Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kδ inhibitors

A novel class of potent PI3Kδ inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kα program, turned moderately selective PI3Kδ compounds into highly potent and selective PI3Kδ inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kδ IC₅₀ ? 1 nM in the enzyme assay, some of the most selective PI3Kδ inhibitors published to date, with a cell potency in a JeKo-cell assay of 20–120 nM.     

The specificity of delayed hypersensitivity to ABA-tyr-pulsed and ABA-coupled macrophages

Guinea pigs immunized with ABA-tyr in CFA respond well by skin test to ABA-tyr-pulsed macrophages but poorly to ABA-coupled macrophages and not at all to ABA-coupled red cells, thymocytes, or L₂C cells. On the other hand, guinea pigs immunized with ABA-coupled macrophages do not respond to ABA-insulin or ABA-tyr-pulsed macrophages but do respond to ABA-coupled macrophages. Similarly guinea pigs immunized with Ars-NCS-coupled macrophages respond only to the homologous antigen. The specificity of these reactions is determined by how ABA is associated with the Ia-positive accessory cell. The presence of Ia molecule is not a sufficient condition since neither Ia-positive L₂C cells nor spleen cells depleted of adherent macrophages are effective as immunogens or elicitors of response when coupled with ABA. These results suggest that the topography of the ABA and Ia complex formed on the accessory cell is the prime determinant of specificity for T-cells responses.     

Effects of penicillin and erythromycin on adherence of invasive and noninvasive isolates of Streptococcus pyogenes to laminin

This study investigated the possible relationship between the invasiveness of group A Streptococcus (GAS) strains and their abilities to adhere to laminin and assessed the effects of subinhibitory concentrations of penicillin and erythromycin on the ability of GAS to adhere to laminin. The adherence of noninvasive and highly invasive isolates of GAS to laminin was significantly higher than the adherence displayed by isolates of low invasiveness. Antibiotic treatment caused significant reductions in adherence to laminin in all three groups of strains. Penicillin was more successful in reducing the adherence abilities of the tested GAS strains than erythromycin.     

Gold Nanoparticle Uptake by Tumour Cells of B16 Mouse Melanoma

Because of their photo-optical distinctiveness and biocompatibility, gold nanoparticles have proven to be powerful tools in various nanomedical applications. In this article, we discuss the advantage of gold nanoparticles in image diagnostic application of melanoma. It has demonstrated the potential role of gold nanoparticles in the study of tumour tissue architecture and the utility of gold nanoparticles in the hystopathological exam of B16 melanoma with the benefit of fluorescence emission of gold nanoparticles in UV spectrum. The optical properties of colloidal gold nanoparticles allow spectroscopic detection and identification of melanoma cells. The method proposed is easy, inexpensive and reliable for hystopathological analysis of melanoma. The fluorescence images in the cryosections of tissues depicted a strong luminescence property of gold nanoparticles uptaken in melanoma, results that confirm the role of the gold nanoparticles in biological labelling and imaging applications. To emphasize the AuNPs influence over the biological tissues, a study of the chemical bonds configuration was performed using Raman spectrometry.     

Predicting protein condensate formation using machine learning

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The replicative helicase MCM recruits cohesin acetyltransferase ESCO2 to mediate centromeric sister chromatid cohesion

Chromosome segregation depends on sister chromatid cohesion which is established by cohesin during DNA replication. Cohesive cohesin complexes become acetylated to prevent their precocious release by WAPL before cells have reached mitosis. To obtain insight into how DNA replication, cohesion establishment and cohesin acetylation are coordinated, we analysed the interaction partners of 55 human proteins implicated in these processes by mass spectrometry. This proteomic screen revealed that on chromatin the cohesin acetyltransferase ESCO2 associates with the MCM2‐7 subcomplex of the replicative Cdc45‐MCM‐GINS helicase. The analysis of ESCO2 mutants defective in MCM binding indicates that these interactions are required for proper recruitment of ESCO2 to chromatin, cohesin acetylation during DNA replication, and centromeric cohesion. We propose that MCM binding enables ESCO2 to travel with replisomes to acetylate cohesive cohesin complexes in the vicinity of replication forks so that these complexes can be protected from precocious release by WAPL. Our results also indicate that ESCO1 and ESCO2 have distinct functions in maintaining cohesion between chromosome arms and centromeres, respectively.