PFTK1 kinase regulates axogenesis during development via RhoA activation.

Cyclin Dependent Kinase family members include members of the non-cell cycle CDK, such as PFTK1/Eip63E. Eip63E expresses primarily in postnatal and adult nervous system in Drosophila melanogaster but its role in CNS development remains unknown. We sought to understand its role in the CNS by studying the fly ventral nerve cord during development. Eip63E regulates axogenesis in neurons and its deficiency leads to neuronal defects. We describe a functional interaction between Eip63E and Rho1. Studies in cultured cortical neurons from PFTK1 knockout mice, confirmed that PFTK1 plays a role in axonal outgrowth and its deficiency resulted in faster growing axons. We demonstrate that GDP bound RhoA is a substrate of PFTK1 and this phosphorylation resulted in higher activity of RhoA. In conclusion, our work represents the first steps in the characterization of the neuronal functions of PFTK1 and points to RhoA activation in the regulation of PFTK1 mediated axogenesis.

Ensemble learning from ensemble docking: revisiting the optimum ensemble size problem

Despite considerable advances obtained by applying machine learning approaches in protein–ligand affinity predictions, the incorporation of receptor flexibility has remained an important bottleneck. While ensemble docking has been used widely as a solution to this problem, the optimum choice of receptor conformations is still an open question considering the issues related to the computational cost and false positive pose predictions. Here, a combination of ensemble learning and ensemble docking is suggested to rank different conformations of the target protein in light of their importance for the final accuracy of the model. Available X-ray structures of cyclin-dependent kinase 2 (CDK2) in complex with different ligands are used as an initial receptor ensemble, and its redundancy is removed through a graph-based redundancy removal, which is shown to be more efficient and less subjective than clustering-based representative selection methods. A set of ligands with available experimental affinity are docked to this nonredundant receptor ensemble, and the energetic features of the best scored poses are used in an ensemble learning procedure based on the random forest method. The importance of receptors is obtained through feature selection measures, and it is shown that a few of the most important conformations are sufficient to reach 1 kcal/mol accuracy in affinity prediction with considerable improvement of the early enrichment power of the models compared to the different ensemble docking without learning strategies. A clear strategy has been provided in which machine learning selects the most important experimental conformers of the receptor among a large set of protein–ligand complexes while simultaneously maintaining the final accuracy of affinity predictions at the highest level possible for available data. Our results could be informative for future attempts to design receptor-specific docking-rescoring strategies.

Ginsenoside Rd Attenuates Tau Phosphorylation in Olfactory Bulb, Spinal Cord, and Telencephalon by Regulating Glycogen Synthase Kinase 3β and Cyclin-Dependent Kinase 5

Objective. Ginseng is a plant of the family Acanthopanaceae. It has been used for thousands of years in China. It is known as the king of hundred herbs. It was recorded first in Shennong Baicao Jing. It has been found that ginsenoside Rd is a neuroprotective agent. This article aims to explore the protective roles of ginsenoside Rd in Alzheimer’s disease. Rd, a Chinese herb, may be a promising treatment drug for Alzheimer’s disease (AD) and is also reported to be related to several pathological changes, including the deposition of Aβ and tau hyperphosphorylation in AD as it decreases the deposition of tau hyperphosphorylation in APP transgenic mice. Methods. In this study, APP transgenic mice were pretreated with 10 mg/kg Rd for six months, and the effect of Rd on neuropathological deficits in the olfactory bulb, spinal cord, and telencephalon of APP transgenic mice was investigated. The phosphorylation levels of tau (S199/202, S396, S404, and Tau5) and the activities of the proteins glycogen synthase kinase 3β (Tyr216) and cyclin-dependent kinase 5 (P25/P35) were measured. Results. The pretreatment of Rd effectively decreased the production and deposition of hyperphosphorylated tau (S199/202, S396, and S404) protein by depressing the expression of glycogen synthase kinase 3β (GSK-3β/Tyr216) and cyclin-dependent kinase 5 (CDK5/P25). Conclusion. These findings suggest that ginsenoside Rd could improve the pathological changes of AD in the olfactory bulb, spinal cord, and telencephalon, which further demonstrated the potential therapeutic effect of Rd in early AD.

Differential expression of cyclin dependent kinase inhibitor 3 in triple negative breast cancer.

Women diagnosed with triple negative breast cancer can benefit neither from endocrine therapy nor from HER2-targeted therapies (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding cyclin dependent kinase inhibitor 3, CDKN3, when comparing the tumor cells of patients with triple negative breast cancer to normal mammary ductal cells (2). CDKN3 was also differentially expressed in bulk tumor in human breast cancer (3). CDKN3 mRNA was present at significantly increased quantities in TNBC tumor cells relative to normal mammary ductal cells. Analysis of human survival data revealed that expression of CDKN3 in primary tumors of the breast was correlated with overall survival in patients with basal-like and luminal B type cancer, while within triple negative breast cancer, primary tumor expression of CDKN3 was correlated with distant metastasis-free survival in patients with mesenchymal stem-like subtype disease. CDKN3 may be of relevance to initiation, maintenance or progression of triple negative breast cancers.