protection assay, we determined that the transcription start site is an A residue 80 base pairs 5' of the translation initiation codon. A TATA-like sequence is located 27 base pairs 5' of the transcription start site, and there are potential cis-acting elements (GATA, Sp1, AP-2, E box, CCAC box, and GArC motif) in the 5'-flanking sequence. In transient transfection assays in rat aortic smooth muscle cells in primary culture, 5 kilobases of the Crp2/SmLim 5'-flanking sequence generated a high level of luciferase reporter gene activity. By deletion analysis and gel mobility shift assay, we found that the region between bases -74 and -39 of this 5 kilobase DNA fragment binds Sp1 and confers basal promoter activity in the Crp2/SmLim gene. In vitro, the 5-kilobase fragment was active in multiple cell types. In vivo, however, the 5-kilobase fragment directed high level expression of the lacZ reporter gene preferentially in the VSMC of transgenic mice, indicating the presence of VSMC-specific element(s) in this fragment.
- Published
- 1998
17. Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus
- Author
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Adrian Erlebacher, Dorothy Zhang, Kelly A. Price, Daniela Vencato, and Laurie H. Glimcher
- Subjects
Male ,Ovalbumin ,T cell ,T-Lymphocytes ,Antigen presentation ,Priming (immunology) ,Mice, Transgenic ,Major histocompatibility complex ,Mice ,Immune system ,Fetus ,Antigen ,Pregnancy ,medicine ,Cytotoxic T cell ,Animals ,Mice, Knockout ,Antigen Presentation ,biology ,Egg Proteins ,H-2 Antigens ,General Medicine ,medicine.disease ,Peptide Fragments ,Transplant rejection ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Immunology ,biology.protein ,Mice, Inbred CBA ,Female ,Research Article - Abstract
How the fetus escapes rejection by the maternal immune system remains one of the major unsolved questions in transplantation immunology. Using a system to visualize both CD4+ and CD8+ T cell responses during pregnancy in mice, we find that maternal T cells become aware of the fetal allograft exclusively through “indirect” antigen presentation, meaning that T cell engagement requires the uptake and processing of fetal/placental antigen by maternal APCs. This reliance on a relatively minor allorecognition pathway removes a major threat to fetal survival, since it avoids engaging the large number of T cells that typically drive acute transplant rejection through their ability to directly interact with foreign MHC molecules. Furthermore, CD8+ T cells that indirectly recognize fetal/placental antigen undergo clonal deletion without priming for cytotoxic effector function and cannot induce antigen-specific fetal demise even when artificially activated. Antigen presentation commenced only at mid-gestation, in association with the endovascular invasion of placental trophoblasts and the hematogenous release of placental debris. Our results suggest that limited pathways of antigen presentation, in conjunction with tandem mechanisms of immune evasion, contribute to the unique immunological status of the fetus. The pronounced degree of T cell ignorance of the fetus also has implications for the pathophysiology of immune-mediated early pregnancy loss.
- Published
- 2007
18. Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system
- Author
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Adrian, Erlebacher, Dorothy, Zhang, Albert F, Parlow, and Laurie H, Glimcher
- Subjects
Inflammation ,Receptors, Prolactin ,Tumor Necrosis Factor-alpha ,biochemical phenomena, metabolism, and nutrition ,Primary Ovarian Insufficiency ,Abortion, Spontaneous ,Killer Cells, Natural ,Disease Models, Animal ,Mice ,Corpus Luteum ,Pregnancy ,Commentary ,bacteria ,Animals ,Female ,CD40 Antigens ,Fetal Death ,Signal Transduction - Abstract
We describe a murine model of early pregnancy failure induced by systemic activation of the CD40 immune costimulatory pathway. Although fetal loss involved an NK cell intermediate, it was not due to lymphocyte-mediated destruction of the fetus and placenta. Rather, pregnancy failure resulted from impaired progesterone synthesis by the corpus luteum of the ovary, an endocrine defect in turn associated with ovarian resistance to the gonadotropic effects of prolactin. Pregnancy failure also required the proinflammatory cytokine TNF-alpha and correlated with the luteal induction of the prolactin receptor signaling inhibitors suppressor of cytokine signaling 1 (Socs1) and Socs3. Such links between immune activation and reproductive endocrine dysfunction may be relevant to pregnancy loss and other clinical disorders of reproduction.
- Published
- 2003
19. Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis
- Author
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Peter Carmeliet, Mu-En Lee, Anand Patel, Chengwei Shi, Nicholas E.S. Sibinga, Dorothy Zhang, Edgar Haber, Hong Wang, and Guy L. Reed
- Subjects
Neointima ,Male ,Pathology ,medicine.medical_specialty ,Intimal hyperplasia ,Time Factors ,Physiology ,Lumen (anatomy) ,Muscle, Smooth, Vascular ,Veins ,Mice ,Jugular vein ,Medicine ,Animals ,Coronary Artery Bypass ,Hyperplasia ,business.industry ,Plasminogen ,Anatomy ,medicine.disease ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Circulatory system ,Leukocyte Common Antigens ,Cardiology and Cardiovascular Medicine ,business ,Vein graft disease ,External jugular vein ,Blood vessel - Abstract
Abstract —Recent studies of mice that lack plasminogen have identified a critical role for this zymogen in arterial remodeling. To permit the use of these (and other) genetically modified mice in the analysis of venous injury, we developed a model in which a patch cut from the external jugular vein of a mouse is grafted to repair a surgically created defect in its carotid artery. In wild-type mice, the venous graft showed initial endothelial denudation and formation of a neointima that progressively and reproducibly expanded in a manner analogous to human vein graft disease, albeit at an accelerated pace. This neointima occupied 37±4.6% of the vessel lumen at day 7 and 66±5.7% at day 20. The proliferative index of neointimal cells assessed by proliferating cell nuclear antigen staining was 50.6±3.6% at day 7 and 15.2±2.0% at day 20. CD45-positive leukocytes and α-actin–positive smooth muscle cells accounted for 9.5±1.0% and 9.9±1.1% of intimal area at day 7, respectively, with the latter increasing to 40.9±2.6% at day 20. Collagen accounted for 6.8±0.7% of intimal area at day 7 and 20.7±1.8% at day 20. Surprisingly, even though arterial neointima formation due to electrostatic and immune-mediated injury is impaired in plasminogen –/– mice, in our study vein graft neointima formation in these mice was not significantly different from that in controls (70.9±6.4 versus 65.6±4.4% luminal occlusion, P =NS). Thus, plasmin proteolysis, although critical in extracellular matrix degradation and cellular migration after arterial injury, does not appear to be so important in vein graft neointima formation, perhaps because of the relative lack of structural barriers to cellular migration in the normal vein wall. This novel model of vein graft injury should be useful for further studies of differences in the response to injury of arterial and venous tissues.
- Published
- 1999
20. Donor MHC and adhesion molecules in transplant arteriosclerosis
- Author
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Zhao Ming Dong, Chengwei Shi, Anand Patel, Jose-Carlos Gutierrez-Ramos, Mark W. Feinberg, Susan M. Chapman, Nicholas E.S. Sibinga, Denisa D. Wagner, Edgar Haber, Dorothy Zhang, and Chang U. Sim
- Subjects
Neointima ,P-selectin ,Arteriosclerosis ,Intercellular Adhesion Molecule-1 ,chemical and pharmacologic phenomena ,Major histocompatibility complex ,Article ,Mice ,Transplantation Immunology ,MHC class I ,medicine ,Animals ,Transplantation, Homologous ,biology ,Cell adhesion molecule ,Histocompatibility Antigens Class I ,Histocompatibility Antigens Class II ,General Medicine ,medicine.disease ,Intercellular adhesion molecule ,Molecular biology ,P-Selectin ,Carotid Arteries ,Immunology ,biology.protein ,Mice, Inbred CBA - Abstract
Transplant-associated arteriosclerosis remains an obstacle to long-term graft survival. To determine the contribution to transplant arteriosclerosis of MHC and adhesion molecules from cells of the donor vasculature, we allografted carotid artery loops from six mutant mouse strains into immunocompetent CBA/CaJ recipients. The donor mice were deficient in either MHC I molecules or MHC II molecules, both MHC I and MHC II molecules, the adhesion molecule P-selectin, intercellular adhesion molecule (ICAM)-1, or both P-selectin and ICAM-1. Donor arteries in which ICAM-1, MHC II, or both MHC I and MHC II were absent showed reductions in neointima formation of 52%, 33%, and 38%, respectively, due primarily to a reduction in smooth muscle cell (SMC) accumulation. In P-selectin-deficient donor arteries, neointima formation did not differ from that in controls. In donor arteries lacking both P-selectin and ICAM-1, the size of the neointima was similar to that in those lacking ICAM-1 alone. In contrast, neointima formation increased by 52% in MHC I-deficient donor arteries. The number of CD4-positive T cells increased by 2.8-fold in MHC I-deficient arteries, and that of alpha-actin-positive SMCs by twofold. These observations indicate that ICAM-1 and MHC II molecules expressed in the donor vessel wall may promote transplant-associated arteriosclerosis. MHC I molecules expressed in the donor may have a protective effect.
- Published
- 1999
21. Hypercholesterolemia exacerbates transplant arteriosclerosis via increased neointimal smooth muscle cell accumulation: studies in apolipoprotein E knockout mice
- Author
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Donald L. Fletcher, Dorothy Zhang, Chengwei Shi, Wen Sen Lee, Edgar Haber, John B. Newell, and Mary E. Russell
- Subjects
Apolipoprotein E ,Neointima ,medicine.medical_specialty ,Pathology ,Apolipoprotein B ,Arteriosclerosis ,Hypercholesterolemia ,Muscle, Smooth, Vascular ,chemistry.chemical_compound ,Mice ,Apolipoproteins E ,Risk Factors ,Physiology (medical) ,medicine ,Oil Red O ,Animals ,Mice, Knockout ,biology ,business.industry ,Vascular disease ,medicine.disease ,Surgery ,Transplantation ,Mice, Inbred C57BL ,chemistry ,Knockout mouse ,biology.protein ,Heart Transplantation ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Hypercholesterolemia is thought to be a significant risk factor for coronary vasculopathy in cardiac transplant recipients. Methods and Results We examined the development of arteriosclerosis in mouse carotid artery loops allografted from B.10A(2R) (H-2 h2 ) donors to normocholesterolemic C57BL/6J (H-2 b ) recipients and hypercholesterolemic C57BL/6J recipients in which the apolipoprotein (apo) E gene had been knocked out. Luminal occlusion and cross-sectional neointimal area were greater in arteries allografted into hypercholesterolemic recipients at 15 and 30 days after transplantation. We also measured cellular and extracellular matrix components of the neointima by computerized planimetry of the fractional areas subtended by smooth muscle cells (anti–α-actin stain), collagen (Masson’s trichrome), lipid (oil red O), and leukocytes (anti-CD45). The neointimal area stained for smooth muscle cells was significantly greater in hypercholesterolemic recipients than in normocholesterolemic recipients at 15 and 30 days after allografting. Lipid contributed to neointimal area to a lesser degree, and there was no significant increase in the contribution of collagen or leukocytes. Conclusions Smooth muscle cell accumulation appears to be the principal contributor to the increase in neointimal area observed in arteries allografted into hypercholesterolemic mice.
- Published
- 1997
22. Immunologic basis of transplant-associated arteriosclerosis
- Author
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Donald L. Fletcher, Chengwei Shi, Qi He, John B. Newell, Dorothy Zhang, Wen Sen Lee, and Edgar Haber
- Subjects
Neointima ,CD4-Positive T-Lymphocytes ,Graft Rejection ,Smooth muscle cell migration ,Arteriosclerosis ,Mice, Inbred Strains ,Biology ,CD8-Positive T-Lymphocytes ,Lymphocyte Depletion ,Mice ,Immune system ,Adventitia ,medicine ,Cytotoxic T cell ,Animals ,Transplantation, Homologous ,Receptor ,B-Lymphocytes ,Multidisciplinary ,Macrophages ,medicine.disease ,Mice, Mutant Strains ,Killer Cells, Natural ,medicine.anatomical_structure ,Carotid Arteries ,Immunology ,Heart Transplantation ,Tunica Intima ,CD8 ,Research Article - Abstract
Although immunosuppressive therapy minimizes the risk of graft failure due to acute rejection, transplant-associated arteriosclerosis of the coronary arteries remains a significant obstacle to the long-term survival of heart transplant recipients. The participation of specific inflammatory cell types in the genesis of this lesion was examined in a mouse model in which carotid arteries were transplanted across multiple histocompatibility barriers into seven mutant strains with immunologic defects. An acquired immune response--with the participation of CD4+ (helper) T cells, humoral antibody, and macrophages--was essential to the development of the concentric neointimal proliferation and luminal narrowing characteristic of transplant arteriosclerosis. CD8+ (cytotoxic) T cells and natural killer cells were not involved in the process. Arteries allografted into mice deficient in both T-cell receptors and humoral antibody showed almost no neointimal proliferation, whereas those grafted into mice deficient only in helper T cells, humoral antibody, or macrophages developed small neointimas. These small neointimas and the large neointimas of arteries grafted into control animals contained a similar number of inflammatory cells; however, smooth muscle cell number and collagen deposition were diminished in the small neointimas. Also, the degree of inflammatory reaction in the adventitia did not correlate with the size of the neointima. Thus, the reduction in neointimal size in arteries allografted into mice deficient in helper T cells, humoral antibody, or macrophages may be accounted for by a decrease in smooth muscle cell migration or proliferation.
- Published
- 1996
23. MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice.
- Author
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Weiguo Zou, Greenblatt, Matthew B., Jae-Hyuck Shim, Kant, Shashi, Bo Zhai, Lotinun, Sutada, Brady, Nicholas, Zhang Hu, Dorothy, Gygi, Steven P., Baron, Roland, Davis, Roger J., Jones, Dallas, Glimcher, Laurie H., Zou, Weiguo, Shim, Jae-Hyuck, Zhai, Bo, and Hu, Dorothy Zhang
- Subjects
- *
CELLULAR signal transduction , *DYSPLASIA , *PROTEIN kinases , *BONE growth , *GENETIC mutation , *BONE diseases , *LABORATORY mice , *FACIAL abnormalities , *PROTEIN metabolism , *DWARFISM , *ANIMAL experimentation , *BIOCHEMISTRY , *BIOLOGICAL models , *COMPARATIVE studies , *CONGENITAL heart disease , *FACE , *MALE reproductive organs , *GENETIC techniques , *HAND abnormalities , *PHENOMENOLOGY , *RESEARCH methodology , *X-linked genetic disorders , *MEDICAL cooperation , *MICE , *PROTEINS , *RESEARCH , *TRANSFERASES , *EVALUATION research , *OSTEOBLASTS , *PHYSIOLOGY - Abstract
Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, Runx2. Mutations in FGD1 found in individuals with FGDY ablated its ability to activate MLK3. Consistent with our description of this pathway and the phenotype of patients with FGD1 mutations, mice with a targeted deletion of Mlk3 displayed multiple skeletal defects, including dental abnormalities, deficient calvarial mineralization, and reduced bone mass. Furthermore, mice with knockin of a mutant Mlk3 allele that is resistant to activation by FGD1/CDC42 displayed similar skeletal defects, demonstrating that activation of MLK3 specifically by FGD1/CDC42 is important for skeletal mineralization. Thus, our results provide a putative biochemical mechanism for the skeletal defects in human FGDY and suggest that modulating MAPK signaling may benefit these patients. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
24. Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron.
- Author
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Ansermet C, Moor MB, Centeno G, Auberson M, Hu DZ, Baron R, Nikolaeva S, Haenzi B, Katanaeva N, Gautschi I, Katanaev V, Rotman S, Koesters R, Schild L, Pradervand S, Bonny O, and Firsov D
- Subjects
- Animals, Female, Male, Mice, Xenotropic and Polytropic Retrovirus Receptor, Fanconi Syndrome etiology, Nephrons, Receptors, G-Protein-Coupled physiology, Receptors, Virus physiology, Rickets, Hypophosphatemic etiology
- Abstract
Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is critical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the molecular identity of the protein(s) participating in the basolateral Pi efflux remains unknown. Evidence has suggested that xenotropic and polytropic retroviral receptor 1 (XPR1) might be involved in this process. Here, we show that conditional inactivation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi reabsorption. Analysis of Pi transport in primary cultures of proximal tubular cells or in freshly isolated renal tubules revealed that this Xpr1 deficiency significantly affected Pi efflux. Further, mice with conditional inactivation of Xpr1 in the renal tubule exhibited generalized proximal tubular dysfunction indicative of Fanconi syndrome, characterized by glycosuria, aminoaciduria, calciuria, and albuminuria. Dramatic alterations in the renal transcriptome, including a significant reduction in NaPi-IIa/NaPi-IIc expression, accompanied these functional changes. Additionally, Xpr1 -deficient mice developed hypophosphatemic rickets secondary to renal dysfunction. These results identify XPR1 as a major regulator of Pi homeostasis and as a potential therapeutic target in bone and kidney disorders., (Copyright © 2017 by the American Society of Nephrology.)
- Published
- 2017
- Full Text
- View/download PDF
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