Targeting histone deacetylase activity in rheumatoid arthritis and asthma as prototypes of inflammatory disease: should we keep our HATs on?

Cellular activation, proliferation and survival in chronic inflammatory diseases is regulated not only by engagement of signal trans-duction pathways that modulate transcription factors required for these processes, but also by epigenetic regulation of transcription factor access to gene promoter regions. Histone acetyl trans-ferases coordinate the recruitment and activation of transcription factors with conformational changes in histones that allow gene promoter exposure. Histone deacetylases (HDACs) counteract histone acetyl transferase activity through the targeting of both histones as well as nonhistone signal transduction proteins important in inflammation. Numerous studies have indicated that depressed HDAC activity in patients with inflammatory airway diseases may contribute to local proinflammatory cytokine production and diminish patient responses to corticosteroid treatment. Recent observations that HDAC activity is depressed in rheumatoid arthritis patient synovial tissue have predicted that strategies restoring HDAC function may be therapeutic in this disease as well. Pharmacological inhibitors of HDAC activity, however, have demonstrated potent therapeutic effects in animal models of arthritis and other chronic inflammatory diseases. In the present review we assess and reconcile these outwardly paradoxical study results to provide a working model for how alterations in HDAC activity may contribute to pathology in rheumatoid arthritis, and highlight key questions to be answered in the preclinical evaluation of compounds modulating these enzymes

Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay

Background Histone deacetylase inhibitors (HDACi) display potent therapeutic efficacy in animal models of arthritis and suppress inflammatory cytokine production in rheumatoid arthritis (RA) synovial macrophages and tissue. Objectives To determine the molecular mechanisms contributing to the suppressive effects of HDACi on RA synovial cell activation, using interleukin 6 (IL-6) regulation as a model. Methods RA fibroblast-like synoviocytes (FLS) and healthy donor macrophages were treated with IL-1 beta, tumour necrosis factor (TNF)alpha, lipopolysaccharide or polyinosinic: polycytidylic acid (poly(I:C)) in the absence or presence of the HDACi trichostatin A (TSA) or ITF2357 (givinostat). IL-6 production and mRNA expression was measured by ELISA and quantitative PCR (qPCR), respectively. Protein acetylation and the activation of intracellular signalling pathways were assessed by immunoblotting. The DNA-binding activity of nuclear factor kappa B (NF kappa B) and activator protein 1 (AP-1) components was measured by ELISA-based assays. Results HDACi (0.25-1.0 mu M) suppressed RA FLS IL-6 production induced by IL-1 beta, TNF alpha and Toll-like receptor ligands. Phosphorylation of mitogen-activated protein kinases and inhibitor of kappa B alpha (I kappa B alpha) following IL-1 beta stimulation were unaffected by HDACi, as were AP-1 composition and binding activity, and c-Jun induction. TSA induced a significant reduction in nuclear retention of NF kappa B in FLS 24 h after IL-1 beta stimulation, but this did not reduce NF kappa B transcriptional activity or correlate temporally with reductions in IL-6 mRNA accumulation. HDACi significantly reduced the stability of IL-6 mRNA in FLS and macrophages. Conclusions Our study identifies a novel, shared molecular mechanism by which HDACi can disrupt inflammatory cytokine production in RA synovial cells, namely the promotion of mRNA decay, and suggests that targeting HDAC activity may be clinically useful in suppressing inflammation in R

A Pixel Vertex Tracker for the TESLA Detector

In order to fully exploit the physics potential of a e+e- linear collider, such as TESLA, a Vertex Tracker providing high resolution track reconstruction is required. Hybrid Silicon pixel sensors are an attractive sensor technology option due to their read-out speed and radiation hardness, favoured in the high rate TESLA environment, but have been so far limited by the achievable single point space resolution. A novel layout of pixel detectors with interleaved cells to improve their spatial resolution is introduced and the results of the characterisation of a first set of test structures are discussed. In this note, a conceptual design of the TESLA Vertex Tracker, based on hybrid pixel sensors is presentedComment: 20 pages, 11 figure

High resolution pixel detectors for e+e- linear colliders

The physics goals at the future e+e- linear collider require high performance vertexing and impact parameter resolution. Two possible technologies for the vertex detector of an experimental apparatus are outlined in the paper: an evolution of the Hybrid Pixel Sensors already used in high energy physics experiments and a new detector concept based on the monolithic CMOS sensors.Comment: 8 pages, to appear on the Proceedings of the International Workshop on Linear Colliders LCWS99, Sitges (Spain), April 28 - May 5, 199

High Resolution Hybrid Pixel Sensors for the e+e- TESLA Linear Collider Vertex Tracker

In order to fully exploit the physics potential of a future high energy e+e- linear collider, a Vertex Tracker, providing high resolution track reconstruction, is required. Hybrid Silicon pixel sensors are an attractive option, for the sensor technology, due to their read-out speed and radiation hardness, favoured in the high rate environment of the TESLA e+e- linear collider design but have been so far limited by the achievable single point space resolution. In this paper, a conceptual design of the TESLA Vertex Tracker, based on a novel layout of hybrid pixel sensors with interleaved cells to improve their spatial resolution, is presented.Comment: 12 pages, 5 figures, to appear in the Proceedings of the Vertex99 Workshop, Texel (The Netherlands), June 199

Effects of a Novel Ankle Strengthening Protocol on Later al Ankle Strength and Flexibility

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New generalized fuzzy metrics and fixed point theorem in fuzzy metric space

In this paper, in fuzzy metric spaces (in the sense of Kramosil and Michalek (Kibernetika 11:336-344, 1957)) we introduce the concept of a generalized fuzzy metric which is the extension of a fuzzy metric. First, inspired by the ideas of Grabiec (Fuzzy Sets Syst. 125:385-389, 1989), we define a new G-contraction of Banach type with respect to this generalized fuzzy metric, which is a generalization of the contraction of Banach type (introduced by M Grabiec). Next, inspired by the ideas of Gregori and Sapena (Fuzzy Sets Syst. 125:245-252, 2002), we define a new GV-contraction of Banach type with respect to this generalized fuzzy metric, which is a generalization of the contraction of Banach type (introduced by V Gregori and A Sapena). Moreover, we provide the condition guaranteeing the existence of a fixed point for these single-valued contractions. Next, we show that the generalized pseudodistance J:X×X→[0,∞) (introduced by Włodarczyk and Plebaniak (Appl. Math. Lett. 24:325-328, 2011)) may generate some generalized fuzzy metric NJ on X. The paper includes also the comparison of our results with those existing in the literature

Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets

Objectives To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naive. Methods A total of 50 patients with early arthritis who were DMARD naive (disease duration <1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR). Results ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R-2=0.59, p=0.02) after follow-up, and disease progression in early arthritis (R-2=0.16, p <0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44. Conclusions JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease proces

Cauchyness and convergence in fuzzy metric spaces

[EN] In this paper we survey some concepts of convergence and Cauchyness appeared separately in the context of fuzzy metric spaces in the sense of George and Veeramani. For each convergence (Cauchyness) concept we find a compatible Cauchyness (convergence) concept. We also study the relationship among them and the relationship with compactness and completeness (defined in a natural sense for each one of the Cauchy concepts). In particular, we prove that compactness implies p-completeness.Almanzor Sapena acknowledges the support of Ministry of Economy and Competitiveness of Spain under grant TEC2013-45492-R. Valentín Gregori acknowledges the support of Ministry of Economy and Competitiveness of Spain under grant MTM 2012-37894-C02-01.Gregori Gregori, V.; Miñana, J.; Morillas, S.; Sapena Piera, A. (2017). Cauchyness and convergence in fuzzy metric spaces. Revista de la Real Academia de Ciencias Exactas Físicas y Naturales Serie A Matemáticas. 111(1):25-37. https://doi.org/10.1007/s13398-015-0272-0S25371111Alaca, C., Turkoglu, D., Yildiz, C.: Fixed points in intuitionistic fuzzy metric spaces. Chaos Solitons Fractals 29, 1073–1078 (2006)Edalat, A., Heckmann, R.: A computational model for metric spaces. Theor. Comput. Sci. 193, 53–73 (1998)Engelking, R.: General topology. PWN-Polish Sci. Publ, Warsawa (1977)Fang, J.X.: On fixed point theorems in fuzzy metric spaces. Fuzzy Sets Syst. 46(1), 107–113 (1992)George, A., Veeramani, P.: On some results in fuzzy metric spaces. Fuzzy Sets Syst. 64, 395–399 (1994)George, A., Veeramani, P.: Some theorems in fuzzy metric spaces. J. Fuzzy Math. 3, 933–940 (1995)George, A., Veeramani, P.: On some results of analysis for fuzzy metric spaces. Fuzzy Sets Syst. 90, 365–368 (1997)Grabiec, M.: Fixed points in fuzzy metric spaces. Fuzzy Sets Syst. 27, 385–389 (1989)Gregori, V., Romaguera, S.: Some properties of fuzzy metric spaces. Fuzzy Sets Syst. 115, 485–489 (2000)Gregori, V., Romaguera, S.: On completion of fuzzy metric spaces. Fuzzy Sets Syst. 130, 399–404 (2002)Gregori, V., Romaguera, S.: Characterizing completable fuzzy metric spaces. Fuzzy Sets Syst. 144, 411–420 (2004)Gregori, V., López-Crevillén, A., Morillas, S., Sapena, A.: On convergence in fuzzy metric spaces. Topol. Appl. 156, 3002–3006 (2009)Gregori, V., Miñana, J.J.: Some concepts realted to continuity in fuzzy metric spaces. In: Proceedings of the conference in applied topology WiAT’13, pp. 85–91 (2013)Gregori, V., Miñana, J.-J., Sapena, A.: On Banach contraction principles in fuzzy metric spaces (2015, submitted)Gregori, V., Miñana, J.-J.: std-Convergence in fuzzy metric spaces. Fuzzy Sets Syst. 267, 140–143 (2015)Gregori, V., Miñana, J.-J.: Strong convergence in fuzzy metric spaces Filomat (2015, accepted)Gregori, V., Miñana, J.-J., Morillas, S.: Some questions in fuzzy metric spaces. Fuzzy Sets Syst. 204, 71–85 (2012)Gregori, V., Miñana, J.-J., Morillas, S.: A note on convergence in fuzzy metric spaces. Iran. J. Fuzzy Syst. 11(4), 75–85 (2014)Gregori, V., Morillas, S., Sapena, A.: On a class of completable fuzzy metric spaces. Fuzzy Sets Syst. 161, 2193–2205 (2010)Gregori, V., Morillas, S., Sapena, A.: Examples of fuzzy metric spaces and applications. Fuzzy Sets Syst. 170, 95–111 (2011)Kramosil, I., Michalek, J.: Fuzzy metric and statistical metric spaces. Kybernetika 11, 326–334 (1975)Mihet, D.: On fuzzy contractive mappings in fuzzy metric spaces. Fuzzy Sets Syst. 158, 915–921 (2007)Mihet, D.: Fuzzy $$\varphi$$ φ -contractive mappings in non-Archimedean fuzzy metric spaces. Fuzzy Sets Syst. 159, 739–744 (2008)Mihet, D.: A Banach contraction theorem in fuzzy metric spaces. Fuzzy Sets Syst. 144, 431–439 (2004)Mishra, S.N., Sharma, N., Singh, S.L.: Common fixed points of maps on fuzzy metric spaces Internat. J. Math. Math. Sci. 17(2), 253–258 (1994)Morillas, S., Sapena, A.: On Cauchy sequences in fuzzy metric spaces. In: Proceedings of the conference in applied topology (WiAT’13), pp. 101–108 (2013)Ricarte, L.A., Romaguera, S.: A domain-theoretic approach to fuzzy metric spaces. Topol. Appl. 163, 149–159 (2014)Sherwood, H.: On the completion of probabilistic metric spaces. Z.Wahrschein-lichkeitstheorie verw. Geb. 6, 62–64 (1966)Sherwood, H.: Complete Probabilistic Metric Spaces. Z. Wahrschein-lichkeitstheorie verw. Geb. 20, 117–128 (1971)Tirado, P.: On compactness and G-completeness in fuzzy metric spaces. Iran. J. Fuzzy Syst. 9(4), 151–158 (2012)Tirado, P.: Contraction mappings in fuzzy quasi-metric spaces and [0,1]-fuzzy posets. Fixed Point Theory 13(1), 273–283 (2012)Vasuki, R., Veeramani, P.: Fixed point theorems and Cauchy sequences in fuzzy metric spaces. Fuzzy Sets Syst. 135(3), 415–417 (2003)Veeramani, P.: Best approximation in fuzzy metric spaces. J. Fuzzy Math. 9, 75–80 (2001