Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1.

PD-1 is a co-inhibitory receptor expressed by CD8+ T cells which limits their cytotoxicity. PD-L1 expression on cancer cells contributes to immune evasion by cancers, thus, understanding the mechanisms that regulate PD-L1 protein levels in cancers is important. Here we identify tumor-cell-expressed otubain-2 (OTUB2) as a negative regulator of antitumor immunity, acting through the PD-1/PD-L1 axis in various human cancers. Mechanistically, OTUB2 directly interacts with PD-L1 to disrupt the ubiquitination and degradation of PD-L1 in the endoplasmic reticulum. Genetic deletion of OTUB2 markedly decreases the expression of PD-L1 proteins on the tumor cell surface, resulting in increased tumor cell sensitivity to CD8+ T-cell-mediated cytotoxicity. To underscore relevance in human patients, we observe a significant correlation between OTUB2 expression and PD-L1 abundance in human non-small cell lung cancer. An inhibitor of OTUB2, interfering with its deubiquitinase activity without disrupting the OTUB2-PD-L1 interaction, successfully reduces PD-L1 expression in tumor cells and suppressed tumor growth. Together, these results reveal the roles of OTUB2 in PD-L1 regulation and tumor evasion and lays down the proof of principle for OTUB2 targeting as therapeutic strategy for cancer treatment.

Enzyme-free fluorescence determination of uric acid by combining CdTe quantum dots with metal-organic framework for signal amplification.

The composite of CdTe quantum dots (QDs) with ZIF-8 was elaborately designed and synthesized as an enzyme-free fluorescent probe for the sensitive determination of uric acid (UA), based on the fluorescence detection property of CdTe QDs and the signal amplification function of ZIF-8. The structure and feature of the composite were characterized with transmission electron microscopy, scanning electron microscopy, powder X-ray diffraction, and fluorescence spectrometry. With adding UA to the composite, the emission of CdTe QDs reduced due to the inner filter and dynamic quenching effects of UA, and the adsorption ability of ZIF-8 toward UA promoted the response signal of CdTe QDs. On this basis, UA was quantified by the composite in the concentration range 0.05 to 10 µM with excitation/emission wavelength at 287/615 nm, and the detection limit of the composite toward UA was 32 nM. The reproducibility of the composite for determining UA was further evaluated, and the relative standard deviations were below 10.2%. The composite also exhibited the merits of enzyme-free analysis such as low testing cost, short analysis time (1 min), and loose pH condition (application in whole physiological pH range, 5.0 - 8.0). The composite was applied to the determination of UA in human urine with recoveries of spiked samples in the range 99 to 113%.

Cryo-EM Structure Reveals Polymorphic Ligand-bound States of IGF1R.

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in regulating cellular metabolism and cell growth and has been identified as an anticancer drug target. Although previous studies have revealed some structures of IGF1R with different ligands, the continuous dynamic conformation change remains unclear. Here, we report 10 distinct structures (7.9-3.6 Å) of IGF1R bound to IGF1 or insulin to reveal the polymorphic conformations of ligand-bound IGF1R. These results showed that the α-CT2, disulfide bond (C670-C670'), and FnIII-2 domains had the most flexible orientations for the conformational change that occurs when ligands bind to the receptor. In addition, we found one special conformation (tentatively named the diverter-switch state) in both complexes, which may be one of the apo-IGF1R forms under ligand-treatment conditions. Hence, these results illustrated the mechanism of how different ligands could bind to human IGF1R and provided a rational template for drug design.

Control of pore structure and surface chemistry of activated carbon derived from waste Zanthoxylum bungeanum branches for toluene removal in air.

Activated carbon adsorption has been considered the most efficient technology toward VOC removal. The waste biomass as alternates solved the problems of high price and nonrenewable of traditional raw materials. The waste Zanthoxylum bungeanum branches were firstly selected as raw materials to prepare activated carbons. Interestingly, the pore structure and surface chemistry can be successfully controlled by adjusting the heating rate. The hierarchical porous carbons exhibited great potential for toluene adsorption. The micro-mesopore structure possessed unique spatial effect; micropores played a dominant role in adsorption process, especially narrow micropores (pore size ≤ 1.0 nm) emerged stronger adsorptive force toward toluene molecules due to overlapping attractive forces from neighboring pore walls. And mesopores not only displayed excellent transport diffusion but also provided adsorption sites. Additionally, the high graphitization degree enhanced the interaction between graphene layer equipped electron-rich regions and π-electrons on the aromatic ring by the π-π conjugated effect. The hydroxyl and carbonyl functional groups served as chemisorption sites and led to higher adsorption amounts. Fortunately, the regeneration can be achieved by thermal treatment at the low temperature (≤ 150 °C) or even gas purging at room temperature (20 °C), which avoided an explosion accident in the process of high-temperature regeneration.

Facile synthesis of hierarchically nanostructured bismuth vanadate: An efficient photocatalyst for degradation and detection of hexavalent chromium.

Heterostructured nanomaterials can paid more significant attention in environmental safety for the detection and degradation/removal of hazardous toxic chemicals over a decay. Here, we report the preparation of hierarchically nanostructured shuriken like bismuth vanadate (BiVO4) as a bifunctional catalyst for photocatalytic degradation and electrochemical detection of highly toxic hexavalent chromium (Cr(VI)) using the green deep eutectic solvent reline, which allows morphology control in one of the less energy-intensive routes. The SEM results showed a good dispersion of BiVO4 catalyst and the HR-TEM revealed an average particle size of ca. 5-10 nm. As a result, the BiVO4 exhibited good photocatalytic activity under UV-light about 95% reduction of Cr(VI) to Cr(III) was observed in 160 min. The recyclability of BiVO4 catalyst exhibited an appreciable reusability and stability of the catalyst towards the photocatalytic reduction of Cr(VI). Also, the BiVO4-modified screen printed carbon electrode (BiVO4/SPCE) displayed an excellent electrochemical performance towards the electrochemical detection of Cr(VI). Besides, the BiVO4/SPCE demonstrated tremendous electrocatalytic activity, lower linear range (0.01-264.5 µM), detection limit (0.0035 µM) and good storage stability towards the detection of Cr(VI). Importantly, the BiVO4 modified electrode was also found to be a good recovery in water samples for practical applications.

Distribution patterns of polychlorinated biphenyls in soils collected from Zhejiang province, east China.

Polychlorinated biphenyls (PCBs) were determined in surface soil samples from Zhejiang Province, east China. Concentrations of total PCBs ranged widely from 7.50 to 263 ng kg(-1) with a mean value of 45.4 ng kg(-1) (dry matter basis). In general, concentrations in soil samples from the southern part of the test area and especially from some sites near hills tended to be higher than those from other sites. The prevailing winds may have been the main factor influencing the spatial distribution of PCBs in soils. Other factors may have included the distribution of residential areas and land use variables. In this paper we also discuss the relationships between OCPs and PCBs in soils and relationships between these and land use variables as revealed by correlation analysis.