Ionic liquid catalyzed one pot green synthesis of isoxazolone derivatives via multicomponent reaction

459-464A series of 3-methyl-4-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)isoxazol-5(4H)-one derivatives have been efficiently synthesized by environmentally benign, one-pot three component condensation of substituted 1,3-diaryl-1H-pyrazole-4-carboxyaldehyde, β-keto ester and hydroxyl amine hydrochloride in the presence of ionic liquid [HNMP][HSO4] as a catalyst in ethanol. These derivatives have been synthesized by conventional, ultrasound and microwave irradiation methods. The combination of ionic liquid with ultrasound as well as microwave irradiation makes the protocol fascinating and environmentally benign. In addition, it has several benefits such as simple work-up procedure, clean reaction profile, short reaction time and good yields

Synthesis and Biological Assessment of Carbazole Linked Pyrazole Schiff bases and Diarylthiourea Derivatives

In this study, (E)-9-ethyl-N-((1,3-diphenyl-1H-pyrazol-4-ylmethylene)-9H-carbazol-3-amine (3a–f) and 1-(9-ethyl-9H-carbazol-6-yl)-3-phenylthiourea (5a–f) derivatives were synthesized and their in vitro antimicrobial and antimalarial activities were evaluated. The structures of the synthesized compounds were elucidated and confirmed by using IR, 1H NMR, 13C NMR, and mass spectra. This work is licensed under a Creative Commons Attribution 4.0 International License

TGF-beta reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells

Many lines of evidence have indicated that both genetic and non-genetic determinants can contribute to intra-tumor heterogeneity and influence cancer outcomes. Among the best described sub-population of cancer cells generated by non-genetic mechanisms are cells characterized by a CD44+/CD24- cell surface marker profile. Here, we report that human CD44+/CD24- cancer cells are genetically highly unstable due to intrinsic defects in their DNA repair capabilities. In fact, in CD44+/CD24- cells constitutive activation of the TGF-beta axis was both necessary and sufficient to reduce the expression of genes that are critical in coordinating DNA damage repair mechanisms. Consequently, we observed that cancer cells that reside in a CD44+/CD24- state are characterized by increased accumulation of DNA copy number alterations, greater genetic diversity and improved adaptability to drug treatment. Together, these data suggest that the transition into a CD44+/CD24- cell state can promote intra-tumor genetic heterogeneity, spur tumor evolution and increase tumor fitness

Rapid and tunable method to temporally control gene editing based on conditional Cas9 stabilization

The CRISPR/Cas9 system is a powerful tool for studying gene function. Here, we describe a method that allows temporal control of CRISPR/Cas9 activity based on conditional Cas9 destabilization. We demonstrate that fusing an FKBP12-derived destabilizing domain to Cas9 (DD-Cas9) enables conditional Cas9 expression and temporal control of gene editing in the presence of an FKBP12 synthetic ligand. This system can be easily adapted to co-express, from the same promoter, DD-Cas9 with any other gene of interest without co-modulation of the latter. In particular, when co-expressed with inducible Cre-ERT2, our system enables parallel, independent manipulation of alleles targeted by Cas9 and traditional recombinase with single-cell specificity. We anticipate this platform will be used for the systematic characterization and identification of essential genes, as well as the investigation of the interactions between functional genes

A Unique Safety Signal: Social-Support Figures Enhance Rather Than Protect From Fear Extinction

Following treatment of fear-related disorders, return of fear remains a common occurrence. Currently, the presence of safety signals during treatment procedures is considered harmful, yet recent findings have demonstrated that certain safety signals (social-support figures) lead to enhanced fear extinction and thus might reduce return of fear. Here, we tested the effect of social-support-figure (vs. stranger) images on fear extinction outcomes. We found that, for conditional fear stimuli paired with social-support-figure images during extinction, return of fear was inhibited both immediately after extinction and during a fear reinstatement test 24 hr later; however, return of fear occurred for conditional stimuli paired with images of strangers. These findings suggest that social-support stimuli have unique safety-signaling properties that might enhance fear extinction and improve treatment outcomes for individuals with fear-related disorders

A Unique Safety Signal: Social-Support Figures Enhance Rather Than Protect From Fear Extinction

Following treatment of fear-related disorders, return of fear remains a common occurrence. Currently, the presence of safety signals during treatment procedures is considered harmful, yet recent findings have demonstrated that certain safety signals (social-support figures) lead to enhanced fear extinction and thus might reduce return of fear. Here, we tested the effect of social-support-figure (vs. stranger) images on fear extinction outcomes. We found that, for conditional fear stimuli paired with social-support-figure images during extinction, return of fear was inhibited both immediately after extinction and during a fear reinstatement test 24 hr later; however, return of fear occurred for conditional stimuli paired with images of strangers. These findings suggest that social-support stimuli have unique safety-signaling properties that might enhance fear extinction and improve treatment outcomes for individuals with fear-related disorders