Identification of NEK7 inhibitors: structure based virtual screening, molecular docking, density functional theory calculations and molecular dynamics simulations.

NEK7 is a NIMA related-protein kinase that plays a crucial role in spindle assembly and cell division. Dysregulation of NEK7 protein leads to development and progression of different types of malignancies including colon and breast cancers. Therefore, NEK7 could be considered as an attractive target for anti-cancer drug discovery. However, few efforts have been made for the development of selective inhibitors of NIMA-related kinase but still no FDA approved drug is known to selectively inhibit the NEK7 protein. Dacomitinib and Neratinib are two Enamide derivatives that were approved for treatment against non-small cell lung cancer and breast cancer respectively. Drug repurposing is a time and cost-efficient method for re-evaluating the activities of previously authorized medications. Thus, the present research involves the repurposing of two FDA-approved medications via comprehensive in silico approach including Density functional theory (DFTs) studies which were conducted to determine the electronic properties of the Dacomitinib and Neratinib. Afterward, binding orientation of selected drugs inside NEK7 activation loop was evaluated through molecular docking approach. Selected drugs exhibited potential molecular interactions engaging important amino acid residues of active site. The docking score of Dacomitinib and Neratinib was -30.77 and -26.78 kJ/mol, respectively. The top ranked pose obtained from molecular docking was subjected to Molecular Dynamics (MD) Simulations for investigating the stability of protein-ligand complex. The RMSD pattern revealed the stability of protein-ligand complex throughout simulated trajectory. In conclusion, both drugs displayed inhibitory efficacy against NEK7 protein and provide a prospective therapy option for malignant malignancies linked with NEK7.

Trunk control during repetitive sagittal movements following a real-time tracking task in people with chronic low back pain.

Precision of trunk movement has commonly been examined by testing relocation accuracy rather than evaluating accuracy of tracking dynamic movement. In this study we used a 3-D motion capture system to provide a novel real-time tracking task to assess trunk motor control at varying movement speeds between people with and without chronic non-specific low back pain (LBP). Eleven asymptomatic volunteers and 15 participants with chronic non-specific LBP performed 12 continuous cycles of trunk flexion-extension following real time visual feedback, during which, trunk motion was measured using eight optoelectronic infrared cameras. Significant time differences between the feedback and actual trunk motion were found between groups (P = 0.001). Both groups had similar variability of tracking accuracy when following the feedback (P > 0.05). However, tracking variability at a slow speed correlated (P = 0.03; r = 0.55) with the Fear-Avoidance Beliefs Questionnaire (FABQ) scores in those with LBP. This study shows that both asymptomatic people and individuals with LBP displayed anticipatory behaviour, however, the response of those with LBP was consistently delayed in tracking the visual feedback compared to the asymptomatic group. Additionally, the extent of variability of tracking accuracy over repeated tracking cycles was associated with the degree of fear of movement in people with LBP.

Mechanical stress-induced switching kinetics of ferroelectric thin films at the nanoscale.

We investigate ferroelectric domain structure and piezoelectric response under variable mechanical compressive stress in Pb(Zr0.2TiO0.8)O3 (PZT) thin films using high-resolution piezoresponse force microscopy (PFM) and an in situ sample bending stage. Measurements reveal a drastic change in the ferroelectric domain structure which is presented along with details of the mediating switching process involving domain wall motion, nucleation, and domain wall roughening under an applied external mechanical stimulus. Furthermore, local PFM hysteresis loops reveal significant changes in the observed coercive biases under applied stress. The PFM hysteresis loops become strongly imprinted under increasing applied compressive stress.