Discovery of Potent OTUB1/USP8 Dual Inhibitors Targeting Proteostasis in Non-Small-Cell Lung Cancer.

Deubiquitinating enzymes (DUBs) are key regulatory components of the ubiquitination system. Many DUBs have been revealed to play key roles in normal physiology and diseases. However, only very limited DUB members have well-characterized inhibitors. OTUB1 and USP8 are two DUBs reported to promote both immune evasion and tumorigenesis in tumor models, yet their targeted inhibitors are in the early stages of development. Here, we describe the lead identification and optimization of an OTUB1/USP8 dual inhibitor, 61, which exhibits highly potent and selective inhibition of both targets with subnanomolar IC50s in vitro. By inhibiting both DUBs, 61 phenocopies the double knockdown of OTUB1/USP8 and exerts pronounced antiproliferative effects in H1975 and other non-small-cell lung cancer (NSCLC) cell lines. Moreover, 61 efficaciously mitigates tumor growth in vivo. Collectively, our results provide a useful tool for pharmacological perturbation of OTUB1/USP8 and introduce a promising therapeutic strategy of dual DUB inhibition for treating NSCLC.

Effect of Sputtering Oxygen Partial Pressure on the Praseodymium-Doped InZnO Thin Film Transistor Using Microwave Photoconductivity Decay Method.

The praseodymium-doped indium-zinc-oxide (PrIZO) thin film transistor (TFT) shows broad application prospects in the new generation of display technologies due to its high performance and high stability. However, traditional device performance evaluation methods need to be carried out after the end of the entire preparation process, which leads to the high-performance device preparation process that takes a lot of time and costs. Therefore, there is a lack of effective methods to optimize the device preparation process. In this paper, the effect of sputtering oxygen partial pressure on the properties of PrIZO thin film was studied, and the quality of PrIZO thin film was quickly evaluated by the microwave photoconductivity decay (µ-PCD) method. The µ-PCD results show that as the oxygen partial pressure increases, the peak first increases and then decreases, while the D value shows the opposite trend. The quality of PrIZO thin film prepared under 10% oxygen partial pressure is optimal due to its low localized defect states. The electric performance of PrIZO TFTs prepared under different oxygen partial pressures is consistent with the µ-PCD results. The optimal PrIZO TFT prepared under 10% oxygen partial pressure exhibits good electric performance with a threshold voltage (Vth) of 1.9 V, a mobility (µsat) of 24.4 cm2·V-1·s-1, an Ion/Ioff ratio of 2.03 × 107, and a subthreshold swing (SS) of 0.14 V·dec-1.

Amorphous NdIZO Thin Film Transistors with Contact-Resistance-Adjustable Cu S/D Electrodes.

High-performance amorphous oxide semiconductor thin film transistors (AOS-TFT) with copper (Cu) electrodes are of great significance for next-generation large-size, high-refresh rate and high-resolution panel display technology. In this work, using rare earth dopant, neodymium-doped indium-zinc-oxide (NdIZO) film was optimized as the active layer of TFT with Cu source and drain (S/D) electrodes. Under the guidance of the Taguchi orthogonal design method from Minitab software, the semiconductor characteristics were evaluated by microwave photoconductivity decay (µ-PCD) measurement. The results show that moderate oxygen concentration (~5%), low sputtering pressure (≤5 mTorr) and annealing temperature (≤300 °C) are conducive to reducing the shallow localized states of NdIZO film. The optimized annealing temperature of this device configuration is as low as 250 °C, and the contact resistance (RC) is modulated by gate voltage (VG) instead of a constant value when annealed at 300 °C. It is believed that the adjustable RC with VG is the key to keeping both high mobility and compensation of the threshold voltage (Vth). The optimal device performance was obtained at 250 °C with an Ion/Ioff ratio of 2.89 × 107, a saturation mobility (µsat) of 24.48 cm2/(V·s) and Vth of 2.32 V.

Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2.

The COVID-19 pandemic has been disastrous to society and effective drugs are urgently needed. The papain-like protease domain (PLpro) of SARS-CoV-2 (SCoV2) is indispensable for viral replication and represents a putative target for pharmacological intervention. In this work, we describe the development of a potent and selective SCoV2 PLpro inhibitor, 19. The inhibitor not only effectively blocks substrate cleavage and immunosuppressive function imparted by PLpro, but also markedly mitigates SCoV2 replication in human cells, with a submicromolar IC50. We further present a convenient and sensitive activity probe, 7, and complementary assays to readily evaluate SCoV2 PLpro inhibitors in vitro or in cells. In addition, we disclose the co-crystal structure of SCoV2 PLpro in complex with a prototype inhibitor, which illuminates their detailed binding mode. Overall, these findings provide promising leads and important tools for drug discovery aiming to target SCoV2 PLpro.

Alloy-Electrode-Assisted High-Performance Enhancement-Type Neodymium-Doped Indium-Zinc-Oxide Thin-Film Transistors on Polyimide Flexible Substrate.

Flexible thin-film transistors with high current-driven capability are of great significance for the next-generation new display technology. The effect of a Cu-Cr-Zr (CCZ) copper alloy source/drain (S/D) electrode on flexible amorphous neodymium-doped indium-zinc-oxide thin-film transistors (NdIZO-TFTs) was investigated. Compared with pure copper (Cu) and aluminum (Al) S/D electrodes, the CCZ S/D electrode changes the TFT working mode from depletion mode to enhancement mode, which is ascribed to the alloy-assisted interface layer besides work function matching. X-ray photoelectron spectroscopy (XPS) depth profile analysis was conducted to examine the chemical states of the contact interface, and the result suggested that chromium (Cr) oxide and zirconium (Zr) oxide aggregate at the interface between the S/D electrode and the active layer, acting as a potential barrier against residual free electron carriers. The optimal NdIZO-TFT exhibited a desired performance with a saturation mobility (µ sat) of 40.3 cm2·V-1·s-1, an I on/I off ratio of 1.24 × 108, a subthreshold swing (SS) value of 0.12 V·decade-1, and a threshold voltage (V th) of 0.83 V. This work is anticipated to provide a novel approach to the realization of high-performance flexible NdIZO-TFTs working in enhancement mode.

Study of the Correlation between the Amorphous Indium-Gallium-Zinc Oxide Film Quality and the Thin-Film Transistor Performance.

In this work, we performed a systematic study of the physical properties of amorphous Indium-Gallium-Zinc Oxide (a-IGZO) films prepared under various deposition pressures, O2/(Ar+O2) flow ratios, and annealing temperatures. X-ray reflectivity (XRR) and microwave photoconductivity decay (µ-PCD) measurements were conducted to evaluate the quality of a-IGZO films. The results showed that the process conditions have a substantial impact on the film densities and defect states, which in turn affect the performance of the final thin-film transistors (TFT) device. By optimizing the IGZO film deposition conditions, high-performance TFT was able to be demonstrated, with a saturation mobility of 8.4 cm2/Vs, a threshold voltage of 0.9 V, and a subthreshold swing of 0.16 V/dec.

Effects of Annealing Temperature on Optical Band Gap of Sol-gel Tungsten Trioxide Films.

Tungsten trioxide (WO3) is a wide band gap semiconductor material that is used as an important electrochromic layer in electrochromic devices. In this work, the effects of the annealing temperature on the optical band gap of sol-gel WO3 films were investigated. X-ray Diffraction (XRD) showed that WO3 films were amorphous after being annealed at 100 °C, 200 °C and 300 °C, respectively, but became crystallized at 400 °C and 500 °C. An atomic force microscope (AFM) showed that the crystalline WO3 films were rougher than the amorphous WO3 films (annealed at 200 °C and 300 °C). An ultraviolet spectrophotometer showed that the optical band gap of the WO3 films decreased from 3.62 eV to 3.30 eV with the increase in the annealing temperature. When the Li⁺ was injected into WO3 film in the electrochromic reaction, the optical band gap of the WO3 films decreased. The correlation between the optical band gap and the electrical properties of the WO3 films was found in the electrochromic test by analyzing the change in the response time and the current density. The decrease in the optical band gap demonstrates that the conductivity increases with the corresponding increase in the annealing temperature.

Mobility Enhancement in Amorphous In-Ga-Zn-O Thin-Film Transistor by Induced Metallic in Nanoparticles and Cu Electrodes.

In this work, we fabricated a high-mobility amorphous indium-gallium-zinc-oxide (a-IGZO) thin-film transistor (TFT) based on alumina oxide (Al 2 O 3 ) passivation layer (PVL) and copper (Cu) source/drain electrodes (S/D). The mechanism of the high mobility for a-IGZO TFT was proposed and experimentally demonstrated. The conductivity of the channel layer was significantly improved due to the formation of metallic In nanoparticles on the back channel during Al 2 O 3 PVL sputtering. In addition, Ar atmosphere annealing induced the Schottky contact formation between the Cu S/D and the channel layer caused by Cu diffusion. In conjunction with high conductivity channel and Schottky contact, the a-IGZO TFT based on Cu S/D and Al 2 O 3 PVL exhibited remarkable mobility of 33.5-220.1 cm 2 /Vs when channel length varies from 60 to 560 µ m. This work presents a feasible way to implement high mobility and Cu electrodes in a-IGZO TFT, simultaneously.

Induced nano-scale self-formed metal-oxide interlayer in amorphous silicon tin oxide thin film transistors.

Amorphous Silicon-Tin-Oxide thin film transistors (a-STO TFTs) with Mo source/drain electrodes were fabricated. The introduction of a ~8 nm MoOx interlayer between Mo electrodes and a-STO improved the electron injection in a-STO TFT. Mo adjacent to the a-STO semiconductor mainly gets oxygen atoms from the oxygen-rich surface of a-STO film to form MoOx interlayer. The self-formed MoOx interlayer acting as an efficient interface modification layer could conduce to the stepwise internal transport barrier formation while blocking Mo atoms diffuse into a-STO layer, which would contribute to the formation of ohmic contact between Mo and a-STO film. It can effectively improve device performance, reduce cost and save energy for the realization of large-area display with high resolution in future.

Properties-Adjustable Alumina-Zirconia Nanolaminate Dielectric Fabricated by Spin-Coating.

In this paper, an alumina-zirconia (Al2O3-ZrO2) nanolaminate dielectric was fabricated by spin-coating and the performance was investigated. It was found that the properties of the dielectric can be adjusted by changing the content of Al2O3/ZrO2 in nanolaminates: when the content of Al2O3 was higher than 50%, the properties of nanolaminates, such as the optical energy gap, dielectric strength (Vds), capacitance density, and relative permittivity were relatively stable, while the change of these properties became larger when the content of Al2O3 was less than 50%. With the content of ZrO2 varying from 50% to 100%, the variation of these properties was up to 0.482 eV, 2.12 MV/cm, 135.35 nF/cm², and 11.64, respectively. Furthermore, it was demonstrated that the dielectric strength of nanolaminates were influenced significantly by the number (n) of bilayers. Every increment of one Al2O3-ZrO2 bilayer will enhance the dielectric strength by around 0.39 MV/cm (Vds ≈ 0.86 + 0.39n). This could be contributed to the amorphous alumina which interrupted the grain boundaries of zirconia.