Le bilboquet, un badinage dangereux ? Une étude sur Le Bilboquet de Marivaux

La fable du Bilboquet de Marivaux donne à imaginer la fureur sociale provoquée par ce jeu à l’époque. Poussé par un ressentiment contre le bilboquet qui distrait sa maîtresse, le narrateur développe comment la Folie a conquis les gens de l’Europe à travers cette frivolité. À travers la mise en scène de la contagion du jeu, on observe comment le plaisir qu’il procure ainsi que le désir mimétique des hommes contribuent au succès du bilboquet. Le désordre social résultant de cette frénésie ludique nous amène à nous interroger sur la nature du jeu : s’agit-il simplement d ’une distraction divertissante ou représente-t-il en réalité un danger ? Une telle « bagatelle » peut avoir de graves conséquences, conformément à une logique de réévaluation du « rien » que l’on retrouve dans la plupart des œuvres de Marivaux

Pristimerin induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation by blocking NF-κB signaling and depleting Bcr-Abl

<p>Abstract</p> <p>Background</p> <p>Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. Bcr-Abl-T315I is the notorious point mutation that causes resistance to imatinib and the second generation tyrosine kinase inhibitors, leading to poor prognosis. CML blasts have constitutive p65 (RelA NF-κB) transcriptional activity, and NF-κB may be a potential target for molecular therapies in CML that may also be effective against CML cells with Bcr-Abl-T315I.</p> <p>Results</p> <p>In this report, we discovered that pristimerin, a quinonemethide triterpenoid isolated from Celastraceae and Hippocrateaceae, inhibited growth and induced apoptosis in CML cells, including the cells harboring Bcr-Abl-T315I mutation. Additionally, pristimerin inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Pristimerin blocked the TNFα-induced IκBα phosphorylation, translocation of p65, and expression of NF-κB-regulated genes. Pristimerin inhibited two steps in NF-κB signaling: TAK1→IKK and IKK→IκBα. Pristimerin potently inhibited two pairs of CML cell lines (KBM5 versus KBM5-T315I, 32D-Bcr-Abl versus 32D-Bcr-Abl-T315I) and primary cells from a CML patient with acquired resistance to imatinib. The mRNA and protein levels of Bcr-Abl in imatinib-sensitive (KBM5) or imatinib-resistant (KBM5-T315I) CML cells were reduced after pristimerin treatment. Further, inactivation of Bcr-Abl by imatinib pretreatment did not abrogate the TNFα-induced NF-κB activation while silencing p65 by siRNA did not affect the levels of Bcr-Abl, both results together indicating that NF-κB inactivation and Bcr-Abl inhibition may be parallel independent pathways.</p> <p>Conclusion</p> <p>To our knowledge, this is the first report to show that pristimerin is effective <it>in vitro </it>and <it>in vivo </it>against CML cells, including those with the T315I mutation. The mechanisms may involve inhibition of NF-κB and Bcr-Abl. We concluded that pristimerin could be a lead compound for further drug development to overcome imatinib resistance in CML patients.</p

Passively Q-switched Yb-doped all-fiber laser based on Ag nanoplates as saturable absorber

Abstract We report on a Q-switched Yb-doped all-fiber laser based on a solution-processed Ag nanoplates saturable absorber. Optical deposition procedure is implemented to transfer the Ag nanoplates onto the fiber core area through the thermal effect. The saturable absorber is sandwiched between two fiber connectors, providing simplicity, flexibility, and easy integration into the laser oscillator. The modulation depth and saturation incident fluence are measured to be ~5.8% and ~106.36 μJ/cm2 at 1-μm region, respectively. Self-started stable Q-switched operation is achieved for a threshold pump power of 180 mW. The repetition rates of the pulse trains range from 66.6 to 184.8 kHz when the pump power scales from 210 to 600 mW. The maximum average output power is 10.77 mW, corresponding to the single-pulse energy of 58.3 nJ and minimum pulse duration of ~1.01 μs. To the best of our knowledge, it is the first time that the Ag nanoplates saturable absorbers are utilized in the 1-μm Yb-doped Q-switched fiber laser

The protective role of DOT1L in UV-induced melanomagenesis

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis

Coordinated economic dispatch of the primary and secondary heating systems considering the boiler’s supplemental heating

District heating systems have been widely used in large and medium-sized cities. Typical district heating systems consist of the primary heating system (PHS) and the secondary heating system (SHS) operating in isolation. However, the isolated dispatch of the PHS and the SHS has poor adjustability and large losses, resulting in unnecessary operation costs. To address these issues, a coordinated economic dispatching model (CEDM) for the primary and secondary heating systems considering the boiler’s supplemental heating is proposed in this study, which characterized the physical properties of the PHS and the SHS in detail. Considering that the PHS and the SHS are controlled separately without central operators in practice, it is difficult to dispatch them in a centralized method. Thus, the master-slave splitting algorithm is innovatively introduced to solve the CEDM in a decentralized way. Finally, a P6S12 system is utilized to analyze and verify the effectiveness and optimality of the proposed algorithm

Functional characterization of D9, a novel deazaneplanocin a (DZNep) analog, in targeting acute myeloid leukemia (AML)

10.1371/journal.pone.0122983PLoS ONE104e012298

The protective role of DOT1L in UV-induced melanomagenesis

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis

The conformational control inhibitor of tyrosine kinases DCC-2036 is effective for imatinib-resistant cells expressing T674I FIP1L1-PDGFRα.

The cells expressing the T674I point mutant of FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) in hypereosinophilics syndrome (HES) are resistant to imatinib and some second-generation tyrosine kinase inhibitors (TKIs). There is a desperate need to develop therapy to combat this acquired drug resistance. DCC-2036 has been synthesized as a third-generation TKI to combat especially the Bcr-Abl T315I mutant in chronic myeloid leukemia. This study evaluated the effect of DCC-2036 on FIP1L1-PDGFRα-positive cells, including the wild type (WT) and the T674I mutant. The in vitro effects of DCC-2036 on the PDGFRα signal pathways, proliferation, cell cycling and apoptosis of FIP1L1-PDGFRα-positive cells were investigated, and a nude mouse xenograft model was employed to assess the in vivo antitumor activity. We found that DCC-2036 decreased the phosphorylated levels of PDGFRα and its downstream targets without apparent effects on total protein levels. DCC-2036 inhibited proliferation, and induced apoptosis with MEK-dependent up-regulation of the pro-apoptotic protein Bim in FIP1L1-PDGFRα-positive cells. DCC-2036 also exhibited in vivo antineoplastic activity against cells with T674I FIP1L1-PDGFRα. In summary, FIP1L1-PDGFRα-positive cells are sensitive to DCC-2036 regardless of their sensitivity to imatinib. DCC-2036 may be a potential compound to treat imatinib-resistant HES