Acid Sphingomyelinase Regulates the Localization and Trafficking of Palmitoylated Proteins

In human, loss of Acid Sphingomeylinase (ASM/SMPD1) causes Niemann-Pick Disease, type A. ASM hydrolyzes sphingomyelins to produce ceramides but protein targets of ASM remain largely unclear. ... See full text for complete abstract

Targeting Radioresistant Breast Cancer Cells by Single Agent CHK1 Inhibitor via Enhancing Replication Stress

Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells

Targeting Radioresistant Breast Cancer Cells by Single Agent CHK1 Inhibitor via Enhancing Replication Stress

Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells

Analysis of the Force Characteristics of Two Tandem Cylinders by Internal Waves over Slope Topography

Large-amplitude internal waves (IWs) with strong lateral shear forces can cause destructive effects on marine engineering structures. In this study, a large eddy simulation (LES) method was employed to simulate the generation and propagation of IWs in a three-dimensional numerical wave tank, and the pressure distribution, flow field characteristics, and force behaviors of two tandem cylinders under the coupling effect of the IWs and slope terrain were studied. The influence mechanism of the normalized value of center-to-center spacing (L) and the diameter of the cylinder (D), i.e., (L/D), on the strength of the vortex disturbance between cylinders was studied by comparing the simulation results of two tandem cylinders with those of a single cylinder (SC) to further explore the mechanical response characteristics of the upstream cylinder (P1) and downstream cylinder (P2). The simulation results showed that the vortex interaction between cylinders is the critical factor that affects the forces acting on the cylinders. The strength of the vortex disturbance could be distinguished by the dimensionless critical center-to-center spacing between cylinders (Lc/D = 3.0). When L/D ≤ Lc/D, the vortex disturbance was severe, causing P1 and P2 to experience significant horizontal positive forces and negative forces, respectively. In the case of L/D > Lc/D, the forces acting on both cylinders gradually returned to those on a single cylinder

Numerical Investigation of the Stress on a Cylinder Exerted by a Stratified Current Flowing on Uneven Ground

In this study, a three-dimensional internal wave (IW)—cylinder—terrain coupled numerical model is established. Based on the large-eddy simulation (LES) method, the IW mechanical characteristics of the cylinder and the flow field evolution around the cylinder over different types of terrains are explored. The similarities and differences in the mechanical characteristics of the cylinders in the environments with and without terrains are compared. The research results show that, when the IWs propagate over terrain, the waveform structures are prone to continuous changes. The intense reverse alternating flow of the upper and the lower water, bounded by the pycnocline, results in huge IWs forces differences between the case without terrains and the cases with terrains. In the case without terrains, the maximum horizontal resultant force on the cylinder is positive, while the resultant forces are negative in the cases with terrain. Compared with the case without terrain, the shallow-water effect caused by the combined action of the terrain and the IWs enhances the flow field strength, making the lower parts of the cylinder suffer larger horizontal forces in the opposite direction to the IW direction. Moreover, the additional vortices produced by the interaction between the IWs and the terrain causes a more complex flow field around the cylinder and the greater forces on the cylinder