Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure

Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR1–5). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds 1–20 of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (1–10) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (11–20) showed poor anticancer effect. Compound 10, having the highest cytotoxic effect (48 h, HT29 IC50 = 6.223 µM, HCT116 IC50 = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound 10 inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound 10 increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds 11 and 13 had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities.

Prediction of Vertical Tail Buffet Using CFD/CSD Coupling Method

The vertical tail buffet induced by the vortex breakdown flow is numerically investigated. The unsteady flow is calculated by solving the RANS equations. The structural dynamic equations are decoupled in the modal coordinates. The radial basis functions (RBFs) are employed to generate the deformation mesh. The buffet response of the flexible tail is predicted by coupling the three sets of equations. The results show that the presence of asymmetry flow on the inner and outer surface of the tail forced the structural deflection offsetting the outboard. The frequency of the 2nd bending mode of the tail structure meets the peak frequency of the pressure fluctuation upon the tail surface, and the resonance phenomenon was observed. Therefore, the 2nd bending responses govern the flow field surrounding the vertical tail. Finally, the displacement of the vertical tail is small, while the acceleration with a large quantitation forces the vertical tail undergoing severe addition inertial loads.

Airfoil Analysis and Effect of Wing Shape Optimization on Aerodynamic Parameters in a Steady Flight

The work in this paper deals with reconstructing and optimizing the wing geometry of an Unmanned Combat Aerial Vehicle for improved performance and reviewing the impact of the modification on flight parameters in a steady flight. The behavior of airfoils at planned flight conditions under I.S.A. is checked in XFLR5 software. Following up by 2-D CFD and boundary layer analysis of former and new airfoil, dimensions of the wing are re-developed, keeping the fuselage and tail structure same. The existing wing and the optimized wing design is analyzed by Vortex Lattice Method and Triangular Panel Method, with an objective to make the shape of the wing aerodynamically suitable for an increased Lift to Drag ratio and thereby minimizing drag coefficients.

Artificial Flexible Sperm-like Nanorobot Based on Self-assembly and Its Magnetically Actuated Propulsion Property

Sperm cells can move at a high speed in biofluids based on the flexible flagella, which inspire novel flagellar micro-/nanorobots to be designed. However, mass fabrication of vivid sperm-like nanorobots with flagellar flexibility is still challenging. In this work, a facile and efficient strategy is proposed to produce flexible sperm-like nanorobots with self-assembled head-to-tail structure. The nanorobots were composed of a superparamagnetic head and a flexible Au/PPy flagellum, which were covalently linked via biotin-streptavidin bonding. Under a precessing magnetic field, the head drove the flexible tail to rotate and generated undulatory bending waves propagating along the body. Bidirectional locomotion of the nanorobot was investigated, and moving velocity as well as direction varied with the actuating conditions (field strength, frequency, direction) and the nanorobot’s structure (tail length). Effective flagellar locomotion was observed near the substrate and high velocities were attained in both forward and backward directions. Typical modelling based on elastohydrodynamics and undulatory wave propagation were utilized for propulsion analysis. This research presents novel artificial flexible sperm-like nanorobots with delicate self-assembled head-to-tail structures and remarkable bidirectional locomotion performances, indicating significant potentials for nanorobotic design and future biomedical application.

Actin-based myosin XXI (13) molecular motor is involved in early phase of Leishmania cytokinesis

Leishmania genome encodes for two isoforms of myosin, but only Myosin XXI (Myo21), which is a novel form of myosin in that it contains two ubiquitin associated-like (UBA) domains towards the end of its tail structure, is expressed in both the promastigote and amastigote forms of this protozoan. Earlier studies have shown that in Leishmania promastigotes Myo21 besides localizing throughout the cell body and flagellum, it is prominently localized to the base of the flagellum. It has further been shown that this protein in the promastigotes plays an important role in regulating the cell morphology, motility, flagellum dynamics, growth and intracellular trafficking, As Myo21 depletion has been shown to result in reduced cell growth in culture, we considered it of interest to investigate whether the observed effect of Myo21 on the cell growth is mediated through its possible role in Leishmania cell division cycle. For this, we prepared heterozygous Myo21 mutants of Leishmania promastigotes (Myo21+/−cells) and then analyzed their morphology, growth and cell division cycle, using wild type Leishmania promastigotes (Myo21+/+ cells) as control. The cell division cycle was analyzed by employing flow cytometry and immunofluorescence microscopy. Flow cytometric analysis revealed that the G2/M to G1 phase transition in Myo21+/− cell is significantly delayed, as compared to Myo21+/+ cells. Immunofluorescence confocal microscopic analysis indicated that Myo21+/− cells encountered a significant delay in initiation of cytokinesis, which was mainly due to delay in the flagellar pocket division. Further analysis revealed that actin-based Myo21 motor is essentially required in the initiation phase of Leishmania cytokinesis.

Study on Mechanical Properties and Application of a New Flexible Bolt

As mining depth extends continuously, complex geological environment and strong mining stress pose serious challenges against excavation safety and higher demand for bolt support. To meet the challenges, a new type of flexible bolt is developed that is free from the limitation of excavation height and can be installed quickly. The flexible bolts have a tail structure which is squeezed together by the locking casing and the steel-strand rod. The tail structure forms the thread through the rolling process, and then can be quickly installed by the nut rotation type, which avoids the disadvantages of the cable tension installation. Through the flexible long bolts, the thick anchoring layer of the roof can be constructed, and the safety control of the roadway is realized. To obtain the optimal specifications, locking casings of three diameters and lengths were used to prepare bolt samples for static tensile test. Test results show that when the diameter of locking casing is fixed, the peak resistance increases as the length of locking casing increases, but the increased amplitude tends to reduce gradually. When the length of locking casing is fixed, too large a diameter makes the mechanical property unstable. Finally, the optimal length and diameter of locking casing are set at 120 and 30 mm, respectively. In addition, cyclic loading tests were conducted, the results of which indicate that cyclic loading does not change the stress state within the bolts and that flexible bolts display a stable mechanical property. Field results indicate that flexible bolts achieve low damage of the surrounding rock and control the maximum roof fracture depth within 2.1 m, thus guaranteeing the roadway safety.

Cabs1 Maintains Structural Integrity of Mouse Sperm Flagella during Epididymal Transit of Sperm

The calcium-binding protein spermatid-associated 1 (Cabs1) is a novel spermatid-specific protein. However, its function remains largely unknown. In this study, we found that a long noncoding RNA (lncRNA) transcripted from the Cabs1 gene antisense, AntiCabs1, was also exclusively expressed in spermatids. Cabs1 and AntiCabs1 knockout mice were generated separately (using Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-Cas9 methods) to investigate their functions in spermatogenesis. The genetic loss of Cabs1 did not affect testicular and epididymal development; however, male mice exhibited significantly impaired sperm tail structure and subfertility. Ultrastructural analysis revealed defects in sperm flagellar differentiation leading to an abnormal annulus and disorganization of the midpiece–principal piece junction, which may explain the high proportion of sperm with a bent tail. Interestingly, the proportion of sperm with a bent tail increased during transit in the epididymis. Furthermore, Western blot and immunofluorescence analyses showed that a genetic loss of Cabs1 decreased Septin 4 and Krt1 and increased cyclin Y-like 1 (Ccnyl1) levels compared with the wild type, suggesting that Cabs1 deficiency disturbed the expression of cytoskeleton-related proteins. By contrast, AntiCabs1−/− mice were indistinguishable from the wild type regarding testicular and epididymal development, sperm morphology, concentration and motility, and male fertility. This study demonstrates that Cabs1 is an important component of the sperm annulus essential for proper sperm tail assembly and motility.

DOUBLE-LINE IRRIGATION MODULE FOR DRIP IRRIGATION OF SOME WOODY FRUIT PLANTS CULTIVATED IN GARDEN PLANTINGS

Purpose: to develop a design-layout scheme for a two-line irrigation module of a drip irrigation system, providing effective drip irrigation of perennial tree fruit crops cultivated in garden plantings. Materials and methods. The main requirements for developing an irrigation module scheme are: ensuring the required proportion of moisture area, ensuring a regulated distance between the woody plant stem and the nearest emitter at least 0.2 m, ensuring the possibility of periodically changing the emitter position relative to the plant stem. When developing the scheme of the irrigation module, the methods of search design were used. Results. A constructive scheme of a two-line irrigation module intended for drip irrigation of one row of plants in a perennial tree fruit plantation is proposed, it includes two irrigation lines symmetrically located relative to the axis of a row of plants with emitters arranged in them. Drip tubing with wall thickness from 0.8 to 1.2 mm is recommended for use as irrigation lines. Drip lines are located on supports at a height of 50 cm from the earth's surface and have the ability to change their position relative to the axis of a row of plants. The head and tail structure of the irrigation module are connected to the supply and discharge pipelines through flexible water conduits. The end part of the irrigation module provides for the possibility of collecting and discharging wash water (solution). Conclusions. As a result of the studies carried out, a constructive solution for a two-line irrigation module of a drip irrigation network was proposed, which allows: to increase the proportion of the moistening area from the area of nutrition of each plant to the standard values, to ensure effective watering of the root-inhabited soil space at different stages of plant growth and development, to reduce the intensity of soil degradation during drip irrigation.