Design Synthesis and Biological Evaluation of DYRK1A Inhibitors

DYRK1A is a dual-specificity protein kinase that catalyses not only autophosphorylation on its tyrosine residue but the phosphorylation of serine and threonine residues in its substrates. DYRK1A has been shown to be important for phosphorylation of tau protein and has also been identified as a Down syndrome candidate gene. DYRK1A overexpression has also been found in cancer cells, particularly in glioblastoma, which represents 15% of brain tumours. The increased phosphorylation of sprouty2 mediated by DYRK1A blocks the EGFR degradation as a result of overexpression of EGFR in the cell surface, and the enhanced EGFR signalling eventually leads to tumour survival. On the contrary, DYRK1A inhibition has been found to promote EGFR degradation in glioblastoma cells by triggering the endocytosis and lysosomal degradation, thus reducing the self-renewal ability of tumourigenic cells. Development of small molecule inhibitors of DYRK1A therefore provides attractive treatment strategies. A recently discovered lead compound, DANDY represents one chemotype of the most potent DYRK1A inhibitors. The work in this thesis explores the importance of the 7-azaindole skeleton to DYRK1A inhibition through the systematic modification to structural features of DANDY. The sequential selectivity of promising inhibitors over other off-targets such as DYRK1B, DYRK2 and CLK1, as well as the functional activity against glioblastoma cells has also been explored. Preliminary kinase inhibition assays together with cell viability assays have shown promising trends towards the correlation between DYRK1A inhibition activities and cellular efficacies in vitro. In this thesis, several promising compounds have shown inhibition for DYRK1A with IC50 values being < 50 nM. These compounds have also played effective roles for the in vitro treatment of glioblastoma cell viability assays

Online Schema Evolution is (Almost) Free for Snapshot Databases

Modern database applications often change their schemas to keep up with the changing requirements. However, support for online and transactional schema evolution remains challenging in existing database systems. Specifically, prior work often takes ad hoc approaches to schema evolution with 'patches' applied to existing systems, leading to many corner cases and often incomplete functionality. Applications therefore often have to carefully schedule downtimes for schema changes, sacrificing availability. This paper presents Tesseract, a new approach to online and transactional schema evolution without the aforementioned drawbacks. We design Tesseract based on a key observation: in widely used multi-versioned database systems, schema evolution can be modeled as data modification operations that change the entire table, i.e., data-definition-as-modification (DDaM). This allows us to support schema almost 'for free' by leveraging the concurrency control protocol. By simple tweaks to existing snapshot isolation protocols, on a 40-core server we show that under a variety of workloads, Tesseract is able to provide online, transactional schema evolution without service downtime, and retain high application performance when schema evolution is in progress.Comment: To appear at Proceedings of the 2023 International Conference on Very Large Data Bases (VLDB 2023

KINEMATICAL ANALYSIS OF DISMOUNT OF STRAIGHT BACK SOMERSAULT WITH A TURN OF 900° : A CASE STUDY

The techniques of dismount of straight back somersault with a turn of 900° performed by Tan Sixin (winner of all-round of China's gymnastics championships in 2011) and Jiang Yuyuan(winner of champion of the balance beam of World University Games in 2009) was filmed using 3-D camera method. The kinematics data were collected and analyzed by motion performance analysis system. The conclusions came out that overall execution of Tan Sixin was good, while the action of Jiang Yuyuan needed to be improved. The results of the analysis will provide a theoretical basis of balance beam training for athletics and trainer