Proteasome inhibition in the regulation of natural killer cell function and multiple myeloma cell apoptosis

Multiple myeloma (MM) is a hematologic malignancy mostly occurring in the elderly and characterized by an expansion of monoclonal plasma cells in the bone marrow and increased monoclonal immunoglobulin in plasma. The outcome of this disease has been greatly improved due to introduction of new drugs. The proteasome inhibitor bortezomib (velcade ® ) is one of the therapeutic drugs showing very pronounced efficacy in th e treatment of MM. However, cytotoxic effects of bortezomib on immune - competent cells have also been observed. In the current thesis, we focus on studying regulatory effects of proteasome inhibition on natural killer (NK) cells and MM cell. We found that b ortezomb induces apoptosis of NK cells at a clinically relevant dose, and this is mainly due to induction of reactive oxygen species (ROS). Additionally, bortezomib also decreased NK cell activating receptor NKp46 expression, resulting in impaired NKp46 - me diated redirect ed killing activity. Bay 11 - 7082, a pharmacological inhibitor of NF - ҡB activation, also reduced NKp46 expression and suppressed redirected cytotoxicity, suggesting NF - ҡB was involved in the regulation of NKp46 expression. To further study th e effects of bortezomib on NK cells, we used human interleukin (IL) - 2 activated NK cells. Down regulation of tumor necrosis factor - related apoptosis - inducing ligand (TRAIL) expression at both protein and mRNA level in IL - 2 activated NK cells was observed a fter bortezomib and Bay 11 - 7082 treatment, suggesting that the proteasome is involved in the regulation of TRAIL expression through modulation of NF - ҡB activity. Moreover, perforin - independent killing activity of MM cell line RPMI8226 and U266 was also reduced after bortezomib treat ment, and blocking cell surface - bound TRAIL impaired NK cell - mediated lysis of the TRAIL - sensitive MM cell line, RPMI8226 cells. Next we studied a novel inhibitor of proteasome deubiquitination, b - AP15. We noted accumulation of polyubiquitinated proteins i n RPMI8226 and U266 cells after b - AP15 treatment. Moreover, pro - apoptotic effects of b - AP15 on MM cells were also seen by detecting phosphatidylserine (PS) exposure, processing of pro - caspase - 3, and cleavage of poly (ADP - ribose) polymerase (PARP); apoptosi s was shown to be caspase - dependent. Additionally, b - AP15 also induced apoptosis in NK cells. However, the pro - apoptotic effect of b - AP15 on NK cells was not as pronounced as the effect of bortezomib, highlighting that b - AP15 may have less adverse effects on the immunosurveillance of NK cells against tumors. Furthermore, we evaluated a multifunctional protein HS - 1 associated protein X - 1 (HAX - 1), which is overexpressed in MM, and its potential role in the regulation of MM. Our data indicated that silencing of HAX - 1 expression in the human U266 and RPMI8226 cells can not sensitize cells to bortezomib or b - AP15, nor to NK cell - me diated killing. However, the ability of U266 cells to migration was reduced after HAX - 1 knockdown, indicating that HAX - 1 could play a role in regulating tumor metastasis. In summary, our studies contributed a better understanding of proteasome inhibitors a s anti - cancer drugs and have provided insights into possible adverse effects on immune - competent cells. Our studies also identified HAX - 1 as a possible target in MM treatment

Antiferroelectricity induced by electric field in NaNbO3-based lead-free ceramics

Electric fields are known to favor a ferroelectric phase with parallel electric dipoles over an antiferroelectric phase. We demonstrate in this Letter that electric fields can induce an antiferroelectric phase out of a ferroelectric phase in a NaNbO3-based lead-free polycrystalline ceramic. Such an unlikely ferroelectric-to-antiferroelectric phase transition occurs at fields with a reversed polarity and competes with the ferroelectric polarization reversal process

Advanced research methods and their applications on the nexus of energy efficiency and environment: evidence from five RCEP economies

Using efficient and cleaner energy is environmentally friendly and is vital for combating the negative effect of emissions on the environment. Focusing on both developed and developing nations, it is important to report their environmental conditions while targeting economic and energy-related factors. In this regard, the current study is an attempt to investigate the influence of energy efficiency (ENEF), financial inclusion (FIN), economic growth (GDP), environmental-related technological innovation (ERTI), and human capital index (HCI) on the carbon dioxide (CO2) emissions for the five selected nations of RCEP. The variables are found associated in terms of long-run cointegration relationships. The panel quantile regression estimator is utilized for empirical estimations, which provide highly significant estimates across the three selected quantiles (25th, 50th and 75th). The results report that FIN and GDP significantly aggravate environmental degradation by enhancing the CO2 emission level, among which the strongest CO2 emission growth is found in the second quantile. Besides, the ENEF, ERTI and HCI significantly reduce CO2 emission. Based on the empirical findings, this study provides practical implication focusing on the improvement of energy efficiency policies and revising financial inclusion policies in promotion of green investments

Biological Invasion and Coexistence in Intraguild Predation

Invasion of an exotic species initiated by its local introduction is considered subject to intraguild predation (IGP). Mathematically, the system dynamics is described by three nonlinear diffusion-reaction equations in two spatial dimensions. The key factors that determine successful invasion are investigated by means of extensive numerical simulations. The results reveal high asymmetry. An exotic species can invade successfully if it acted as the top predator and engaged in IGP, and the IGP interactions of the postinvasion web will be kept. While the exotic species were introduced as the intraguild prey (IGprey), they invade and spread through patchy invasion which corresponds to the invasion at the edge of extinction. Increase of the IGprey's dispersal rate and decrease of the IGpredator's may make the IGprey invade. But the interactions of the postinvasion web will change from IGP to competition, which is absolutely different from the first case. Finally, the common existence of IGP was explored once again from the perspective of biological invasion

Effect of Ba content on the stress-sensitivity of the antiferroelectric to ferroelectric phase transition in (Pb,La,Ba,)(Zr,Sn,Ti)O3 ceramics

The effect of Ba content on the stress sensitivity of the antiferroelectric to ferroelectric phase transition in (Pb0.94−xLa0.04Bax)[(Zr0.60Sn0.40)0.84Ti0.16]O3 ceramics is investigated through monitoring electric field-induced polarization and longitudinal strain under compressive prestresses. It is found that incorporation of Ba significantly suppresses the stress sensitivity of the phase transition, as manifested by slight decreases under prestresses up to 100 MPa in the maximum polarization (Pm) and longitudinal strain (xm). The energy storage density is even increased under the mechanical confinement in compositions x = 0.02 and 0.04. X-ray diffraction, transmission electron microscopy, and dielectric measurements indicate that the suppressed stress sensitivity is associated with the disruption of micrometersized antiferroelectric domains into nanodomains and the transition from antiferroelectric to relaxor behavior

Responsivity Enhanced NMOSFET Photodetector Fabricated by Standard CMOS Technology

Increasing the responsivity is one of the important issues for a photodetector. In this paper, we demonstrate an improved NMOSFET photodetector by using deep-n-well (DNW) structure which can improve the responsivity of the photodetector significantly. The experimental results show that the responsivity can be enhanced greatly by the DNW structure and is much larger than the previous work when DNW is biased with 0.5 V, while the dark current exhibits almost no increase. Further characterization indicates that the diode formed by the bulk and DNW can efficiently absorb photons and has a large gain factor of the photocurrent especially under low light condition, which gives a more promising application for the detector to detect the weak light