Voltammetric analysis of glycoproteins containing sialylated and neutral glycans at pyrolytic graphite electrode.

Recently, it was described that neutral glycans can be distinguished from those containing sialic acid at the mercury electrode after modification with osmium(VI) N,N,N',N'-tetramethylethylenediamine (Os(VI)tem). Our work shows the possibility of studying glycans and glycoproteins at pyrolytic graphite electrodes depending on thepresence of sialic acid. Short glycans, glycans released from glycoproteins, and glycoproteins themselves yielded similar voltammetric responses after their modification by Os(VI)tem.

Local Wnt signalling in the asymmetric migrating vertebrate cells.

Wnt signalling is known to generate cellular asymmetry via Wnt/planar cell polarity pathway (Wnt/PCP). Wnt/PCP acts locally (i) to orient membrane polarity and asymmetric establishment of intercellular junctions via conserved set of PCP proteins most specifically represented by Vangl and Prickle, and (ii) to asymmetrically rearrange cytoskeletal structures via downstream effectors of Dishevelled (Dvl). This process is best described on stable phenotypes of epithelial cells.

RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.

RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2.

Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells.

Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is, therefore, of critical importance.

Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway.

Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs.

PTEN-Regulated AID Transcription in Germinal Center B Cells Is Essential for the Class-Switch Recombination and IgG Antibody Responses.

Class-switch recombination (CSR) and somatic hypermutation (SHM) occur during the differentiation of germinal center B cells (GCBs). Activation-induced cytidine deaminase (AID) is responsible for both CSR and SHM in GCBs. Here, we show that ablation of PTEN through the Cγ1-Cre mediated recombination significantly influences the CSR and SHM responses.

Comparative cell cycle transcriptomics reveals synchronization of developmental transcription factor networks in cancer cells.

The cell cycle coordinates core functions such as replication and cell division. However, cell-cycle-regulated transcription in the control of non-core functions, such as cell identity maintenance through specific transcription factors (TFs) and signalling pathways remains unclear. Here, we provide a resource consisting of mapped transcriptomes in unsynchronized HeLa and U2OS cancer cells sorted for cell cycle phase by Fucci reporter expression.

Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation.

Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy.