Humanized cereblon mice reveal two distinct pathways of immunomodulatory drugs

Immunomodulatory drugs (IMiDs), including thalidomide derivatives such as lenalidomide and pomalidomide, offer therapeutic benefit in several hematopoietic malignancies and autoimmune/inflammatory diseases. However, it is difficult to study the IMiD mechanism of action in murine disease models because murine cereblon (CRBN), the substrate receptor for IMiD action, is resistant to some of IMiDs therapeutic effects. To overcome this difficulty, we generated humanized cereblon (CRBNI391V) mice thereby providing an animal model to unravel complex mechanisms of action in a murine physiological setup. In our current study, we investigated the degradative effect toward IKZF1 and CK-1α, a target substrate of IMiDs. Unlike WT mice which were resistant to lenalidomide and pomalidomide, T lymphocytes from CRBNI391V mice responded with a higher degree of IKZF1 and CK-1α protein degradation. Furthermore, IMiDs resulted in an increase in IL-2 among CRBNI391V mice but not in the WT group. We have also tested a thalidomide derivative, FPFT-2216, which showed an inhibitory effect toward IKZF1 protein level. As opposed to pomalidomide, FPFT-2216 and lenalidomide degrades CK-1α. Additionally, we assessed the potential therapeutic effects of IMiDs in dextran sodium sulfate (DSS)-induced colitis. In both WT and humanized mice, lenalidomide showed a significant therapeutic effect in the DSS model of colitis, while the effect of pomalidomide was less pronounced. Thus, while IMiDs’ degradative effect on IKZF1 and CK-1α, and up-regulation of IL-2, is dependent on CRBN, the therapeutic benefit of IMiDs in a mouse model of inflammatory bowel disease occurs through a CRBN–IMiD binding region independent pathway

Numerical and experimental study of dispersive mixing of agglomerates

Best paper 2006 award in the Extrusion divisionInternational audienceThe degree of filler dispersion has a major influence on the physical properties of rubber compounds. Typical fillers, e.g. carbon black and silica, are difficult to disperse, particularly if they are fine and low structured. As a result, the quantity of undispersed fillers generally amounts for 1% to 10% of the compound. The elimination, or at least the reduction, of agglomerates will result in rubber parts (e.g. tires, seals, belts) with improved properties and higher reliability. Clearly, a better understanding of the physics of batch mixers would help improve their mixing performance. Due to the complexity of the real process, experiments on a representative device were held from which a model has been deduced. It appears to be a generalization of the law of Kao and Mason, but for high viscous matrices. The next step was to get a model available for statistically large number of pellets as can be found in any sample taken out of the mixer. A statistical approach is used where we define a model describing the evolution of mass density function of agglomerate sizes. Eventually, we implement this model within available numerical simulation tools to estimate dispersion in real mixers

Isolation of biologically active metabolites from Bougainvillea spectabilis Willd. cultivated in Egypt

Bougainvillea spectabilis Willd.  is an ornamental plant cultivated in tropical, subtropical regions and other places as Egypt. The present study aimed to perform bioassay guided fractionation and isolation of some of the bioactive compounds from the Egyptian cultivate. The total ethanol extracts of the leaves (T.ET.L.), stems (T.ET.S.) and flowers (T.ET.F.) were screened for some pharmacological activities viz. in vivo anti-oxidant and anti-hepatotoxic, in addition to in vitro cytotoxic activities. The anti-oxidant effect was assessed by measuring serum glutathione level (GSH) in alloxan-induced diabetic rats. The anti-hepatotoxic activity was evaluated via measuring serum markers level viz. alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in CCl4-induced hepatotoxicity in rats. In vitro cytotoxicity of the different extracts was estimated for liver cancer cell line (HEPG2) adopting Sulforhodamine B stain assay. T.ET.L. exhibited significantly potent anti-oxidant and anti-hepatotoxic activities, while T.ET.S. showed the highest cytotoxic activity. Through biological guided fractionation, leaves and stems were subjected to successive solvent extraction, whereas the leaves ethyl acetate (Et.Ac.L.) and the stems ethanol 70% (Et.70%S.) extracts showed highly potent activities. Thus, different chromatographic techniques were performed on Et.Ac.L. and Et.70%S. extracts leading to the isolation of five bioactive metabolites. Three flavonoids were isolated from Et.Ac.L.; genistein-7-O-rutinoside (1), formononetin-7-O-rutinoside (2) and myricetin (3), while orobol-7-O-glucoside (4) and hesperidin (5) were isolated from Et.70%S. This work demonstrated the importance of the plant as a promising anti-oxidant, anti-hepatotoxic and cytotoxic product for nutraceutical use

Study of an Optimized Micro-Grid’s Operation with Electrical Vehicle-Based Hybridized Sustainable Algorithm

Recently, the expansion of energy communities has been aided by the lowering cost of storage technologies and the appearance of mechanisms for exchanging energy that is driven by economics. An amalgamation of different renewable energy sources, including solar, wind, geothermal, tidal, etc., is necessary to offer sustainable energy for smart cities. Furthermore, considering the induction of large-scale electric vehicles connected to the regional micro-grid, and causes of increase in the randomness and uncertainty of the load in a certain area, a solution that meets the community demands for electricity, heating, cooling, and transportation while using renewable energy is needed. This paper aims to define the impact of large-scale electric vehicles on the operation and management of the microgrid using a hybridized algorithm. First, with the use of the natural attributes of electric vehicles such as flexible loads, a large-scale electric vehicle response dispatch model is constructed. Second, three factors of micro-grid operation, management, and environmental pollution control costs with load fluctuation variance are discussed. Third, a hybrid gravitational search algorithm and random forest regression (GSA-RFR) approach is proposed to confirm the method’s authenticity and reliability. The constructed large-scale electric vehicle response dispatch model significantly improves the load smoothness of the micro-grid after the large-scale electric vehicles are connected and reduces the impact of the entire grid. The proposed hybridized optimization method was solved within 296.7 s, the time taken for electric vehicle users to charge from and discharge to the regional micro-grid, which improves the economy of the micro-grid, and realizes the effective management of the regional load. The weight coefficients λ1 and λ2 were found at 0.589 and 0.421, respectively. This study provides key findings and suggestions that can be useful to scholars and decisionmakers

Some entanglement features of three-atoms Tavis-Cummings model: Cooperative case

In this paper we consider a system of identical three two-level atoms interacting at resonance with a single-mode of the quantized field in a lossless cavity. The initial cavity field is prepared in the coherent state while the atoms are taken initially to be either in the uppermost excited state "$|eee>$" or The $\textmd{GHZ}$-state or the $\textmd{W}$-state. For this system we investigate different kinds of atomic inversion and entanglement, which arise between the different parts of the system due to the interaction. Also the relationship, between entanglement and some other nonclassical effects in the statistical properties, such as collapses and revivals in the atomic inversion where superharmonic effects appear, is discussed. The $Q$-functions for different cases are discussed. Most remarkably it is found that the $\textmd{GHZ}$-state is more robust against energy losses, showing almost coherent trapping and Schr\"odinger-cat states can not be produced from such state. Also the entanglement of $\textmd{GHZ}$-state is more robust than the $\textmd{W}$-state. Another interesting feature found is that the state which has no pairwise entanglement initially will have a much improvement of such pairwise entanglement through the evolution. Sudden death and sudden revival of atoms-pairwise entanglement are produced with the $\textmd{W}$-state.Comment: 14 pages, 7 figure

SYNTHESIS, ANTICANCER ACTIVITY AND MOLECULAR DOCKING STUDY OF NOVEL 1, 3-DIHETEROCYCLES INDOLE DERIVATIVES

Objective: The present work aimed to synthesize some new 1, 3-diheterocyles indolyl derivatives and study their cytotoxic activity. In addition, explore the probability of the most promising antiproliferative compounds to inhibit TopoI enzyme theoretically via molecular docking study.Methods: Reaction of ethyl 2-(3-formyl-1H-indol-1-yl)acetate (1) with 2-cyanoacetic acid hydrazide, 3-amino-5-pyrazolone and 2'-acetyl-2-cyanoacetohydrazide in an equal molar ratio led to the formation of compounds 2, 6, 8 and 10, respectively, which in turn reacted with another molecule of 2-cyanoacetic acid hydrazide and/or 3-amino-5-pyrazolone (1:1 molar ratio) to give novel series of 1,3-dipyrazole indole derivatives 3, 7, 9 and 11, respectively. On the other hand, Knoevenagel condensation of 1 with malononitrile gave ethyl 2-(3-(2, 2-dicyanovinyl)-1H-indol-1-yl) acetate (11). Reaction of 11 with 2-cyanoacetic acid hydrazide, 3-amino-5-pyrazolone, hydrazine hydrate, urea, thiourea and/or guanidine yielded 1, 6-diaminopyridine 12, pyrano(2,3-c)pyrazole 14, pyrazole 16 and pyrimidine derivatives 18a-c, respectively. Reaction of the latter compounds with 3-amino-5-pyrazolone furnished a novel series of 1, 3-diheterocycle indole derivatives 13, 15, 17 and 19a-c, respectively. Ten new target compounds 3, 6, 8, 10, 13, 15, 17 and 19a-c were tested for in vitro antiproliferative activity against A-549, MCF7, HCT-116 and HEPG2 cancer cell lines. In addition, molecular docking study of the most promising antiproliferative compounds against human DNA Topoisomerase I (PDB ID: 1T8I) theoretically is discussed.Results: Compounds 3, 6, 8 and 17 showed potent in vitro antiproliferative activity. Docking scores of the latter compounds were observed better than co-crystalline ligand.Conclusion: Further work is recommended to confirm the inhibition of TopoI in a specific bioassay

Information loss in local dissipation environments

The sensitivity of entanglement to the thermal and squeezed reservoirs' parameters is investigated regarding entanglement decay and what is called sudden-death of entanglement, ESD, for a system of two qubit pairs. The dynamics of information is investigated by means of the information disturbance and exchange information. We show that for squeezed reservoir, we can keep both of the entanglement and information survival for a long time. The sudden death of information is seen in the case of thermal reservoir