Free Trailing Research Articles

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate of their parental fibroblasts, and TRAIL produced by iNSCs was naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed that Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays demonstrated that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts by approximately 3000-fold compared to treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a novel, easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy.

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

Aspect ratio-dependent hysteresis response of a heavy inverted flag

The bistable fluttering response of heavy inverted flags with different aspect ratios ( $AR$ ) is investigated to determine how the vortical structures affect the intermittent vibration response of the flag. A heavy inverted flag in a uniform flow may exhibit several response modes; amongst them are three major modes that occur over an extended velocity range: stationary, large-scale periodic oscillation and one-sided deflected modes. Significant hysteretic bistability is observed at the transition between these modes for all $AR$ , which is notably different from the conventional flag vibration with a fixed leading edge and free trailing edge where no hysteresis is observed at the lower $AR$ limit ( $AR<1$ ). The difference is associated with the distinct roles of vortices around the flag. Experiments with flags made of spring steel are conducted in a wind tunnel, where the flow speed is steadily increased and later decreased to obtain different oscillatory modes of the heavy inverted flags. The experimental results are used to validate the numerical model of the same problem. It is found that different critical velocities exist for increasing and decreasing flow velocities, and there is a sustained hysteresis for all $AR$ controlled by the initiation threshold and growth of the leading-edge and side-edge vortices. The effect of the vortices in the bistable oscillation regime is quantified by formulating a modal force partitioning approach. It is shown that $AR$ can significantly alter the static and dynamic vortex interaction with the flexible plate, thereby changing the flag's hysteresis behaviour and bistable response.

Static aeroelastic instability of an inverted cantilevered plate in inviscid channel flow

The static aeroelastic instability of an inverted cantilevered plate confined inside a two-dimensional channel is examined in this paper. In our present study, the inverted plate, in contrast to the typical one with a fixed leading edge and a free trailing edge, is clamped at the trailing edge but free at the leading edge. The airflow in the channel is assumed inviscid, low-speed, and potential. A theoretical analysis strategy for instability within differential operators and convergent numerical solutions is proposed. The fluid solution has been presented as a Possio integral equation, a composite operator involving the Hilbert and Tricomi operators. We derive the instability equation by operator theory in state–space formulation and model such an instability problem as a mathematical function approximation problem. The least-square method assesses its numerical solutions with the help of the Weierstrass theorem. Compared with the other results, the present way successfully predicts the divergence instability of the inverted cantilevered plate in a confined channel flow. Numerical results show that the channel confinement plays a destabilizing effect, and the critical flow velocity significantly decreases as it is increased. Asymmetric plate placement in the channel also leads to a significant decrease in the critical flow velocity. The critical plate slopes, i.e., the plate instability modes, are not dependent on the channel parameters, and their values at the leading edge remain constant. Further theoretical exploration allows a semi-analytical approximation of the instability boundary.

Flapping dynamics of a flexible flag clamped vertically in a viscous uniform flow

A numerical simulation of a single flexible flag clamped vertically (here, ‘vertical flag’) in a viscous uniform flow is performed to explore the flapping dynamics of the flag. Four typical flapping modes of the vertical flag are identified as the bending rigidity (γ) and mass ratio (μ) vary at a fixed Reynolds number Re = 200, i.e., biased, flapping, deflected and deflected-flapping modes. As μ increases, the flapping state of the vertical flag changes from the deflected mode to the flapping mode and to the deflected-flapping mode, whereas it is reversed with an increase in γ. For a vertical flag in the flapping mode, a continuous increase of the mean amplitude is observed, and the drag coefficient is proportional to the streamwise amplitude of the flag. In addition, when the vertical flag is in the flapping and deflected modes, the streamwise amplitude of the trailing edge is characterized by two peaks with different amplitudes due to the process of forming the negative leading edge vortex. A comparison of the deflected-flapping mode of the vertical flag with the flapping mode of a single flexible flag where the leading edge of the flag is fixed at an upstream location with a free trailing edge (here, ‘conventional flag’) indicates that the amplitude and frequency of the conventional flag are greater than those of the vertical flag in the irregular flapping state with accompanying vortex dynamics. An inspection of snapping events with rapid changes in the drag and acceleration of the flags shows that the number of snapping events for the conventional flag is higher than that for the vertical flag, indicating the presence of more intermittent and violent irregular flapping for the conventional flag. Finally, a comparison of the hysteresis phenomena between the vertical and conventional flags suggests that the loop width of the vertical flag is larger than that of the conventional flag due to the high elastic restoration energy.

Multifunctionalized polyethyleneimine-based nanocarriers for gene and chemotherapeutic drug combination therapy through one-step assembly strategy.

Gene therapy combined with chemotherapy to achieve synergistic therapeutic effects has been a hot topic in recent years. In this project, the human tumor necrosis factor-related apoptosis-inducing ligand-encoding plasmid gene (TRAIL) and doxorubicin (Dox)-coloaded multi-functional nanocarrier was constructed based on the theory of circulation, accumulation, internalization, and release. Briefly, polyethyleneimine (PEI) was selected as skeleton material to synthesize PEI–polyethylene glycol (PEG)–TAT (PPT). Dox was conjugated to PEI using C6-succinimidyl 6-hydrazinonicotinate acetone hydrazone (C6-SANH), and a pH-sensitive Dox-PEI (DP) conjugate was obtained. Then, intracellular cationic pH-sensitive cellular assistant PPT and DP were mixed to condense TRAIL, and TRAIL–Dox coloaded PPT/DP/TRAIL (PDT) nanocarriers were obtained by one-step assembly. TRAIL was completely condensed by DP or PPT when mass ratios (DP/PPT to TRAIL) were up to 100:64, which indicated that DP and PPT could be mixed at any ratio for TRAIL condensation. The intracellular uptake rate of PDT was enhanced (P<0.05) when the contents of PPT in PPT+DP increased from 0 to 30%. Free Dox and TRAIL-loaded nanocarriers (PPT/C6-SANH-PEI/TRAIL [PCT]) were selected as controls to verify the synergistic antitumor effects of PDT. Compared with free TRAIL, TRAIL-protein expression was upregulated by PDT and PCT on Western blotting assays. The in vitro cytotoxicity of PDT was significantly enhanced compared to free Dox and PCT (P<0.01). Furthermore, murine PDT nanocarriers showed higher in vivo antitumor ability than both the Dox group (P<0.05) and the murine PCT group (P<0.05). These results indicated that the TRAIL + Dox synergistic antitumor effect could be achieved by PDT, which paves the way to gene–drug combination therapy for cancer.

Fluid structure interactions with multicell membrane wings

Flexible wing surfaces can be observed in many natural flyers and their use in small engineered flying vehicles has translated too many beneficial properties. These benefits have manifested themselves in the aerodynamic forces as well as flight stability which are an effect of how the flow and the membranes interact both statically and dynamically. In this work, time dependent particle image velocimetry and digital image correlation are used to study the fluid structure interaction for flow over a membrane wing. The wings examined here are multi-cell silicon rubber membrane wings which have a scalloped free trailing edge with different levels of pretension. The pretension effects the natural frequencies of the membranes and is shown to affect the extension magnitude and membrane motion frequency which are both also affected by aerodynamic loading. Examinations of the membranes through time based and frequency domain analysis motions shows they are highly correlated with the flow. The velocity measurements demonstrated the effects of membranes motion alter the characteristics of the flow over wing leading to changes in the overall aerodynamic properties such as the stall angle and the wake deficit.

Flapping dynamics of an inverted flag

AbstractThe dynamics of an inverted flag are investigated experimentally in order to find the conditions under which self-excited flapping can occur. In contrast to a typical flag with a fixed leading edge and a free trailing edge, the inverted flag of our study has a free leading edge and a fixed trailing edge. The behaviour of the inverted flag can be classified into three regimes based on its non-dimensional bending stiffness scaled by flow velocity and flag length. Two quasi-steady regimes, straight mode and fully deflected mode, are observed, and a limit-cycle flapping mode with large amplitude appears between the two quasi-steady regimes. Bistable states are found in both straight to flapping mode transition and flapping to deflected mode transition. The effect of mass ratio, relative magnitude of flag inertia and fluid inertia, on the non-dimensional bending stiffness range for flapping is negligible, unlike the instability of the typical flag. Because of the unsteady fluid force, a flapping sheet can produce elastic strain energy several times larger than a sheet of the deformed mode, improving the conversion of fluid kinetic energy to elastic strain energy. According to the analysis of the leading-edge vortex formation process, the time scale of optimal vortex formation correlates with efficient conversion to elastic strain energy during bending.

Passive flow control by membrane wings for aerodynamic benefit

The coupling of passive structural response of flexible membranes with the flow over them can significantly alter the aerodynamic characteristic of simple flat-plate wings. The use of flexible wings is common throughout biological flying systems inspiring many engineers to incorporate them into small engineering flying systems. In many of these systems, the motion of the membrane serves to passively alter the flow over the wing potentially resulting in an aerodynamic benefit. In this study, the aerodynamic loads and the flow field for a rigid flat-plate wing are compared to free trailing-edge membrane wings with two different pre-tensions at a chord-based Reynolds number of approximately 50,000. The membrane was silicon rubber with a scalloped free trailing edge. The analysis presented includes load measurements from a sting balance along with velocity fields and membrane deflections from synchronized, time-resolved particle image velocimetry and digital image correlation. The load measurements demonstrate increased aerodynamic efficiency and lift, while the synchronized flow and membrane measurements show how the membrane motion serves to force the flow. This passive flow control introduced by the membranes motion alters the flows development over the wing and into the wake region demonstrating how, at least for lower angles of attack, the membranes motion drives the flow as opposed to the flow driving the membrane motion.

The influence of the wake on the stability of cantilevered flexible plates in axial flow

Cantilevered flexible plates in axial flow lose stability through flutter. Using the inextensibility condition for the cantilevered nonlinear plate equation of motion and the unsteady lumped-vortex model to calculate the fluid loads, a flutter boundary has been obtained. In the time-domain analysis performed to this end, the wake behind the oscillating cantilevered plate is assumed to issue tangentially from the free trailing edge and extend downstream with an undulating form. The influence of the wake on system stability may be characterized in terms of the non-dimensional mass ratio, reduced flow velocity and flutter frequency. For large values of the mass ratio, the plate vibrates with high frequency and high-order mode content. It is shown that the wake has less influence on system stability for long plates than it does for short ones.

Kinematics of subduction and subduction‐induced flow in the upper mantle

Results of fluid dynamical experiments are presented to model the kinematics of lithospheric subduction in the upper mantle. The experiments model a dense high‐viscosity plate (subducting lithosphere) overlying a less dense low‐viscosity layer (upper mantle). The overriding lithosphere is not incorporated. Several important features of slab behavior were investigated including the temporal variability of hinge line migration, the kinematic behavior of the slab and the subduction‐induced upper mantle flow. Both fixed and free trailing edge boundary conditions of the subducting plate were investigated. Results show that hinge line retreat is a natural consequence of subduction of a negatively buoyant slab. The migration rate increases until the slab approaches the upper‐lower mantle discontinuity, resulting in a decrease in migration rate followed by a renewed increase and finally approaching a steady state. Slab retreat results in mantle flow, with material initially located underneath the slab flowing around the lateral slab edges toward the mantle wedge. Experimental results indicate that all rollback‐induced flow occurs around the lateral slab edges, forcing the hinge line to attain a convex shape toward the direction of retreat. No signs for poloidal flow underneath the slab tip have been detected. Only a small component of toroidal‐type flow was observed underneath slanting slab tips. For a fixed trailing edge, the slab does not sink vertically downward, but sinks at an angle in a regressive manner. For a free trailing edge, slab sinking is oriented more vertically while the surface part of the subducting plate is pulled into the subduction zone.

AN EXPERIMENTAL STUDY OF MASS TRANSFER FROM FLUTTERING FLAGS

Mass transfer from a whole flag with free trailing edge fluttering vigorously with large amplitude in vertical wind and from parts of flags fluttering with arc-shapes between fixed leading edges and nodes was experimentally investigated in the ranges of the Reynolds number Re = 3 × 10 4 -4. 5 × 10 4 and 1 × 10 4 -5 X 10 4 , respectively. The arc-shape fluttering causes an increase in the Sherwood number only by 15% whereas it has fluttering frequencies much larger than the vigorous fluttering with the free trailing edge, which causes a rapid increase in the Sherwood number with wind velocity up to 3.2 times what is measured for the flags being still in the wind. The abrupt 14-fold increase in the drag of flags due to fluttering and the smoke flow visualization presented by Taneda and the 2-6-fold increase in heat transfer from a flat surface due to flow separation and reattachment measured by Ota and Kon strongly indicate that flow separation and reattachment occur on the vigorously fluttering flag to cause the 3.2-fold increase in the Sherwood number

Numerical Simulation of the Form of the Free Trailing Vortex Sheet in 3-D Compressible Rotor Flow

Article Numerical Simulation of the Form of the Free Trailing Vortex Sheet in 3-D Compressible Rotor Flow was published on December 1, 1998 in the journal International Journal of Turbo & Jet-Engines (volume 15, issue 4).