Genome-wide expression analysis reveals TORC1-dependent and -independent functions of Sch9

The protein kinase Sch9 is proposed to be a downstream effector of TORC1 that is required for activation of ribosome biogenesis and repression of entry into G(0). However, Sch9 apparently functions antagonistically to TORC1, when considering the induction of several stress defence genes that are normally repressed by TORC1. To further investigate the relationship between Sch9 and TORC1, we compared the rapamycin-induced transcriptional responses in an sch9 Delta mutant and the isogenic wild type. The data indicate that Sch9 is necessary for proper integration of the rapamycin-induced stress signal, i.e. in sch9 Delta cells, typical effects of rapamycin-like repression of ribosomal protein genes and induction of stress response genes are diminished or abolished. Moreover, they reveal for the first time a direct link between Sch9 and nitrogen metabolism. A sch9 Delta mutant has an increased basal activation of targets of the general amino acid control pathway and of the nitrogen discrimination pathway, including the ammonium permease MEP2 and the amino acid permease GAP1. The mutant also shows enhanced expression of the transcription factor Gcn4 required for amino acid biosynthesis. Our data favour a model in which (1) the role of Sch9 in the general stress response switches depending on TORC1 activity and (2) Sch9 and TORC1 have independent and additive effects on genes induced upon nitrogen and amino acid starvation

Searching for New Leads for Tuberculosis: Design, Synthesis, and Biological Evaluation of Novel 2‑Quinolin-4-yloxyacetamides

In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic stability of the series. The best compounds obtained exhibited MIC values in the low micromolar range, excellent intracellular antimycobacterial activity, and an improved physicochemical profile without cytotoxic effects. Further investigation revealed that the amide bond was the source for the poor blood stability observed, while some of the compounds exhibited hERG affinity. Compound <b>83</b> which contains a benzoxazole ring instead of the amide group was found to be a good alternative, with good blood stability and no hERG affinity, providing new opportunities for the series. Overall, the obtained results suggest that further optimization of solubility and microsomal stability of the series could provide a strong lead for a new anti-TB drug development program

Gut microbiota dynamics and uraemic toxins: one size does not fit all

status: publishe

Pancreatic autoantibodies and autoantibodies against goblet cells in pediatric patients with inflammatory bowel disease

BACKGROUND: Significance of pancreatic autoantibodies determined by using exocrine pancreas (PAB) and antibodies against recombinant pancreas antigen (rPAB), as well as the importance of autoantibodies against goblet cells (GAB), is not known in pediatric patients with inflammatory bowel disease (IBD). Our aim was to determine the complex analysis of PAB, rPAB, GAB, antibodies against Saccharomyces cerevisiae, and perinuclear components of neutrophils in pediatric patients with IBD. Moreover, association with NOD2/CARD15 and disease phenotype was determined. METHODS: A total of 152 pediatric patients (median age 13.9 years) with IBD (103 patients with Crohn disease [CD] and 49 patients with ulcerative colitis [UC]) and 104 controls were included. Serum autoantibodies were determined by indirect immunofluorescence assay. NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism. RESULTS: The presence of PAB and rPAB was significantly higher in CD (34% and 35.9%) and in UC (20.4% and 24.5%) compared with pediatric control cohort (0% and 0%, P<0.0001). In addition, GAB positivity was significantly increased in patients with UC in comparison with CD and controls, respectively (UC, 12.2%; CD, 1.9%; controls, 1.9%; P=0.02). Specificity of PAB and rPAB was 100%; however, sensitivity was low. The combination of PAB and/or antibodies against Saccharomyces cerevisiae/perinuclear components of neutrophils improved the sensitivity of serological markers in CD (87.4%) and in UC (79.6%); specificities were 89.3% and 93.2%, respectively. Pancreatic autoantibodies (PAB, rPAB) and GAB were not related to clinical presentation, medical therapy, or need for surgery in CD or in UC. CONCLUSIONS: Pancreatic autoantibodies and GAB were specific for IBD, but the sensitivity was limited as well because there was lack of correlation with clinical phenotype. Combinations of these antibodies have shown increased sensitivity; therefore, it may be recommended in the diagnostic procedure of IBD