Characterization of SN38-resistant T47D breast cancer cell sublines overexpressing BCRP, MRP1, MRP2, MRP3, and MRP4.

BACKGROUND: Although several novel resistant breast cancer cell lines have been established, only a few resistant breast cancer cell lines overexpress breast cancer resistance proteins (BCRP). The aim of this study was to establish new resistant breast cancer cell lines overexpressing BCRP using SN38 (7-ethyl-10-hydroxycamptothecin), an active metabolite of irinotecan and was to discover genes and mechanisms associated with multidrug resistance. METHODS: SN38-resistant T47D breast cancer cell sublines were selected from the wild-type T47D cells by gradually increasing SN38 concentration. The sensitivity of the cells to anti-cancer drugs was assessed by 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Expression profiles of the resistance-related transporters were examined using RT-qPCR, and western blot analysis. Intracellular fluorescent dye accumulation in the resistant cells was determined using flow cytometry. RESULTS: The SN38-resistant T47D breast cancer cell sublines T47D/SN120 and T47D/SN150 were established after long-term exposure (more than 16 months) of wild-type T47D cells to 120 nM and 150 nM SN38, respectively. T47D/SN120 and T47D/SN150 cells were more resistant to SN38 (14.5 and 59.1 times, respectively), irinotecan (1.5 and 3.7 times, respectively), and topotecan (4.9 and 12 times, respectively), than the wild-type parental cells. Both T47D/SN120 and T47D/SN150 sublines were cross-resistant to various anti-cancer drugs. These resistant sublines overexpressed mRNAs of MRP1, MRP2, MRP3, MRP4, and BCRP. The DNA methylase inhibitor 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor trichostatin A increased the expression levels of BCRP, MRP1, MRP2, MRP3, and MRP4 transcripts in T47D/WT cells. Fluorescent dye accumulation was found to be lower in T47D/SN120 and T47D/SN150 cells, compared to that in T47D/WT cells. However, treatment with known chemosensitizers increased the intracellular fluorescent dye accumulation and sensitivity of anti-tumor agents. CONCLUSION: T47D/SN120 and T47D/SN150 cells overexpressed MRP1, MRP2, MRP3, MRP4, and BCRP, which might be due to the suppression of epigenetic gene silencing via DNA hypermethylation and histone deacetylation. Although these resistant cells present a higher resistance to various anti-cancer drugs than their parental wild-type cells, multidrug resistance was overcome by treatment with chemosensitizers. These SN38 resistant T47D breast cancer cell sublines expressing resistance proteins can be useful for the development of new chemosensitizers.

The wound-healing effect of 7,3',4'-trimethoxyflavone through increased levels of prostaglandin E2 by 15-hydroxyprostaglandin dehydrogenase inhibition.

OBJECTIVE: To find an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) that rapidly metabolises Prostaglandin E2 (PGE2) as a mediator of wound healing, we examined seven flavonoids for this role. RESULTS: 7,3',4'-Trimethoxyflavone (TMF) had the lowest IC50 value of 0.34 µM for 15-PGDH inhibition but >400 µM for cytotoxicity, indicating a high therapeutic index. TMF elevated PGE2 levels in a concentration-dependent manner in both A549 lung cancer and HaCaT cells. It also significantly increased mRNA expression of multidrug resistance-associated protein 4 (MRP4) and of prostaglandin transporter (PGT) slightly in HaCaT cells. In addition, TMF facilitated in vitro wound healing in a HaCaT scratch model, which was completely inhibited by adding both 15-PGDH and NAD+ as cofactor, confirming the involvement of PGE2 in its wound healing effect. CONCLUSION: TMF with a high therapeutic index can facilitate wound healing through PGE2 elevation by 15-PGDH inhibition.

The anticancer effect of (1S,2S,3E,7E,11E)-3,7,11, 15-cembratetraen-17,2-olide(LS-1) through the activation of TGF-ß signaling in SNU-C5/5-FU, fluorouracil-resistant human colon cancer cells.

The anticancer effect of (1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1) from Lobophytum sp. has been already reported in HT-29 human colorectal cancer cells. In this study, we examined the effect of LS-1 on the apoptosis induction of SNU-C5/5-FU, fluorouracil-resistant human colon cancer cells. Furthermore, we investigated whether the apoptosis-induction effect of LS-1 could arise from the activation of the TGF-ß pathway. In SNU-C5/5-FU treated with LS-1 of 7.1 µM (IC50), we could observe the various apoptotic characteristics, such as the increase of apoptotic bodies, the increase of the sub-G1 hypodiploid cell population, the decrease of the Bcl-2 level, the increase of procaspase-9 cleavage, the increase of procaspase-3 cleavage and the increase of poly(ADP-ribose) polymerase cleavage. Interestingly, the apoptosis-induction effect of LS-1 was also accompanied by the increase of Smad-3 phosphorylation and the downregulation of c-Myc in SNU-C5/5-FU. LS-1 also increased the nuclear localization of phospho-Smad-3 and Smad-4. We examined whether LS-1 could downregulate the expression of carcinoembryonic antigen (CEA), a direct inhibitor of TGF-ß signaling. LS-1 decreased the CEA level, as well as the direct interaction between CEA and TGF-ßR1 in the apoptosis-induction condition of SNU-C5/5-FU. To examine whether LS-1 can induce apoptosis via the activation of TGF-ß signaling, the SNU-C5/5-FU cells were treated with LS-1 in the presence or absence of SB525334, a TGF-ßRI kinase inhibitor. SB525334 inhibited the effect of LS-1 on the apoptosis induction. These findings provide evidence demonstrating that the apoptosis-induction effect of LS-1 results from the activation of the TGF-ß pathway via the downregulation of CEA in SNU-C5/5-FU.

Double-gate structure enabling remote Coulomb scattering-free transport in atomic-layer-deposited IGO thin-film transistors with HfO2 gate dielectric through insertion of SiO2 interlayer.

In this paper, high-performance indium gallium oxide (IGO) thin-film transistor (TFT) with a double-gate (DG) structure was developed using an atomic layer deposition route. The device consisting of 10-nm-thick IGO channel and 2/48-nm-thick SiO2/HfO2 dielectric was designed to be suitable for a display backplane in augmented and virtual reality applications. The fabricated DG TFTs exhibit outstanding device performances with field-effect mobility (µFE) of 65.1 ± 2.3 cm2V-1 s-1, subthreshold swing of 65 ± 1 mVdec-1, and threshold voltage (VTH) of 0.42 ± 0.05 V. Both the (µFE) and SS are considerably improved by more than two-fold in the DG IGO TFTs compared to single-gate (SG) IGO TFTs. Important finding was that the DG mode of IGO TFTs exhibits the nearly temperature independent µFE variations in contrast to the SG mode which suffers from the severe remote Coulomb scattering. The rationale for this disparity is discussed in detail based on the potential distribution along the vertical direction using technology computer-aided design simulation. Furthermore, the DG IGO TFTs exhibit a greatly improved reliability with negligible VTH shift of - 0.22 V under a harsh negative bias thermal and illumination stress condition with an electric field of - 2 MVcm-1 and blue light illumination at 80 °C for 3600 s. It could be attributed to the increased electrostatic potential that results in fast re-trapping of the electrons generated by the light-induced ionization of deep level oxygen vacancy defects.

Strong Immunity to Drain-Induced Barrier Lowering in ALD-Grown Preferentially Oriented Indium Gallium Oxide Transistors.

Drain-induced barrier lowering (DIBL) is one of the most critical obstacles degrading the reliability of integrated circuits based on miniaturized transistors. Here, the effect of a crystallographic structure change in InGaO [indium gallium oxide (IGO)] thin-films on the DIBL was investigated. Preferentially oriented IGO (po-IGO) thin-film transistors (TFTs) have outstanding device performances with a field-effect mobility of 81.9 ± 1.3 cm2/(V s), a threshold voltage (VTH) of 0.07 ± 0.03 V, a subthreshold swing of 127 ± 2.0 mV/dec, and a current modulation ratio of (2.9 ± 0.2) × 1011. They also exhibit highly reliable electrical characteristics with a negligible VTH shift of +0.09 (-0.14) V under +2 (-2) MV/cm and 60 °C for 3600 s. More importantly, they reveal strong immunity to the DIBL of 17.5 ± 1.2 mV/V, while random polycrystalline In2O3 (rp-In2O3) and IGO (rp-IGO) TFTs show DIBL values of 197 ± 5.3 and 46.4 ± 1.2 mV/V, respectively. This is quite interesting because the rp- and po-IGO thin-films have the same cation composition ratio (In/Ga = 8:2). Given that the lateral diffusion of oxygen vacancies from the source/drain junction to the channel region via grain boundaries can reduce the effective length (Leff) of the oxide channel, this improved immunity could be attributed to suppressed lateral diffusion by preferential growth. In practice, the po-IGO TFTs have a longer Leff than the rp-In2O3 and -IGO TFTs even with the same patterned length. The effect of the crystallographic-structure-dependent Leff variation on the DIBL was corroborated by technological computer-aided design simulation. This work suggests that the atomic-layer-deposited po-IGO thin-film can be a promising candidate for next-generation electronic devices composed of the miniaturized oxide transistors.

Effect of Metformin on the Functional and Electrophysiological Recovery of Crush Injury-Induced Facial Nerve Paralysis in Diabetic Rats.

The impact of metformin on the rat facial nerve following crush injury has only occasionally been documented to date. The purpose of the current investigation was to use functional and electrophysiological evaluations to investigate the effects of metformin administration on recovery following crush injury to the rat facial nerve. The rats were randomly divided into four groups: the nonDM/PBS group (n = 4), the nonDM/metformin group (n = 4), the DM/PBS group (n = 4), and the DM/metformin group (n = 4). Diabetes was generated by an intraperitoneal injection of streptozotocin. Facial nerve paralysis was induced by a crush injury 7 days after diabetes induction. The blood glucose levels of the DM/PBS and DM/metformin groups were maintained at over 300 mg/dL, whereas the blood glucose levels of the nonDM/PBS and nonDM/metformin groups were maintained at less than 150 mg/dL. There was no significant difference between the two nonDM groups. In comparison to the PBS group, the metformin group's recurrence of vibrissa fibrillation occurred noticeably sooner over time. The nonDM/metformin group showed the highest recovery rate in the second, third, and fourth weeks post-crush, respectively. The threshold of action potential 4 weeks after crush injury showed that the nonDM/metformin group had a significantly lower mean threshold of MAP compared to other groups. The short-term effect of metformin on the recovery of facial nerve blood flow (FNBF) was significantly increased compared to the DM/PBS group. However, there was no significant difference in FNBF between the nonDM/metformin and nonDM/PBS groups. A diabetic condition promoted a delay in FN regeneration. Metformin is able to accelerate functional recovery in diabetic or nondiabetic FN-injured rats. Further studies using a morphometric or molecular approach are planned to understand the pharmacologic mechanism of metformin.

Progress, Challenges, and Opportunities in Oxide Semiconductor Devices: A Key Building Block for Applications Ranging from Display Backplanes to 3D Integrated Semiconductor Chips.

As Si has faced physical limits on further scaling down, novel semiconducting materials such as 2D transition metal dichalcogenides and oxide semiconductors (OSs) have gained tremendous attention to continue the ever-demanding downscaling represented by Moore's law. Among them, OS is considered to be the most promising alternative material because it has intriguing features such as modest mobility, extremely low off-current, great uniformity, and low-temperature processibility with conventional complementary-metal-oxide-semiconductor-compatible methods. In practice, OS has successfully replaced hydrogenated amorphous Si in high-end liquid crystal display devices and has now become a standard backplane electronic for organic light-emitting diode displays despite the short time since their invention in 2004. For OS to be implemented in next-generation electronics such as back-end-of-line transistor applications in monolithic 3D integration beyond the display applications, however, there is still much room for further study, such as high mobility, immune short-channel effects, low electrical contact properties, etc. This study reviews the brief history of OS and recent progress in device applications from a material science and device physics point of view. Simultaneously, remaining challenges and opportunities in OS for use in next-generation electronics are discussed.

High Mobility IZTO Thin-Film Transistors Based on Spinel Phase Formation at Low Temperature through a Catalytic Chemical Reaction.

In this paper, In0.22 Znδ Sn0.78- δ O1.89- δ (δ = 0.55) films with a single spinel phase are successfully grown at the low temperature of 300 °C through careful cation composition design and a catalytic chemical reaction. Thin-film transistors (TFTs) with amorphous In0 .22 Znδ Sn0.78- δ O1.89- δ (δ = 0.55) channel layers have a reasonable mobility of 41.0 cm2 V-1 s-1 due to the synergic intercalation of In and Sn ions. In contrast, TFTs with polycrystalline spinel In0 .22 Znδ Sn0.78- δ O1.89- δ (δ = 0.55) channel layers, achieved through a metal-induced crystallization at 300 °C, exhibit a remarkably high field-effect mobility of ≈83.2 cm2 V-1 s-1 and excellent stability against external gate bias stress, which is attributed to the uniform formation of the highly ordered spinel phase. The relationships between cation composition, microstructure, and performance for the In2 O3 -ZnO-SnO2 ternary component system are investigated rigorously to attain in-depth understanding of the roles of various crystalline phases, including spinel Zn2- y Sn1- y In2 y O4 (y = 0.45), bixbyite In2-2 x Znx Inx O4 (x = 0.4), rutile SnO2 , and a homologous compound of compound (ZnO)k (In2 O3 ) (k = 5). This work concludes that the cubic spinel phase of Zn2- y Sn1- y In2 y O4 (y = 0.45) film is a strong contender as a substitute for semiconducting polysilicon as a backplane channel ingredient for mobile active-matrix organic light-emitting diode displays.

High-Performance Indium-Based Oxide Transistors with Multiple Channels Through Nanolaminate Structure Fabricated by Plasma-Enhanced Atomic Layer Deposition.

An atomic-layer-deposited oxide nanolaminate (NL) structure with 3 dyads where a single dyad consists of a 2-nm-thick confinement layer (CL) (In0.84Ga0.16O or In0.75Zn0.25O), and a barrier layer (BL) (Ga2O3) was designed to obtain superior electrical performance in thin-film transistors (TFTs). Within the oxide NL structure, multiple-channel formation was demonstrated by a pile-up of free charge carriers near CL/BL heterointerfaces in the form of the so-called quasi-two-dimensional electron gas (q2DEG), which leads to an outstanding carrier mobility (µFE) with band-like transport, steep gate swing (SS), and positive threshold voltage (VTH) behavior. Furthermore, reduced trap densities in oxide NL compared to those of conventional oxide single-layer TFTs ensures excellent stabilities. The optimized device with the In0.75Zn0.25O/Ga2O3 NL TFT showed remarkable electrical performance: µFE of 77.1 ± 0.67 cm2/(V s), VTH of 0.70 ± 0.25 V, SS of 100 ± 10 mV/dec, and ION/OFF of 8.9 × 109 with a low operation voltage range of ≤2 V and excellent stabilities (ΔVTH of +0.27, -0.55, and +0.04 V for PBTS, NBIS, and CCS, respectively). Based on in-depth analyses, the enhanced electrical performance is attributed to the presence of q2DEG formed at carefully engineered CL/BL heterointerfaces. Technological computer-aided design (TCAD) simulation was performed theoretically to confirm the formation of multiple channels in an oxide NL structure where the formation of a q2DEG was verified in the vicinity of CL/BL heterointerfaces. These results clearly demonstrate that introducing a heterojunction or NL structure concept into this atomic layer deposition (ALD)-derived oxide semiconductor system is a very effective strategy to boost the carrier-transporting properties and improve the photobias stability in the resulting TFTs.

Comparative Study on Indium Precursors for Plasma-Enhanced Atomic Layer Deposition of In2O3 and Application to High-Performance Field-Effect Transistors.

Indium oxide (In2O3) is a transparent wide-bandgap semiconductor suitable for use in the back-end-of-line-compatible channel layers of heterogeneous monolithic three-dimensional (M3D) devices. The structural, chemical, and electrical properties of In2O3 films deposited by plasma-enhanced atomic layer deposition (PEALD) were examined using two different liquid-based precursors: (3-(dimethylamino)propyl)-dimethyl indium (DADI) and (N,N-dimethylbutylamine)trimethylindium (DATI). DATI-derived In2O3 films had higher growth per cycle (GPC), superior crystallinity, and low defect density compared with DADI-derived In2O3 films. Density functional theory calculations revealed that the structure of DATI can exhibit less steric hindrance compared with that of DADI, explaining the superior physical and electrical properties of the DATI-derived In2O3 film. DATI-derived In2O3 field-effect transistors (FETs) exhibited unprecedented performance, showcasing a high field-effect mobility of 115.8 cm2/(V s), a threshold voltage of -0.12 V, and a low subthreshold gate swing value of <70 mV/decade. These results were achieved by employing a 10-nm-thick HfO2 gate dielectric layer with an effective oxide thickness of 3.9 nm. Both DADI and DATI-derived In2O3 FET devices exhibited remarkable stability under bias stress conditions due to a high-quality In2O3 channel layer, good gate dielectric/channel interface matching, and a suitable passivation layer. These findings underscore the potential of ALD In2O3 films as promising materials for upper-layer channels in the next generation of M3D devices.

Insight into the binding of the wild type and mutated alginate lyase (AlyVI) with its substrate: a computational and experimental study.

The homology model of the wild type alginate lyase (AlyVI) marine bacterium Vibrio sp. protein, was built using the crystal structure of the Family 7 alginate lyase from Sphingomonas sp. A1. To rationalize the observed structure-affinity relationships of aliginate lyase alyVI with its (GGG) substrate, molecular docking, MD imulations and binding free energy calculations followed by site-directed mutagenesis and alyVI activity assays were carried out. Per-residue decomposition of the (GGG) binding energy revealed that the most important contributions were from polar and charged residues, such as Asn138, Arg143, Asn217, and Lys308, while van der Waals interactions were responsible for binding with the catalytic His200 and Tyr312 residues. The mutants H200A, K308A, Y312A, Y312F, and W165A were found to be inactive or almost inactive. However, the catalytic efficiency (k(cat)/K(m)) of the double mutant L224V/D226G increased by two-fold compared to the wild type enzyme. This first structural model with its substrate binding mode and the agreement with experimental results provide a suitable base for the future rational design of new mutated alyVI structures with improved catalytic activity.

Proteasome inhibition-induced p38 MAPK/ERK signaling regulates autophagy and apoptosis through the dual phosphorylation of glycogen synthase kinase 3ß.

Proteasome inhibition is a promising approach for cancer treatment; however, the underlying mechanisms involved have not been fully elucidated. Here, we show that proteasome inhibition-induced p38 mitogen-activated protein kinase regulates autophagy and apoptosis by modulating the phosphorylation status of glycogen synthase kinase 3ß (GSK3ß) and 70kDa ribosomal S6 kinase (p70S6K). The treatment of MDA-MB-231 cells with MG132 induced endoplasmic reticulum stress through the induction of ATF6a, PERK phosphorylation, and CHOP, and apoptosis through the cleavage of Bax and procaspase-3. MG132 caused the phosphorylation of GSK3ß at Ser(9) and, to a lesser extent, Thr(390), the dephosphorylation of p70S6K at Thr(389), and the phosphorylation of p70S6K at Thr(421) and Ser(424). The specific p38 inhibitor SB203080 reduced the p-GSK3ß(Ser9) and autophagy through the phosphorylation of p70S6K(Thr389); however, it augmented the levels of p-ERK, p-GSK3ß(Thr390), and p-70S6K(Thr421/Ser424) induced by MG132, and increased apoptotic cell death. The GSK inhibitor SB216763, but not lithium, inhibited the MG132-induced phosphorylation of p38, and the downstream signaling pathway was consistent with that in SB203580-treated cells. Taken together, our data show that proteasome inhibition regulates p38/GSK(Ser9)/p70S6K(Thr380) and ERK/GSK3ß(Thr390)/p70S6K(Thr421/Ser424) kinase signaling, which is involved in cell survival and cell death.

Histone H4 deacetylation down-regulates catalase gene expression in doxorubicin-resistant AML subline.

We explored if epigenetic mechanisms could be involved in the down-regulated expression of catalase gene (CAT) in the doxorubicin-resistant acute myelogenous leukemia (AML)-2/DX100 cells. Down-regulated CAT expression in AML-2/DX100 cells was completely recovered after treatment of hydrogen peroxide (H(2)O(2)) and histone deacetylase inhibitor, trichostatin A (TSA) but was increased slightly by the treatment of DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-AdC). Bisulfite-sequencing PCR revealed that a CpG island of CAT was not methylated in AML-2/DX100 cells. Chromatin immunoprecipitation assay confirmed that acetylation of histone H4 in AML-2/DX100 cells significantly decreased as compared with that in AML-2/WT cells, which was significantly increased by TSA more than 5-AdC. Meanwhile, overexpression of other up-regulated peroxidase genes appears to make compensation for decreased H(2)O(2)-scavenging activity for the down-regulated CAT expression in AML-2/DX100 cells. These results suggest that histone H4 deacetylation is responsible for the down-regulated CAT expression in AML-2/DX100 cells, which are well adapted to oxidative stress.

Comparative Study of Atomic Layer Deposited Indium-Based Oxide Transistors with a Fermi Energy Level-Engineered Heterojunction Structure Channel through a Cation Combinatorial Approach.

Amorphous indium-gallium-zinc oxide (a-IGZO) has become a standard channel ingredient of switching/driving transistors in active-matrix organic light-emitting diode (AMOLED) televisions. However, mobile AMOLED displays with a high pixel density (≥500 pixels per inch) and good form factor do not often employ a-IGZO transistors due to their modest mobility (10-20 cm2/(V s)). Hybrid low-temperature polycrystalline silicon and oxide transistor (LTPO) technology is being adapted in high-end mobile AMOLED devices due to its ultralow power consumption and excellent current drivability. The critical issues of LTPO (including a complicated structure and high fabrication costs) require a search for alternative all-oxide thin-film transistors (TFTs) with low-cost processability and simple device architecture. The atomic layer deposition (ALD) method is a promising route for high-performance all-oxide TFTs due to its unique features, such as in situ cation composition tailoring ability, precise nanoscale thickness controllability, and excellent step coverage. Here, we report an in-depth comparative investigation of TFTs with indium-gallium oxide (IGO)/gallium-zinc oxide (GZO) and indium-zinc oxide (IZO)/GZO heterojunction stacks using an ALD method. IGO and IZO layers with different compositions were tested as a confinement layer (CL), whereas the GZO layer was used as a barrier layer (BL). Optimal IGO/GZO and IZO/GZO channels were carefully designed on the basis of their energy band properties, where the formation of a quasi-two-dimensional electron gas (q2DEG) near the CL/BL interface is realized by rational design of the band gaps and work-functions of the IGO, IZO, and GZO thin films. To verify the effect of q2DEG formation, the device performances and stabilities of TFTs with CL/BL oxide heterojunction stacks were examined and compared to those of TFTs with a single CL layer. The optimized device with the In0.75Zn0.25O/Ga0.80Zn0.20O stack showed remarkable electrical performance: µFE of 76.7 ± 0.51 cm2/(V s), VTH of -0.37 ± 0.19 V, SS of 0.13 ± 0.01 V/dec, and ION/OFF of 2.5 × 1010 with low operation voltage range of ≥2 V and excellent stabilities (ΔVTH of +0.35, -0.67, and +0.08 V for PBTS, NBIS, and CCS, respectively). This study suggests the feasibility of using high-performance ALD-derived oxide TFTs (which can compete with the performance of LTPO transistors) for high-end mobile AMOLED displays.

High-Performance Broadband Phototransistor Based on TeOx/IGTO Heterojunctions.

Ultraviolet to infrared broadband spectral detection capability is a technological challenge for sensing materials being developed for high-performance photodetection. In this work, we stacked 9 nm-thick tellurium oxide (TeOx) and 8 nm-thick InGaSnO (IGTO) into a heterostructure at a low temperature of 150 °C. The superior photoelectric characteristics we achieved benefit from the intrinsic optical absorption range (300-1500 nm) of the hexagonal tellurium (Te) phase in the TeOx film, and photoinduced electrons are driven effectively by band alignment at the TeOx/IGTO interface under illumination. A photosensor based on our optimized heterostructure exhibited a remarkable detectivity of 1.6 × 1013 Jones, a responsivity of 84 A/W, and a photosensitivity of 1 × 105, along with an external quantum efficiency of 222% upon illumination by blue light (450 nm). Simultaneously, modest detection properties (responsivity: ∼31 A/W, detectivity: ∼6 × 1011 Jones) for infrared irradiation at 970 nm demonstrate that this heterostructure can be employed as a broadband phototransistor. Furthermore, its low-temperature processability suggests that our proposed concept might be used to design array optoelectronic devices for wide band detection with high sensitivity, flexibility, and stability.

Hydrogen-Doping-Enabled Boosting of the Carrier Mobility and Stability in Amorphous IGZTO Transistors.

This study investigated the effect of hydrogen (H) on the performance of amorphous In-Ga-Zn-Sn oxide (a-In0.29Ga0.35Zn0.11Sn0.25O) thin-film transistors (TFTs). Ample H in plasma-enhanced atomic layer deposition (PEALD)-derived SiO2 can diffuse into the underlying a-IGZTO film during the postdeposition annealing (PDA) process, which affects the electrical properties of the resulting TFTs due to its donor behavior in the a-IGZTO. The a-In0.29Ga0.35Zn0.11Sn0.25O TFTs at the PDA temperature of 400 °C exhibited a remarkably higher field-effect mobility (µFE) of 85.9 cm2/Vs, a subthreshold gate swing (SS) of 0.33 V/decade, a threshold voltage (VTH) of -0.49 V, and an ION/OFF ratio of ∼108; these values are superior compared to those of unpassivated a-In0.29Ga0.35Zn0.11Sn0.25O TFTs (µFE = 23.3 cm2/Vs, SS = 0.36 V/decade, and VTH = -3.33 V). In addition, the passivated a-In0.29Ga0.35Zn0.11Sn0.25O TFTs had good stability against the external gate bias duration. This performance change can be attributed to the substitutional H doping into oxygen sites (HO) leading to a boost in ne and µFE. In contrast, the beneficial HO effect was barely observed for amorphous indium gallium zinc oxide (a-IGZO) TFTs, suggesting that the hydrogen-doping-enabled boosting of a-IGZTO TFTs is strongly related to the existence of Sn cations. Electronic calculations of VO and HO using density functional theory (DFT) were performed to explain this disparity. The introduction of SnO2 in a-IGZO is predicted to cause a conversion from shallow VO to deep VO due to the lower formation energy of deep VO, which is effectively created around Sn cations. The formation of HO by H doping in the IGZTO facilitates the efficient connection of atomic states forming the conduction band more smoothly. This reduces the effective mass and enhances the carrier mobility.

Achieving a Low-Voltage, High-Mobility IGZO Transistor through an ALD-Derived Bilayer Channel and a Hafnia-Based Gate Dielectric Stack.

Ultrahigh-resolution displays for augmented reality (AR) and virtual reality (VR) applications require a novel architecture and process. Atomic-layer deposition (ALD) enables the facile fabrication of indium-gallium zinc oxide (IGZO) thin-film transistors (TFTs) on a substrate with a nonplanar surface due to its excellent step coverage and accurate thickness control. Here, we report all-ALD-derived TFTs using IGZO and HfO2 as the channel layer and gate insulator, respectively. A bilayer IGZO channel structure consisting of a 10 nm base layer (In0.52Ga0.29Zn0.19O) with good stability and a 3 nm boost layer (In0.82Ga0.08Zn0.10O) with extremely high mobility was designed based on a cation combinatorial study of the ALD-derived IGZO system. Reducing the thickness of the HfO2 dielectric film by the ALD process offers high areal capacitance in field-effect transistors, which allows low-voltage drivability and enhanced carrier transport. The intrinsic inferior stability of the HfO2 gate insulator was effectively mitigated by the insertion of an ALD-derived 4 nm Al2O3 interfacial layer between HfO2 and the IGZO film. The optimized bilayer IGZO TFTs with HfO2-based gate insulators exhibited excellent performances with a high field-effect mobility of 74.0 ± 0.91 cm2/(V s), a low subthreshold swing of 0.13 ± 0.01 V/dec, a threshold voltage of 0.20 ± 0.24 V, and an ION/OFF of ∼3.2 × 108 in a low-operation-voltage (≤2 V) range. This promising result was due to the synergic effects of a bilayer IGZO channel and HfO2-based gate insulator with a high permittivity, which were mainly attributed to the effective carrier confinement in the boost layer with high mobility, low free carrier density of the base layer with a low VO concentration, and HfO2-induced high effective capacitance.

High-Performance Indium Gallium Tin Oxide Transistors with an Al2O3 Gate Insulator Deposited by Atomic Layer Deposition at a Low Temperature of 150 °C: Roles of Hydrogen and Excess Oxygen in the Al2O3 Dielectric Film.

In this work, high-performance amorphous In0.75Ga0.23Sn0.02O (a-IGTO) transistors with an atomic layer-deposited Al2O3 dielectric layer were fabricated at a maximum processing temperature of 150 °C. Hydrogen (H) and excess oxygen (Oi) in the Al2O3 film, which was controlled by adjusting the oxygen radical density (PO2: flow rate of O2/[Ar+O2]) in the radio-frequency (rf) plasma during ALD growth of Al2O3, significantly affected the performance and stability of the resulting IGTO transistors. The concentrations of H and Oi in Al2O3/IGTO stacks according to PO2 were characterized by secondary ion mass spectroscopy, X-ray photoelectron spectroscopy, hard X-ray photoemission spectroscopy, and thermal desorption spectroscopy. The high concentration of H at a low PO2 of 2.5% caused heavy electron doping in the underlying IGTO during thermal annealing at 150 °C, leading to a conductive behavior in the resulting transistor without modulation capability. In contrast, a high PO2 condition of 20% introduced O2 molecules (or Oi) into the Al2O3 film, which negatively impacted the carrier mobility and caused anomalous photo-bias instability in the IGTO transistor. Through in-depth understanding of how to manipulate H and Oi in Al2O3 by controlling the PO2, we fabricated high-performance IGTO transistors with a high field-effect mobility (µFE) of 58.8 cm2/Vs, subthreshold gate swing (SS) of 0.12 V/decade, threshold voltage (VTH) of 0.5 V, and ION/OFF ratio of ∼109 even at the maximum processing temperature of 150 °C. Simultaneously, the optimized devices were resistant to exposure to external positive gate bias stress (PBS) and negative bias stress (NBS) for 3600 s, where the VTH shifts for exposure to PBS and NBS for this duration were 0.1 V and -0.15 V, respectively.

Autophagy induction by capsaicin in malignant human breast cells is modulated by p38 and extracellular signal-regulated mitogen-activated protein kinases and retards cell death by suppressing endoplasmic reticulum stress-mediated apoptosis.

In our previous study, we showed that capsaicin induces autophagy in several cell lines. Here, we investigated the molecular mechanisms of capsaicin-induced autophagy in malignant (MCF-7 and MDA-MB-231) and normal (MCF10A) human breast cells. Capsaicin caused nonapoptotic cell cycle arrest of MCF-7 and MDA-MB-231 cells but induced apoptosis in MCF10A cells. In MCF-7 and MDA-MB-231 cells, capsaicin induced endoplasmic reticulum (ER) stress via inositol-requiring 1 and Chop and induced autophagy, as demonstrated by microtubule-associated protein 1 light chain-3 (LC3) conversion. Autophagy blocking by 3-methyladenine (3MA) or bafilomycin A1 (BaF1) activated caspase-4 and -7 and enhanced cell death. In MCF-7 and MDA-MB-231 cells, p38 was activated for more than 48 h by capsaicin treatment, but extracellular signal-regulated kinase (ERK) activation decreased after 12 h, and LC3II levels continuously increased. Furthermore, treatment with 3MA markedly down-regulated capsaicin-induced p38 activation and LC3 conversion, and BaF1 completely down-regulated ERK activation and led to LC3II accumulation. In addition, pharmacological blockade or knockdown of the p38 gene down-regulated Akt activation and LC3II levels but did not affect ERK, and pharmacological blockade or knockdown of the ERK gene up-regulated LC3II induction by capsaicin. Knockdown of inositol-requiring 1 down-regulated p38-Akt signaling. In MCF10A cells, capsaicin did not elicit p38 activation and LC3 conversion and caused the sustained activation of caspase-4. Collectively, capsaicin-induced autophagy is regulated by p38 and ERK; p38 controls autophagy at the sequestration step, whereas ERK controls autophagy at the maturation step, and that autophagy is involved in the retardation of cell death by blocking capsaicin-induced ER stress-mediated apoptosis in MCF-7 and MDA-MB-321 cells.

Regulation of DNA topoisomerase IIalpha stability by the ECV ubiquitin ligase complex.

In this study, we attempted to elucidate the E3 ubiquitin ligase for topo IIalpha. When cullins and VHL were ectopically expressed in HT1080 and HEK293T cells, topo IIalpha was degraded most prominently in cullin 2- and VHL-expressing cells. Cullin 2 and the beta domain (aa 114-123) of VHL, a subunit of the ECV (Elongin B/C-cullin 2-VHL protein) complex, specifically interact with the ATPase domain of topo IIalpha. We identified that topo IIalpha associated with endogenous Elongin C. In HT1080 cells co-transfected with deletion mutants of topo IIalpha GRDD (glucose-regulated destruction domain) and VHL, topo IIalpha was degraded by VHL expression. These results demonstrate that ECV acts as E3 ubiquitin ligase targeting GRDD-independent topo IIalpha to the ubiquitin-proteasome pathway.