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1.
J Comput Electron ; 15: 939-958, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27610051

RESUMEN

The Boltzmann transport equation is commonly considered to be the best semi-classical description of carrier transport in semiconductors, providing precise information about the distribution of carriers with respect to time (one dimension), location (three dimensions), and momentum (three dimensions). However, numerical solutions for the seven-dimensional carrier distribution functions are very demanding. The most common solution approach is the stochastic Monte Carlo method, because the gigabytes of memory requirements of deterministic direct solution approaches has not been available until recently. As a remedy, the higher accuracy provided by solutions of the Boltzmann transport equation is often exchanged for lower computational expense by using simpler models based on macroscopic quantities such as carrier density and mean carrier velocity. Recent developments for the deterministic spherical harmonics expansion method have reduced the computational cost for solving the Boltzmann transport equation, enabling the computation of carrier distribution functions even for spatially three-dimensional device simulations within minutes to hours. We summarize recent progress for the spherical harmonics expansion method and show that small currents, reasonable execution times, and rare events such as low-frequency noise, which are all hard or even impossible to simulate with the established Monte Carlo method, can be handled in a straight-forward manner. The applicability of the method for important practical applications is demonstrated for noise simulation, small-signal analysis, hot-carrier degradation, and avalanche breakdown.

3.
Genes Immun ; 12(8): 643-52, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21753787

RESUMEN

In the search for specific genes regulated by DNA methylation in rheumatoid arthritis (RA), we investigated the expression of CXCL12 in synovial fibroblasts (SFs) and the methylation status of its promoter and determined its contribution to the expression of matrix metalloproteinases (MMPs). DNA was isolated from SFs and methylation was analyzed by bisulfite sequencing and McrBC assay. CXCL12 protein was quantified by enzyme-linked immunosorbent assay before and after treatment with 5-azacytidine. RASFs were transfected with CXCR7-siRNA and stimulated with CXCL12. Expression of MMPs was analyzed by real-time PCR. Basal expression of CXCL12 was higher in RASFs than osteoarthritis (OA) SFs. 5-azacytidine demethylation increased the expression of CXCL12 and reduced the methylation of CpG nucleotides. A lower percentage of CpG methylation was found in the CXCL12 promoter of RASFs compared with OASFs. Overall, we observed a significant correlation in the mRNA expression and the CXCL12 promoter DNA methylation. Stimulation of RASFs with CXCL12 increased the expression of MMPs. CXCR7 but not CXCR4 was expressed and functional in SFs. We show here that RASFs produce more CXCL12 than OASFs due to promoter methylation changes and that stimulation with CXCL12 activates MMPs via CXCR7 in SFs. Thereby we describe an endogenously activated pathway in RASFs, which promotes joint destruction.


Asunto(s)
Artritis Reumatoide/genética , Quimiocina CXCL12/genética , Metilación de ADN , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Membrana Sinovial/metabolismo , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/metabolismo , Quimiocina CXCL12/metabolismo , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis/genética , Osteoartritis/metabolismo , Regiones Promotoras Genéticas , Interferencia de ARN , Receptores CXCR/genética , Receptores CXCR/metabolismo , Regulación hacia Arriba
4.
Z Rheumatol ; 70(3): 205-8, 210-2, 2011 Apr.
Artículo en Alemán | MEDLINE | ID: mdl-21424428

RESUMEN

The human genome comprises approximately 30000 genes needed for the formation and function of approximately 1 Million proteins in the human body. Differentiation leads to the deactivation of genes that are not needed in the specific tissues or cells. To regulate the cell specific gene expression in normal cells epigenetic modifications work in concert with genetic mechanisms. In contrast to genetic mutations, epigenetics encompasses the wide range of heritable changes in gene expression that do not result from alteration in the DNA sequence itself. A dysregulation of epigenetic modifications results in diseases such as cancer or autoimmune diseases. Since these epigenetic modifications of the DNA and the histones are reversible they are good targets for novel therapeutic intervention.


Asunto(s)
Epigénesis Genética/genética , Regulación de la Expresión Génica/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genética , Enfermedades Reumáticas/genética , Humanos
5.
Praxis (Bern 1994) ; 100(1): 37-43, 2011 Jan 05.
Artículo en Alemán | MEDLINE | ID: mdl-21210359

RESUMEN

Epigenetic modifications are heritable changes in genome function that occur without a change in DNA sequence. They turn genes on or off by small chemical modifications. Thereby, they change the structure of the DNA making them accessible or not for transcription factors or other DNA binding molecules. MicroRNAs are a new class of regulatory non-coding RNAs that modulate gene expression and influences epigenetic mechanisms. miRNAs offer novel mechanisms of therapeutic strategies for cancer and autoimmune diseases. Here, we summarize which miRNAs play a role in rheumatic diseases and their biological function.


Asunto(s)
Artritis Reumatoide/genética , Epigenómica , MicroARNs/genética , Artritis Reumatoide/inmunología , Artritis Reumatoide/terapia , Autoanticuerpos/sangre , Regulación de la Expresión Génica/genética , Humanos
6.
Arthritis Rheum ; 62(1): 93-104, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20039430

RESUMEN

OBJECTIVE: To search for novel autoantibodies in patients with rheumatoid arthritis (RA) in an effort to better understand the processes of joint destruction in this disease. METHODS: Using a modified SEREX technique and complementary DNA derived from RA synovium, serpin E2 was identified as a novel autoantigen and was analyzed by immunohistochemistry. Levels of anti-serpin E2 autoantibodies in serum and synovial fluid from patients with RA, osteoarthritis (OA), psoriatic arthritis, and ankylosing spondylitis, and/or from healthy individuals were assessed by enzyme-linked immunosorbent assay. Since serpin E2 is an inhibitor of serine proteases, we studied the inhibitory activity of serpin E2 toward its target, urokinase plasminogen activator (uPA), in vitro in the presence of isolated anti-serpin E2 autoantibodies and in vivo using the uPA activity assay. RESULTS: We identified autoantibodies against serpin E2 by the SEREX technique. Serpin E2 was overexpressed in RA synovial tissues as compared with OA synovial tissues. Significantly higher levels of anti-serpin E2 autoantibodies were present in samples of synovial fluid (28%) and serum (22%) from RA patients as compared with OA patients (0 and 6%, respectively) or with healthy individuals (6% of sera). Most importantly, anti-serpin E2 autoantibodies isolated from RA sera reversed the inhibitory activity of serpin E2 by 70%. Furthermore, the levels of anti-serpin E2 autoantibodies correlated with the uPA activity in vivo. CONCLUSION: This study characterizes a functional property of a novel autoantibody in RA. Since anti-serpin E2 autoantibodies interfere with the inhibitory activity of serpin E2 toward serine proteases, they might facilitate the joint destruction in RA.


Asunto(s)
Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Serpinas/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Artritis Psoriásica/sangre , Artritis Psoriásica/inmunología , Artritis Reumatoide/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteoartritis/sangre , Osteoartritis/inmunología , Proteínas Recombinantes/inmunología , Espondilitis Anquilosante/sangre , Espondilitis Anquilosante/inmunología , Líquido Sinovial/inmunología , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores , Adulto Joven
7.
Ann Rheum Dis ; 65(7): 910-2, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16284094

RESUMEN

BACKGROUND: Histone acetylation/deacetylation has a critical role in the regulation of transcription by altering the chromatin structure. OBJECTIVE: To analyse the effect of trichostatin A (TSA), a streptomyces metabolite which specifically inhibits mammalian histone deacetylases, on TRAIL-induced apoptosis of rheumatoid arthritis synovial fibroblasts (RASF). METHODS: Apoptotic cells were detected after co-treatment of RASF with TRAIL (200 ng/ml) and TSA (0.5, 1, and 2 micromol/l) by flow cytometry using propidium iodide/annexin-V-FITC staining. Cell proliferation was assessed using the MTS proliferation test. Induction of the cell cycle inhibitor p21Waf/Cip1 by TSA was analysed by western blot. Expression of the TRAIL receptor-2 (DR5) on the cell surface of RASF was analysed by flow cytometry. Levels of soluble TRAIL were measured in synovial fluid of patients with RA and osteoarthritis (OA) by ELISA. RESULTS: Co-treatment of the cells with TSA and TRAIL induced cell death in a synergistic and dose dependent manner, whereas TRAIL and TSA alone had no effect or only a modest effect. RASF express DR5 (TRAIL receptor 2), but treatment of the cells with TSA for 24 hours did not change the expression level of DR5, as it is shown for cancer cells. TSA induced cell cycle arrest in RASF through up regulation of p21Waf1/Cip1. Levels of soluble TRAIL were significantly higher in RA than in OA synovial fluids. CONCLUSION: Because TSA sensitises RASF for TRAIL-induced apoptosis, it is concluded that TSA discloses sensitive sites in the cascade of TRAIL signalling and may represent a new principle for the treatment of RA.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/farmacología , Artritis Reumatoide/patología , Fibroblastos/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Glicoproteínas de Membrana/farmacología , Membrana Sinovial/patología , Factor de Necrosis Tumoral alfa/farmacología , Anciano , Apoptosis/efectos de los fármacos , Artritis Reumatoide/metabolismo , Western Blotting/métodos , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/análisis , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis/metabolismo , Osteoartritis/patología , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF
8.
Ann N Y Acad Sci ; 1051: 291-8, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16126970

RESUMEN

The key pathologic mechanism in rheumatoid arthritis (RA) is the destruction of cartilage by fibroblasts. In a severe combined immunodeficient (SCID) mouse model, this process can be modulated by gene transfer using invasive LS48 fibroblasts. This study aims to investigate the effect of interleukins (IL) -11 and -12 on cartilage destruction when transferred into LS48, and of IL-15 when transfected into non-invasive 3T3 cells; to compare three transduction systems (a lentiviral vector system, a retroviral vector system, and a particle-mediated gene transfer); and to establish an in vitro cartilage destruction system based on LS48 cells. Transduced fibroblasts were injected into SCID mice knee joints, and disease progression assessed microscopically. Distinctive morphologic pattern revealed invasion of fibroblasts into the articular cartilage by transfected, as well as non-transfected, LS48 cells. IL-12 and IL-15 did not alter swelling or cartilage destruction. Animals treated with IL-11-transfected cells showed reduced cartilage damage but no changes in swelling. Efficacy of gene transfer to establish transfected fibroblasts was shown to be >85% for lentiviral transfer, compared to <10% for retroviral transfer and gene gun. Furthermore, cells were co-incubated with porcine cartilage. Transduction of IL-11 led to a reduction of apoptosis in chondrocytes. These findings suggest that cartilage destruction by invasive fibroblasts can be modulated by gene transfer. Lentiviral vector systems offer the most effective approach for gene transduction. In vitro fibroblast/cartilage co-cultures present a convenient system for the assessment of novel therapeutic strategies toward reduction of articular destruction.


Asunto(s)
Artritis Reumatoide/patología , Cartílago Articular/patología , Fibroblastos/fisiología , Células 3T3 , Animales , Biolística , Femenino , Interleucina-11/genética , Interleucina-11/fisiología , Articulación de la Rodilla/patología , Ratones , ARN Mensajero/análisis
9.
Ann Rheum Dis ; 64(3): 419-24, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15345499

RESUMEN

BACKGROUND: Galectin-3 is expressed in the synovial tissue of patients with rheumatoid arthritis (RA), particularly at sites of joint destruction. OBJECTIVE: To explore the possibilities that galectin-3 is induced either by proinflammatory cytokines or by adhesion to cartilage components. METHODS: Cell culture plates were coated with fibronectin, collagens I-VI, or cartilage oligomeric matrix protein (COMP), and the suspended cells were then added. The medium was changed after 1 hour at 37 degrees C. Adherent cells were further incubated for 18 hours in the presence or absence of tumour necrosis factor alpha (TNF alpha) or interleukin 1 beta. Cells were pretreated with murine IgG1, anti-CD29, -CD51, -CD61 (integrins), or -CD3 monoclonal antibodies and transferred to culture plates coated with COMP. Adherent cells were counted by light microscopy. The expression of intracellular galectin-3, or cell surface CD29, CD51, and CD61 was determined by flow cytometry before and after adhesion. RESULTS: Four times more RA synovial fibroblasts (SF) than osteoarthritis SF adhered to COMP. RA SF presented more cell surface integrins, and monoclonal antibodies against CD51 inhibited the adhesion to COMP by 80%. TNF alpha reduced the expression of CD61 and the adhesion to COMP, but did not reverse the adhesion once it had taken place. The adhesion of RA SF to COMP was found to increase the intracellular level of galectin-3. In contrast, intracellular galectin-3 decreased after exposure to TNF alpha. CONCLUSION: The increase of galectin-3 occurs after adhesion to COMP, and the alpha V beta 3 receptor (CD51/CD61) has a pivotal role in this process.


Asunto(s)
Artritis Reumatoide/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Galectina 3/metabolismo , Glicoproteínas/metabolismo , Membrana Sinovial/metabolismo , Proteína de la Matriz Oligomérica del Cartílago , Adhesión Celular , Células Cultivadas , Matriz Extracelular/metabolismo , Humanos , Integrina alfaV/metabolismo , Integrina beta3/metabolismo , Proteínas Matrilinas , Factor de Necrosis Tumoral alfa/farmacología
10.
J Autoimmun ; 15(3): 301-13, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11040071

RESUMEN

The objective of this study was to verify whether isolated rheumatoid arthritis (RA) synovial fibroblasts induce chronic arthritis in SCID mice, in analogy to whole tissue pieces. Fibroblasts were isolated from the synovial membrane of four RA patients (or controls) by out-growth and repeated-passage culture. Following flow-cytometry characterization, 2x10(6)cells were transferred into the left knee joint of SCID mice. The development of arthritis was assessed by joint swelling and histological changes. Human and murine cytokines were measured in vitro in co-cultures (or Transwelltrade mark systems) of human and murine cells. Purified RA synovial fibroblasts, but not healthy synovial or skin fibroblasts, induced hu/mu arthritis within 6 weeks. In-vitro secretion of murine and human interleukin(IL)-6, as well as murine tumour necrosis factor (TNF)-alpha, indicated cross-activation between murine macrophages and human RA fibroblasts. Soluble-factor mechanisms proved more effective than cell-contact mechanisms. Purified RA fibroblasts can, alone, induce hu/mu SCID arthritis. The cytokine profile suggests that xenogeneic interaction between human fibroblasts and murine macrophages may determine the sequence of events leading to hu/mu arthritis.


Asunto(s)
Artritis Reumatoide/inmunología , Fibroblastos/fisiología , Animales , Artritis Reumatoide/etiología , Artritis Reumatoide/patología , Separación Celular , Trasplante de Células , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Fibroblastos/citología , Fibroblastos/trasplante , Humanos , Técnicas para Inmunoenzimas , Articulación de la Rodilla/patología , Ratones , Ratones SCID , Membrana Sinovial/citología , Factores de Tiempo
11.
Ann Rheum Dis ; 58(7): 428-34, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10381487

RESUMEN

OBJECTIVES: To evaluate in vivo the contribution of tumour necrosis factor alpha (TNFalpha) to the chimeric transfer model of human rheumatoid arthritis synovial membrane into SCID mice (hu/mu SCID arthritis), systemic anti-TNFalpha treatment was performed and the clinical, serological, and histopathological effects of this treatment assessed. METHODS: Animals were treated with the rat-antimouse TNFalpha monoclonal antibody V1q, starting on day 1 after hu/mu engraftment, twice weekly for 12 weeks. Joint swelling, serum concentrations of human and murine interleukin 6 (IL6), and serum amyloid P (SAP) were measured. Histopathological and immunohistochemical analyses of the joints were also performed at the end of treatment. RESULTS: Neutralisation of murine TNFalpha induced the following effects: (a) reduction of extent and duration of the acute arthritis phase, with significant reduction of joint swelling at two weeks; (b) decrease of murine SAP concentrations after the first antibody administration; and (c) increase of murine IL6 in the serum. At the end of treatment, there was a significant reduction of the inflammatory infiltration in the engrafted joints. Because of the mild degree of joint erosion, no treatment effects could be demonstrated on the destructive process. CONCLUSION: In the lymphocyte independent hu/mu SCID arthritis, anti-TNFalpha treatment reduces local and systemic signs of inflammation.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/terapia , Factor de Necrosis Tumoral alfa/inmunología , Enfermedad Aguda , Animales , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Modelos Animales de Enfermedad , Estudios de Evaluación como Asunto , Humanos , Inmunohistoquímica , Interleucina-6/sangre , Articulaciones/inmunología , Articulaciones/patología , Ratones , Ratones SCID , Membrana Sinovial/trasplante , Factor de Necrosis Tumoral alfa/análisis
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