Saturation Mode Research Articles

Features of the reversible sensitivity-resistance transition in PI3K/PTEN/AKT signalling network after HER2 inhibition

Systems biology approaches that combine experimental data and theoretical modelling to understand cellular signalling network dynamics offer a useful platform to investigate the mechanisms of resistance to drug interventions and to identify combination drug treatments. Extending our work on modelling the PI3K/PTEN/AKT signalling network (SN), we analyse the sensitivity of the SN output signal, phospho-AKT, to inhibition of HER2 receptor. We model typical aberrations in this SN identified in cancer development and drug resistance: loss of PTEN activity, PI3K and AKT mutations, HER2 overexpression, and overproduction of GSK3β and CK2 kinases controlling PTEN phosphorylation. We show that HER2 inhibition by the monoclonal antibody pertuzumab increases SN sensitivity, both to external signals and to changes in kinetic parameters of the proteins and their expression levels induced by mutations in the SN. This increase in sensitivity arises from the transition of SN functioning from saturation to non-saturation mode in response to HER2 inhibition. PTEN loss or PIK3CA mutation causes resistance to anti-HER2 inhibitor and leads to the restoration of saturation mode in SN functioning with a consequent decrease in SN sensitivity. We suggest that a drug-induced increase in SN sensitivity to internal perturbations, and specifically mutations, causes SN fragility. In particular, the SN is vulnerable to mutations that compensate for drug action and this may result in a sensitivity-to-resistance transition. The combination of HER2 and PI3K inhibition does not sensitise the SN to internal perturbations (mutations) in the PI3K/PTEN/AKT pathway: this combination treatment provides both synergetic inhibition and may prevent the SN from acquired mutations causing drug resistance. Through combination inhibition treatments, we studied the impact of upstream and downstream interventions to suppress resistance to the HER2 inhibitor in the SN with PTEN loss. Comparison of experimental results of PI3K inhibition in the PTEN upstream pathway with PDK1 inhibition in the PTEN downstream pathway shows that upstream inhibition abrogates resistance to pertuzumab more effectively than downstream inhibition. This difference in inhibition effect arises from the compensatory mechanism of an activation loop induced in the downstream pathway by PTEN loss. We highlight that drug target identification for combination anti-cancer therapy needs to account for the mutation effects on the upstream and downstream pathways.

Linearized flavor-stability analysis of dense neutrino streams

Neutrino-neutrino interactions in dense neutrino streams, like those emitted by a core-collapse supernova, can lead to self-induced neutrino flavor conversions. While this is a nonlinear phenomenon, the onset of these conversions can be examined through a standard stability analysis of the linearized equations of motion. The problem is reduced to a linear eigenvalue equation that involves the neutrino density, energy spectrum, angular distribution, and matter density. In the single-angle case, we reproduce previous results and use them to identify two generic instabilities: The system is stable above a cutoff density ("cutoff mode"), or can approach an asymptotic instability for increasing density ("saturation mode"). We analyze multi-angle effects on these generic types of instabilities and find that even the saturation mode is suppressed at large densities. For both types of modes, a given multi-angle spectrum typically is unstable when the neutrino and electron densities are comparable, but stable when the neutrino density is much smaller or much larger than the electron density. The role of an instability in the SN context depends on the available growth time and on the range of affected modes. At large matter density, most modes are off-resonance even when the system is unstable.

Overview of physics results from MAST

Major developments on the Mega Amp Spherical Tokamak (MAST) have enabled important advances in support of ITER and the physics basis of a spherical tokamak (ST) based component test facility (CTF), as well as providing new insight into underlying tokamak physics. For example, L–H transition studies benefit from high spatial and temporal resolution measurements of pedestal profile evolution (temperature, density and radial electric field) and in support of pedestal stability studies the edge current density profile has been inferred from motional Stark effect measurements. The influence of the q-profile and E × B flow shear on transport has been studied in MAST and equilibrium flow shear has been included in gyro-kinetic codes, improving comparisons with the experimental data. H-modes exhibit a weaker q and stronger collisionality dependence of heat diffusivity than implied by IPB98(y,2) scaling, which may have important implications for the design of an ST-based CTF. ELM mitigation, an important issue for ITER, has been demonstrated by applying resonant magnetic perturbations (RMPs) using both internal and external coils, but full stabilization of type-I ELMs has not been observed. Modelling shows the importance of including the plasma response to the RMP fields. MAST plasmas with q > 1 and weak central magnetic shear regularly exhibit a long-lived saturated ideal internal mode. Measured plasma braking in the presence of this mode compares well with neo-classical toroidal viscosity theory. In support of basic physics understanding, high resolution Thomson scattering measurements are providing new insight into sawtooth crash dynamics and neo-classical tearing mode critical island widths. Retarding field analyser measurements show elevated ion temperatures in the scrape-off layer of L-mode plasmas and, in the presence of type-I ELMs, ions with energy greater than 500 eV are detected 20 cm outside the separatrix. Disruption mitigation by massive gas injection has reduced divertor heat loads by up to 70%.

Model for Power SiC Vertical JFET With Unified Description of Linear and Saturation Operating Regimes

A novel SiC junction field-effect transistor (JFET) model that uses a unified description of linear and saturated conduction modes is proposed. Advantages of the proposed model are improved robustness and convergence, inclusion of field-dependent mobility effects, and more physical description of the current saturation phenomenon. The model is validated against a normally off JFET sample over a wide temperature range. Finite-element simulations are used to demonstrate the physics-based nature of the proposed model.

Organic inverter: Theoretical analysis using load matching technique

This paper reports the analysis of key parameters affecting voltage transfer characteristics of pseudo PMOS organic inverters. Pentacene has been used as active material for PMOS Organic Thin Film transistor (OTFT). We have used two different inverter configurations for thorough analysis. Each configuration comprises of an enhancement mode driver ( V Threshold = −9.7 V) and a depletion mode load ( V Threshold = 11.7 V). First configuration has its source and gate terminals shorted. While, second configuration differs with its drain and gate terminals shorted. In order to surmise the theoretical performance of the inverters, we have used load matching technique. After investigating various parameters such as inverting gain, noise margin values (immunity to noise error signals) and threshold voltage value, influencing the voltage inverting efficiency of the two configurations mentioned above, it was found that an inverter with shorted source-gate load configuration is better of the two due to privileges such as saturation mode operation of load, low driver current with early saturation of enhancement mode driver, which facilitates full swing output voltage operation. Second configuration with shorted drain-gate load, lacks saturation mode operation of load and fails to deliver high voltage swing along with acceptable noise margin values and inverting gain.

Macroscopic stability of high β MAST plasmas

The high-beta capability of the spherical tokamak, coupled with a suite of world-leading diagnostics on MAST, has facilitated significant improvements in the understanding of performance-limiting core instabilities in high performance plasmas. For instance, the newly installed motional Stark effect diagnostic, with radial resolution <25 mm, has enabled detailed study of saturated long-lived modes in hybrid scenarios. Similarly, the upgraded Thomson scattering system, with radial resolution <10 mm and the possibility of temporal resolution of 1 µs, has allowed detailed analysis of the density and temperature profiles during transient activity in the plasma, such as at a sawtooth crash. High resolution charge exchange recombination spectroscopy provided measurement of rotation braking induced by both applied magnetic fields and by magnetohydrodynamic (MHD) instabilities, allowing tests of neoclassical toroidal viscosity theory predictions. Finally, MAST is also equipped with internal and external coils that allow non-axisymmetric fields to be applied for active MHD spectroscopy of instabilities near the no-wall beta limit. MAST has been able to operate above the pressure at which the resonant field amplification is observed to strongly increase. In order to access such high pressures, the resistive wall mode must be damped, and so numerical modelling has focused on assessing the kinetic damping of the mode and its nonlinear interaction with other instabilities. The enhanced understanding of the physical mechanisms driving deleterious MHD activity given by these leading-edge capabilities has provided guidance to optimize operating scenarios for improved plasma performance.

Au/CaF 2/ nSi(1 1 1) tunnel emitter phototransistor

Owing to the improved growth technology of the 1–2 nm calcium fluoride films on silicon, tunnel metal–insulator–semiconductor transistors have been fabricated. Measured output characteristics show both saturation and active mode of operation. Estimated value of current gain exceeds 1000 approaching the theoretically estimated value in this system. This result supports the candidacy of calcium fluoride for being a vital dielectric in silicon-based functional electronics.

Magnetohydrodynamic equilibrium and the stability of tokamak and reversed-field pinch systems with 3D helical cores

Bifurcated magnetohydrodynamic (MHD) equilibrium states are computed for ITER hybrid scenario and RFX-mod SHAx configurations with very flat or reversed core magnetic shear conditions. In the ITER studies, the minimum inverse rotational transform qmin is near unity, while for RFX-mod it is 1/8. Two equilibrium states are obtained: one is axisymmetric, the other displays a 3D helical core. In tokamak devices, the structure resembles a saturated ideal MHD internal kink mode. In the reversed-field pinch, the structure is seven-fold toroidally periodic. The equilibrium magnetic field spectrum in the Boozer coordinate frame is calculated in both the ITER and RFX-mod configurations and the implications are discussed. The RFX-mod equilibria are strongly unstable to external ideal MHD kink modes, which become stabilized with a closely fitting conducting shell when the equilibrium state has a weak reversed core shear. It is marginally unstable with a monotonic q-profile. Unstable modes are driven by the Ohmic current, with pressure and Pfirsch–Schlüter currents having a very weak effect. The external kink mode spectrum is dominated by coupled m = 1, n = 6 and m = 2, n = 13 Fourier components, which revert to m = 1, n = 8 and m = 2, n = 15 terms with a conducting wall in proximity to the plasma–vacuum interface.

Effect of pressure-driven MHD instabilities on confinement in reactor-relevant high-beta helical plasmas

Through the experiment data analysis in the large helical device (LHD), the influence of the global MHD instability and the relatively short wave length MHD instabilities driven turbulence on the confinement performance in reactor-relevant high-beta helical plasmas is studied. The comparison of the energy confinement time between just before global MHD instability disappears and after that, and the estimation of the saturated mode structure by the multi-channel soft x-ray measurement enable us to quantitatively estimate the influence of the global interchange type MHD instability with different saturated mode structures on the confinement performance. According to the comparison between thermal conductivities in experiments and those predicted by theoretical transport models, the transport properties in the peripheral region of high beta LHD plasmas are quite similar with anomalous transport model based on an interchange type MHD instability driven turbulence, and that result is supported by the dependence of the density fluctuation with relatively short wave length on beta value.

Resonant drive and nonlinear suppression of gradient-driven instabilities via interaction with shear Alfvén waves

The nonlinear interaction of shear Alfvén waves and gradient-driven instabilities on pressure gradients in the Large Plasma Device (LAPD) [Gekelman et al., Rev. Sci. Instrum. 62, 2875 (1991)] at UCLA is explored. Nonlinear response at the beat frequency between two shear Alfvén waves is shown to resonantly drive unstable modes as well as otherwise damped modes. Resonantly driving the damped modes is shown to suppress the originally unstable mode, leaving only the beat-driven response with an overall reduction in fluctuation amplitude. A threshold is observed in the suppression behavior, requiring that the driven damped mode power be of order 10% of the power in the saturated unstable mode. The interaction is also observed to be dependent on the parallel wavenumber of the driven beat wave; efficient coupling and suppression is only observed for co-propagating beat waves with small parallel wavenumber, consistent with the parallel wavenumber of the gradient-driven modes.

A comprehensive study for advanced in situ contact dry cleaning

An advanced in situ pre-contact dry cleaning process with fluorine species has been comprehensively investigated to effectively remove the native oxide on the top surface of Ni-salicide layer for ensuring lower contact resistance (Rc) without the drawbacks, including the clipping of contact top opening, the formation of by-product re-deposition and severe Ni-salicide loss, of the conventional argon ion bombardment process. In this study, two kinds of in situ dry cleaning approaches, called saturation and low etch rate (LER) modes, have been evaluated to further reduce Rc and prevent the contact to poly short issue as keeping contact size scaling down to 28nm node. The Rc reduction of ~40% at 45nm and no contact to poly short issue at 28nm contact design rules can be simultaneously demonstrated by implementing optimized in situ saturation and LER dry cleaning conditions.

Global linear and nonlinear stability of viscous confined plane wakes with co-flow

The global stability of confined uniform density wakes is studied numerically, using two-dimensional linear global modes and nonlinear direct numerical simulations. The wake inflow velocity is varied between different amounts of co-flow (base bleed). In accordance with previous studies, we find that the frequencies of both the most unstable linear and the saturated nonlinear global mode increase with confinement. For wake Reynolds number Re = 100 we find the confinement to be stabilising, decreasing the growth rate of the linear and the saturation amplitude of the nonlinear modes. The dampening effect is connected to the streamwise development of the base flow, and decreases for more parallel flows at higher Re. The linear analysis reveals that the critical wake velocities are almost identical for unconfined and confined wakes at Re ≈ 400. Further, the results are compared with literature data for an inviscid parallel wake. The confined wake is found to be more stable than its inviscid counterpart, whereas the unconfined wake is more unstable than the inviscid wake. The main reason for both is the base flow development. A detailed comparison of the linear and nonlinear results reveals that the most unstable linear global mode gives in all cases an excellent prediction of the initial nonlinear behaviour and therefore the stability boundary. However, the nonlinear saturated state is different, mainly for higher Re. For Re = 100, the saturated frequency differs less than 5% from the linear frequency, and trends regarding confinement observed in the linear analysis are confirmed.

Global linear and nonlinear stability of viscous confined plane wakes with co-flow

The global stability of confined uniform density wakes is studied numerically, using two-dimensional linear global modes and nonlinear direct numerical simulations. The wake inflow velocity is varied between different amounts of co-flow (base bleed). In accordance with previous studies, we find that the frequencies of both the most unstable linear and the saturated nonlinear global mode increase with confinement. For wake Reynolds numberRe= 100 we find the confinement to be stabilising, decreasing the growth rate of the linear and the saturation amplitude of the nonlinear modes. The dampening effect is connected to the streamwise development of the base flow, and decreases for more parallel flows at higherRe. The linear analysis reveals that the critical wake velocities are almost identical for unconfined and confined wakes atRe≈ 400. Further, the results are compared with literature data for an inviscid parallel wake. The confined wake is found to be more stable than its inviscid counterpart, whereas the unconfined wake is more unstable than the inviscid wake. The main reason for both is the base flow development. A detailed comparison of the linear and nonlinear results reveals that the most unstable linear global mode gives in all cases an excellent prediction of the initial nonlinear behaviour and therefore the stability boundary. However, the nonlinear saturated state is different, mainly for higherRe. ForRe= 100, the saturated frequency differs less than 5% from the linear frequency, and trends regarding confinement observed in the linear analysis are confirmed.

Analysis of the transfer functions of a transformer with using the harmonic balance method

The article presents transformer transfer functions derivation based on harmonic balance method. The normal and saturated modes of transformer is considered

Study of the Powerful Nd:YLF Laser Amplifiers for the CTF3 Photoinjectors

A high-power neodymium-doped yttrium lithium fluoride (Nd:YLF) mode-locked 1.5-GHz laser currently used to drive the two photoinjectors of the Compact Linear Collider Test Facility project at the European Organization for Nuclear Research is described. A phenomenological characterization of the two powerful Nd:YLF amplifiers is presented and compared with the measurements. The laser system operates in a saturated steady-state mode. This mode provides good shot-to-shot stability with pulse train mean power in the 10 kW range.

Diode-pumped passively mode-locked Nd:YVO_4 laser at 1342 nm with periodically poled LiNbO_3

In this Letter, we demonstrate a nonlinear-mirror (NLM) mode-locked diode-pumped solid-state Nd:YVO4 laser operating at 1342 nm, in which the NLM comprises a periodically poled LiNbO3 crystal and a dichroic mirror. The self-starting threshold for cw mode locking is 1.5 W, which is significantly lower than that of saturable absorber mode locking. An average power of 1.52 W at 1342 nm is obtained under diode pump power of 10 W at 808 nm, with the slope efficiency being up to 16.8%. The pulse width and the repetition rate of the mode-locked laser output are about 9.5 ps and 101 MHz, respectively.

Helical ITER hybrid scenario equilibria

Numerical computations of ITER equilibria in the hybrid scenario using a three-dimensional (3D) magnetohydrodynamic equilibrium code with nested magnetic flux surfaces demonstrate the formation of internal 3D helical cores similar to saturated ideal internal kink modes under reversed magnetic shear conditions when the minimum value of the inverse rotational transform is in the neighbourhood of unity.

Physical limitations of the diffusive approximation in semiconductor device modeling

Criteria for occurrence of the quasineutral diffusion mode have been investigated in terms of a generalized approach that takes into account the dependences of the electron and hole velocities on the electric field. These criteria should be used to describe the carrier transport in bases of forward biased bipolar semiconductor devices (diodes, thyristors, and power bipolar transistors in the saturation mode). The criteria appreciably differ from the previously obtained commonly accepted criteria. It is demonstrated that equations describing the carrier transport in the quasineutral approximation in n- and p-type semiconductors are different. These equations are used to obtain analytical conditions in which the diffusion mode is operative. The applicability limits of the diffusion approximation in simulation of semiconductor structures are found. The analytical results are confirmed by a numerical experiment.

Bipolar outflow in the active region orion KL

The fine structure of the region of formation of a protostar in the dense molecular cloud OMC-1 of the Orion Nebula was studied during a period of enhanced activity in 1998–1999, with an angular resolution of 50 µas and a velocity resolution of Δv = 0.053 km/s. Inclusions of ice granules in the bipolar outflow were detected and identified. The velocity of the outflow reaches ∼50 km/s, while that of the granules is 5 mas), bullets corresponding to maser emission excited by the outflow in the surrounding medium are observed. The emission is amplified by the external medium at a velocity of vLSR = 7.65 km/s in the bandwidth Δv ≈ 0.5 km/s. The sources of pumping are clusters of infrared sources. The bipolar outflow is inclined at a small angle to the plane of the sky. The acceleration of the maser inclusions also increases the longitudinal component of the velocity, reducing amplification of the emission. The brightness temperature of the components decreases: Tb ∼ ρ−0.8±0.1. The activity terminates with the exponential decline of the maser emission, F ∼ exp(−0.5t2); in the saturated mode this is determined by a decrease in the optical depth, τ ∼ t2. The material of the surrounding space, including the ice granules, is drawn into the disk, moves along spirals toward the nozzle, and is ejected as a highly collimated bipolar flow. The density of material in the outflow exceeds the surrounding density by three to four orders of magnitude. The accretion of the surrounding material and ejection of the bipolar outflow are a unified process accompanying the initial phase of formation of protostars. The counter motion of material at the center stimulates the formation of a central massive object, whose gravitational field accelerates the process and stabilizes the system. The ratio of the durations of periods of high and low activity is determined by the rates of ejection and disk replenishment, and is ∼1:10. The rotating bipolar flow is self-focused.

Raman fiber laser pumped by a semiconductor disk laser and mode locked by a semiconductor saturable absorber mirror

A 1.6µm mode-locked Raman fiber laser pumped by a 1480nm semiconductor disk laser is demonstrated. Watt-level core pumping of the single-mode fiber Raman lasers with low-noise disk lasers together with semiconductor saturable absorber mirror mode locking represents a highly practical solution for short-pulse operation.