Strategies to inhibit the spread of HIV infection consist of moter. This fusion mutant was also examined for its a number of specific molecular approaches. Since viral capacity to block both Tat-mediated transactivation and production is dependent upon Tat-mediated transactivation HIV replication. We show that three mutants Tat⌬53, of the HIV promoter through the Tat activating region Tat⌬58 and Tat⌬53/Eng result in a transdominant pheno-(TAR), tat antisense RNA, anti-tat ribozymes, TAR decoys type inhibiting wild-type Tat-mediated transactivation, and and dominant negative Tat mutant proteins have been sugthat the inhibiting potential is increased by the presence of gested as therapeutic inhibitors. We produced and tested the entire basic domain or the fusion of a repressor several Tat mutant proteins, including a newly generated domain. However, only the transdominant mutants Tat⌬58 form Tat⌬58, for the ability to inhibit Tat-mediated transand Tat⌬53/Eng significantly inhibit HIV-1 replication after activation and HIV production. In addition, we generated a infection of transfected T cell lines. These results demonnew Tat fusion mutant between a C-terminus truncated strate the potent inhibiting activity of Tat mutants on HIV form of Tat (Tat⌬53) and the Drosophila Engrailed (Eng) replication, and suggest a synergistic effect of Tat transtranscription repressor domain to test the hypothesis that dominant mutant fusion with the Drosophila Engrailed trantranscriptional repression can be targeted to the HIV proscription repressor domain.

Examination of the interaction between human immunodeficiency virus (HIV) regulatory gene products and the host immune system is fundamental to understanding the pathogenesis of HIV and could reveal possible targets for therapeutic intervention in the treatment of AIDS. The HIV Tat gene is a potential candidate for this type of strategy. Transgenic mice can be used to investigate the in vivo effects of Tat on the developing and dynamic immune system and on cellular gene expression. Thus, we have generated transgenic mice that harbor the HIV type 1 Tat gene under the transcriptional control of the human CD2 gene regulatory elements. This expression cassette results in high-level, tissue-specific transcription of the transgene within the T-cell compartment. In this report, we demonstrate the effects of Tat on the in vivo immune system. CD2-Tat transgenic mice show no signs of aberrant thymic development and have normal levels of T-cell subsets in the thymus and peripheral lymphoid organs. However, activated T cells from transgenic mice contain increased levels of tumor necrosis factor beta mRNA as well as biologically active tumor necrosis factor protein and express elevated levels of transforming growth factor ␤ and interleukin-4 receptor mRNA. These increased cytokine levels do not appear to alter mitogen-or antigen-stimulated responses or induce the formation of dermal lesions in ageing mice. Such investigations should provide insight into the combination of host immune factors mediating pathogenesis in HIV infection.

In spite of the fact that compounding is really pervasive in the world's languages and despite the huge volume of literatures on compounding in languages including African languages, a critical assessment of the extant literature on compounding in African linguistics reveals that providing satisfactory criteria for defining compoundhood still requires both language specific and cross-linguistic investigations for dependable linguistic generalizations. In Ígálà, in particular, not much attention has been devoted to describing compounding. The present study therefore investigates compounding in Igala, a West Benue-Congo language spoken in north central Nigeria. Defining compoundhood and distinguishing compound words in Igala, the study shows and favours semantic criteria above phonological and syntactic considerations. Compounding generally has been found to be a highly productive word formation process in Iglala in terms of forms and functions.

BackgroundChronic and exaggerated fibroblast activation is a central hallmark of Systemic Sclerosis (SSc) fibrotic disease and results in a high morbidity and mortality. Epigenetic changes might play important roles in mediating chronic fibroblast activation. Trimethylation of H3 at lysine residue K27 (H3K27me3) is a repressive epigenetic mark that was recently identified as an important negative regulator of fibroblast activation [1]. Jumonji domain containing protein 3 (JMJD3) mediates H3K27me3–demethylation. JMJD3 inhibitors are being tested as therapeutic strategies in malignant diseases.ObjectivesThe aim of this study was to characterize the role of JMJD3 in fibrotic disease and to explore JMJD3 as a potential drug target in SSc.MethodsExpression analyses of JMJD3 were performed using qPCR, IF and Western blot. siRNA mediated knockdown and the pharmacologic H3K27me3-demethylase inhibitor GSKJ4 were used to target JMJD3. In vivo, we analyzed the effects of GSKJ4 in bleomycin-induced dermal fibrosis and in Topoisomerase-I-induced (TopoI) fibrosis. H3K27me3 levels at the Fra2 promotor were analyzed by CHIP.ResultsWe observed increased expression of JMJD3 in SSc skin compared to healthy controls. Fibroblast-specific overexpression of JMJD3 was also reflected in experimental fibrosis models. TGFβ upregulated JMJD3. Inhibition of JMJD3 increased H3K27me3 in vitro and in vivo. Inhibition of JMJD3 reverted the activated fibroblast phenotype in SSc fibroblasts and decreased the expression of contractile fibers and of α-smooth muscle actin. In addition, JMJD3 inhibition reduced the basal and TGFβ induced collagen secretion of SSc fibroblasts. JMJD3 regulated the TGFβ induced expression of Fra2. GSKJ4 reverted the TGFβ induced reduction of H3K27me3 at the Fra2 promotor. Moreover, the anti-fibrotic effects of JMJD3 inhibition were evened in Fra2 knockout fibroblasts. Overexpression of Fra2 in JMJD3-knockdown fibroblasts restored the profibrotic effect of JMJD3. In vivo, inhibition of JMJD3 ameliorated fibrosis in bleomycin- and TopoI- induced experimental fibrosis and reduced dermal thickening, hydroxyproline content and myofibroblast differentiation.ConclusionsWe present first evidence that JMJD3 contributes to the activated phenotype of SSc fibroblasts. TGFβ upregulated JMJD3. Inhibition of JMJD3 prevented the aberrant activation of fibroblasts in vitro and ameliorated dermal fibrosis in several mouse models in vivo. The profibrotic effects of JMJD3 might be mediated by reducing the H3K27me3 at the Fra2 promotor and consecutive overexpression of Fra2.References Kramer, M., et al., Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann Rheum Dis, 2013. 72(4): p. 614–20. Disclosure of InterestNone declared

BackgroundScleroderma (SSc) is an autoimmune connective tissue disease involving complex interactions between various cell types leading to organ-based tissue fibrosis. Emergence of the monocytes (Mo)/macrophages (Mφ) lineage(s) as key contributors to inflammation, vascular dysfunction and scarring in scleroderma1,2 have led to increased scrutiny of their phenotype and function.ObjectivesTo determine the circulating Mo subpopulations and phenotypes of Mφ in SSc.MethodsPBMC were collected from healthy (HC) and SSc donors, and analysed by flow cytometry using Mo phenotypic antibodies or purified and cultured in vitro. For flow cytometry immunophenotyping, Mo were gated on CD3-CD19-CD56-HLA-DR+populations, and subsets defined by CD14, CD16, CD163 and CD206 expression. For Mφ cultures, Mo were negatively selected from PBMCs, cultured for 7 days, and treated with IFN-γ(5 ng/ml) or IL-4(20 ng/ml) for 24 hours. Cytokine levels in the conditioned media were evaluated by MSD analyses and normalised to total protein levels.ResultsThe frequency of circulating CD163+ non-classical Mo (CD14loCD16hi) was 2-fold higher in SSc patients than in HC (unpaired t-test, p=0.026). No difference was found in the frequency of CD206+ monocyte subsets between HC and SSc. In vitro, unstimulated SSc Mφ (M0) secreted higher levels of classically-activated pro-inflammatory (M1) and alternatively-activated pro-regenerative (M2) cytokines. Compared to HC cells, SSc Mφ were more readily polarised towards an M1 phenotype or an M2 phenotype, when cultured in the presence of IFN-γ or IL-4, respectively. Th17 markers and MMPs were significantly increased in SSc Mφ (table 2).Abstract FRI0406 – Table 1Demographics.Mo (flow cytometry)Mφ supernatant (cytokine assay) nHC n=9SSc n=10HC n=13SSc n=27 Age (years)56.7±14.350.7±5.760.6±16.752.1±13.0Female : Male7:28:26:726:5SSc subtype-dcSSc(10-dcSSc(27Disease duration-≤5 years(10-≤5 years(,15>5 year(12Abstract FRI0406 – Table 2Cytokines significantly increased in SSc vs control. Unpaired t-tests, *p<0.05, **P<0.01.ConclusionsStudies exploring Mo have revealed distinct populations with selective biological functions. Our observation of an increased number of CD163+ non-classical Mo in SSc suggests that this subpopulation may play a key role in inflammatory-driven fibrosis and act as an important source of pro-fibrotic cytokines. This data is consistent with previous reports of elevated serum levels of CD163 and increased CD163 secretion by SSc PBMCs3. SSc Mφ showed a pronounced and enhanced dual M1 and M2 polarisation basally compared to HC, indicating cells were ‘primed’ to undergo phenotypic polarisation. Our studies support the notion that Mφ cytokine secretion generates a pro-fibrotic milieu in scleroderma tissues, playing a prominent role in dysregulated tissue repair in fibrosis.References[1] Chia JJ, Lu TT. Curr Opin Rheumatol2015Nov;27(6):530–536.[2] Christmann RB, Lafyatis R. Arthritis Res Ther. 2010;12(5):146.[3] Hassan WASE, et al. Eur J Rheumatol2016Sep;3(3):95–100.Disclosure of InterestNone declared