Hydroxyphenylpyruvate Dioxygenase Is a Metabolic Immune Checkpoint for UTX-deficient Colorectal Cancer.

BACKGROUND & AIMS: Aberrant epigenetic events mediated by histone methyltransferases and demethylases contribute to malignant progression of colorectal cancer (CRC). However, the role of the histone demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in CRC remains poorly understood. METHODS: UTX conditional knockout mice and UTX-silenced MC38 cells were used to investigate UTX function in tumorigenesis and development of CRC. We performed time of flight mass cytometry to clarify the functional role of UTX in remodeling immune microenvironment of CRC. To investigate metabolic interaction between myeloid-derived suppressor cells (MDSCs) and CRC, we analyzed metabolomics data to identify metabolites secreted by UTX-deficient cancer cells and taken up by MDSCs. RESULTS: We unraveled a tyrosine-mediated metabolic symbiosis between MDSC and UTX-deficient CRC. Loss of UTX in CRC resulted in methylation of phenylalanine hydroxylase, preventing its degradation and subsequently increasing tyrosine synthesis and secretion. Tyrosine taken up by MDSCs was metabolized to homogentisic acid by hydroxyphenylpyruvate dioxygenase. Homogentisic acid modified protein inhibitor of activated STAT3 via carbonylation of Cys 176, and relieved the inhibitory effect of protein inhibitor of activated STAT3 on signal transducer and activator of transcription 5 transcriptional activity. This in turn, promoted MDSC survival and accumulation, enabling CRC cells to acquire invasive and metastatic traits. CONCLUSIONS: Collectively, these findings highlight hydroxyphenylpyruvate dioxygenase as a metabolic checkpoint to restrict immunosuppressive MDSCs and to counteract malignant progression of UTX-deficient CRC.

A novel method for synthesizing authentic SARS-CoV-2 main protease.

The SARS-CoV-2 main protease (Mpro) plays a crucial role in virus amplification and is an ideal target for antiviral drugs. Currently, authentic Mpro is prepared through two rounds of proteolytic cleavage. In this method, Mpro carries a self-cleavage site at the N-terminus and a protease cleavage site followed by an affinity tag at the C-terminus. This article proposes a novel method for producing authentic Mpro through single digestion. Mpro was constructed by fusing a His tag containing TEV protease cleavage sites at the N-terminus. The expressed recombinant protein was digested by TEV protease, and the generated protein had a decreased molecular weight and significantly increased activity, which was consistent with that of authentic Mpro generated by the previous method. These findings indicated that authentic Mpro was successfully obtained. Moreover, the substrate specificity of Mpro was investigated. Mpro had a strong preference for Phe at position the P2, which suggested that the S2 subsite was an outstanding target for designing inhibitors. This article also provides a reference for the preparation of Mpro for sudden coronavirus infection in the future.

Hierarchical Synergistic Structure for High Resolution Strain Sensor with Wide Working Range.

Strain sensors have been attracting tremendous attention for the promising application of wearable devices in recent years. However, the trade-off between high resolution, high sensitivity, and broad detection range is a great challenge for the application of strain sensors. Herein, a novel design of hierarchical synergistic structure (HSS) of Au micro cracks and carbon black (CB) nanoparticles is reported to overcome this challenge. The strain sensor based on the designed HSS exhibit high sensitivity (GF > 2400), high strain resolution (0.2%) even under large loading strain, broad detection range (>40%), outstanding stability (>12000 cycles), and fast response speed simultaneously. Further, the experiments and simulation results demonstrate that the carbon black layer greatly changed the morphology of Au micro-cracks, forming a hierarchical structure of micro-scale Au cracks and nano-scale carbon black particles, thus enabling synergistic effect and the double conductive network of Au micro-cracks and CB nanoparticles. Based on the excellent performance, the sensor is successfully applied to monitoring tiny signals of the carotid pulse during body movement, which illustrates the great potential in the application of health monitoring, human-machine interface, human motion detection, and electronic skin.

Optimization of the expression of the main protease from SARS-CoV-2.

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a vital role in viral replication. To study the function of Mpro and screen inhibitors targeting Mpro, it is necessary to prepare high-purity and high-activity Mpro. In this study, four types of SARS-CoV-2 Mpros containing different termini were prepared, and their activities were determined successfully. The results showed that the activity of wild-type (WT) Mpro was the highest, and the additional residues at the N-terminus but not at the C-terminus had a major effect on the enzyme activity. To explain this, the alignment of structures of different forms of Mpro was determined, and the additional residues at the N-terminus were found to interfere with the formation of the substrate binding pocket. This study confirms the importance of the natural N-terminus to the activity of Mpro and suggests that WT-GPH6 (Mpro with eight additional residues at the C-terminus) can be used as a substitute for authentic Mpro to screen inhibitors. In short, this study provides a reference for the expression and purification of new coronaviruses confronted in the future.

Biodegradable, Breathable Leaf Vein-Based Tactile Sensors with Tunable Sensitivity and Sensing Range.

Resistive pressure sensors have been widely studied for application in flexible wearable devices due to their outstanding pressure-sensitive characteristics. In addition to the outstanding electrical performance, environmental friendliness, breathability, and wearable comfortability also deserve more attention. Here, a biodegradable, breathable multilayer pressure sensor based piezoresistive effect is presented. This pressure sensor is designed with all biodegradable materials, which show excellent biodegradability and breathability with a three-dimensional porous hierarchical structure. Moreover, due to the multilayer structure, the contact area of the pressure sensitive layers is greatly increased and the loading pressure can be distributed to each layer, so the pressure sensor shows excellent pressure-sensitive characteristics over a wide pressure sensing range (0.03-11.60 kPa) with a high sensitivity (6.33 kPa-1 ). Furthermore, the sensor is used as a human health monitoring equipment to monitor the human physiological signals and main joint movements, as well as be developed to detect different levels of pressure and further integrated into arrays for pressure imaging and a flexible musical keyboard. Considering the simple manufacturing process, the low cost, and the excellent performance, leaf vein-based pressure sensors provide a good concept for environmentally friendly wearable devices.

Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas.

Recurrent tumors originate from cancer stem cells (CSCs) that survive conventional treatments. CSCs consist of heterogeneous subpopulations that display distinct sensitivity to anticancer drugs. Such a heterogeneity presents a significant challenge in preventing tumor recurrence. In the current study, we observed that quiescent CUB-domain-containing protein 1 (CDCP1)+ CSCs are enriched after chemotherapy in mutant Kirsten rat sarcoma viral oncogene homolog (Kras) colorectal carcinomas (CRCs) and serve as a reservoir for recurrence. Mechanistically, glucose catabolism in CDCP1+ CSCs is routed to the oxidative pentose phosphate pathway (PPP); multiple cycling of carbon backbones in the oxidative PPP potentially maximizes NADPH reduction to counteract chemotherapy-induced reactive oxygen species (ROS) formation, thereby allowing CDCP1+ CSCs to survive chemotherapeutic attack. This is dependent on silent mating type information regulation 2 homolog 5 (Sirt5)-mediated inhibition of the glycolytic enzyme triosephosphate isomerase (TPI) through demalonylation of Lys56. Blocking demalonylation of TPI at Lys56 increases chemosensitivity of CDCP1+ CSCSs and delays recurrence of mutant Kras CRCs in vivo. These findings pinpoint a new therapeutic approach for combating mutant Kras CRCs.

In Situ Generated UiO-66/Cotton Fabric Easily Recyclable for Reactive Dye Adsorption.

In view of the environmental pollution caused by the widespread use of reactive dyes in the printing and dyeing industry, the modified cotton fabric was loaded with the extremely stable metal-organic frame (MOF) material UiO-66 for removing reactive dyes from colored wastewater. UiO-66/cotton fabric was prepared by in situ synthesis, and its surface morphology and structure were analyzed by XRD, SEM, BET, and XPS. The adsorption performance of UiO-66/cotton fabric on reactive dyes was investigated by adsorbent dosage, adsorption time and temperature, dye concentration, pH, and so on. The results indicated that the adsorption equilibrium time of UiO-66/cotton fabric on reactive orange 16 was 120 min, and the removal rate was about 98%. The adsorption process belongs to simple molecular layer chemisorption and can be regarded as a spontaneous heat absorption reaction, which was consistent with the proposed secondary kinetic model and Langmuir isothermal adsorption model. In addition, the reactive dyes with a higher molecular weight of each sulfonic acid group are more hydrophobic, and the dyes are more likely to aggregate and deposit on the adsorbent surface by electrostatic attraction, hydrogen bonding, and π-π accumulation. Therefore, this work provides a potential UiO-66/cotton fabric application for the effective adsorption of reactive dyes in textile wastewater.

Electrochemical Synthesis of Cyclic Diaryl Phosphinamides via Intramolecular sp2 C-H Phosphinamidation.

We developed an oxidant- and transition-metal-free approach to construct six-membered cyclic phosphinamides via an intramolecular electrochemical C-H phosphinamidation process. With nBu4NBr as the catalyst and electrolyte, cyclic phosphinamides bearing a variety of functional groups (22 examples) were readily accessed under mild conditions. Meanwhile, this protocol provided an alternative route to organic electroluminescent materials and P-N ligands.

3,4-Bisthiolated Pyrroles: Concise Construction and Their Electronic Properties.

3,4-Bisthiolated pyrroles constitute key cores in pyrrole-based semiconductors, and their electronic properties could be improved by the bisthio groups via the S-effect. Herein, a convenient method for the synthesis of 3,4-bisthiolated pyrroles has been developed through the AlCl3-catalyzed thiolation/cyclization of homopropargylic azides, and cyclic voltammetry and DFT calculations indicated that the desired 3,4-bisthiolated pyrroles had higher HOMO orbital energies and lower band gaps than the parent unsubstituted 2,5-diphenylpyrrole.

Divergent Synthesis of Fluorinated Alkenes, Allenes, and Enynes via Reaction of 2-Trifluoromethyl-1,3-enynes with Carbon Nucleophiles.

Herein, inorganic base K3PO4 promoted divergent synthesis of CF3-substituted allenes, cyclopentenes, alkynes, and fluorinated enynes via regioselective nucleophilic addition of carbon nucleophiles to 2-trifluoromethyl-1,3-enynes was developed. With the choice of different carbon nucleophiles, various fluorinated compounds could be obtained under K3PO4/DMF reaction system. When malononitriles were used as nucleophiles, CF3-substituted allenes, cyclopentenes, and alkynes could be obtained, respectively. By using 1,3-dicarbonyl compounds as nucleophiles, ring-monofluorinated 4H-pyrans could be prepared, and 1,1-difluoro-1,3-enynes could be furnished with the participation of diethyl malonate. Moreover, these five kinds of fluorinated allenes, alkenes, and enynes are valuable building blocks.

Co-Benefits of Pollutant Removal, Water, and Heat Recovery from Flue Gas through Phase Transition Enhanced by Corona Discharge.

Pollutant removal and resource recovery from high-humidity flue gas after desulfurization in a thermal power plant are crucial for improving air quality and saving energy. This study developed a flue gas treatment method involving phase transition enhanced by corona discharge based on laboratory research and established a field-scale unit for demonstration. The results indicate that an adequate increase in size will improve the ease of particle capture. A wet electrostatic precipitator is applied before the condensing heat exchangers to enhance the particle growth and capture processes. This results in an increase of 58% in the particle median diameter in the heat exchanger and an emission concentration below 1 mg/m3. Other pollutants, such as SO3 and Hg, can also be removed with emission concentrations of 0.13 mg/m3 and 1.10 µg/m3, respectively. Under the condensation enhancement of the method, it is possible to recover up to 3.26 t/h of water from 200 000 m3/h saturated flue gas (323 K), and the quality of the recovered water meets the standards stipulated in China. Additionally, charge-induced condensation is shown to improve heat recovery, resulting in the recovery of more than 43.34 kJ/h·m3 of heat from the flue gas. This method is expected to save 2628 t of standard coal and reduce carbon dioxide emission by 2% annually, contributing to environmental protection and global-warming mitigation.

Preparation of zeolitic imidazolate framework-67/wool fabric and its adsorption capacity for reactive dyes.

Zeolitic imidazolate framework-67 (ZIF-67) formed by Co2+ and 2-methylimidazole (MIM) is widely used for adsorption and separation of pollutants. However, there are some disadvantages for ZIF-67 powder, such as strong electrostatic interaction and difficulty in recovery from the liquid phase. The available way to solve the above problems is choosing a suitable substrate to load ZIF-67. The amino and hydroxyl of wool fabrics effectively capture and fix ZIF-67, making it easy to separate ZIF-67 by taking out the composite materials from aqueous solution. In this study, ZIF-67/Wool fabric (ZW) was successfully prepared. The results show that ZIF-67 has better adsorption performance for reactive dyes with more sulfonic groups, higher molecular weight and lower steric resistance. The equilibrium adsorption capacity of ZW for reactive red 195 was 4.15 mg g-1. The adsorption accorded with pseudo-second-order kinetic model and Langmuir isotherm. This study improved the application of ZIF-67, which provided a treatment method for dyeing wastewater and made it possible to recycle waste wool.

Homocouplings of Sodium Arenesulfinates: Selective Access to Symmetric Diaryl Sulfides and Diaryl Disulfides.

Symmetrical diaryl sulfides and diaryl disulfides have been efficiently and selectively constructed via the homocoupling of sodium arenesulfinates. The selectivity of products relied on the different reaction systems: symmetrical diaryl sulfides were predominately obtained under the Pd(OAc)2 catalysis, whereas symmetrical diaryl sulfides were exclusively yielded in the presence of the reductive Fe/HCl system.

Rh(I)-Catalyzed Carbene Migration/Carbonylation/Cyclization: Straightforward Construction of Fully Substituted Aryne Precursors.

The Rh(I)-catalyzed cascade formation of carbenoid followed by a carbonylative cyclization of silyl diynes has been established to achieve diverse ortho silyl-substituted phenolics, enabling access to fully substituted aryne precursors via a one-step fluorosulfurylation. The silyl mask on the termini of alkynes is demonstrated not only to suppress the undesired oxidation but also to control the selectivity of CO insertion. Straightforward access to fully substituted arynes was comprehensively established and applied for the efficient construction of polycyclic aromatic molecules.

Synthesis of Cyclopentenes and Cyclohexenes Via Cobalt(II)-Catalyzed Oxidative Cyclization.

A unique method for the synthesis of cyclopentenes and cyclohexenes has been achieved by the coupling of diketones and alkenes under cobalt(II) catalysis and dimethyl sulfoxide involvement. Under optimal conditions, the formation of five- and six-membered rings can be readily controlled by the α-position substitution of styrenes. This process is proposed to proceed through a reaction sequence of oxidative coupling (mediated by K2S2O8), regioselective alkene insertion (promoted by cobalt), and intramolecular attack of the resulting allylcobalt species on the carbonyl group or methyl group in the reactive methylene process.

NBS/DBU-Promoted One-Pot Three-Component Cycloaddition of Malonic Acid Derivatives, Nitrosoarenes, and Alkenes: Synthesis of Isoxazolidines.

A general DBU-mediated one-pot three-component cycloaddition reaction of easily accessible malonic acid derivatives, nitrosoarenes, and alkenes has been successfully established with the aid of NBS to provide direct access to highly functionalized isoxazolidine derivatives with generally good to excellent yields, broad functional group tolerance, and excellent regio- and diastereo-selectivities under mild conditions. The mechanism study shows that the NBS-mediated formation of bromomalonic acid derivatives from malonic acid derivatives and DBU-promoted synthesis of nitrone intermediates via the reaction of bromomalonic acid derivatives with nitrosoarenes are key steps.

Access to highly functionalized imidazolones bearing α-amino acid esters via KOH-promoted annulation of amidines, nitrosoarenes and malonic esters.

An efficient approach to obtain highly functionalized imidazolones bearing α-amino acid esters through KOH-mediated one-pot three-component annulation of amidines, nitrosoarenes and malonic esters is reported. This reaction features broad substrate scope, a cheap and readily available promoter, good to high yields for most substrates and mild reaction conditions. The mechanism study shows that the KOH-mediated formation of the imine intermediate via the reaction of nitrosoarenes with malonic esters is a key step.

The design and application of an automated microscope developed based on deep learning for fungal detection in dermatology.

BACKGROUND: Light microscopy to study the infection of fungi in skin specimens is time-consuming and requires automation. OBJECTIVE: We aimed to design and explore the application of an automated microscope for fungal detection in skin specimens. METHODS: An automated microscope was designed, and a deep learning model was selected. Skin, nail and hair samples were collected. The sensitivity and the specificity of the automated microscope for fungal detection were calculated by taking the results of human inspectors as the gold standard. RESULTS: An automated microscope was built, and an image processing model based on the ResNet-50 was trained. A total of 292 samples were collected including 236 skin samples, 50 nail samples and six hair samples. The sensitivities of the automated microscope for fungal detection in skin, nails and hair were 99.5%, 95.2% and 60%, respectively, and the specificities were 91.4%, 100% and 100%, respectively. CONCLUSION: The automated microscope we developed is as skilful as human inspectors for fungal detection in skin and nail samples; however, its performance in hair samples needs to be improved.

Electrochemical Arylation of Aldehydes, Ketones, and Alcohols: from Cathodic Reduction to Convergent Paired Electrolysis.

Arylation of carbonyls, one of the most common approaches toward alcohols, has received tremendous attention, as alcohols are important feedstocks and building blocks in organic synthesis. Despite great progress, there is still a great gap to develop an ideal arylation method featuring mild conditions, good functional group tolerance, and readily available starting materials. We now show that electrochemical arylation can fill the gap. By taking advantage of synthetic electrochemistry, commercially available aldehydes (ketones) and benzylic alcohols can be readily arylated to provide a general and scalable access to structurally diverse alcohols (97 examples, >10 gram-scale). More importantly, convergent paired electrolysis, the ideal but challenging electrochemical technology, was employed to transform low-value alcohols into more useful alcohols. Detailed mechanism study suggests that two plausible pathways are involved in the redox neutral α-arylation of benzylic alcohols.

Visible-Light-Enabled C-H Functionalization by a Direct Hydrogen Atom Transfer Uranyl Photocatalyst.

The development of the uranyl cation as a powerful photocatalyst is seriously delayed in comparison with the advances in its fundamental and structural chemistry. However, its characteristic high oxidative capability in the excited state ([UO2 ]2+ * (+2.6 V vs. SHE; SHE=standard hydrogen electrode) combined with blue-light absorption (hv=380-500 nm) and a long-lived fluorescence lifetime up to microseconds have reveals that the uranyl cation approaches an ideal photocatalyst for visible-light-driven organic transformations. Described herein is the successful use of uranyl nitrate as a photocatalyst to enable C(sp3 )-H activation and C-C bond formation through hydrogen atom transfer (HAT) under blue-light irradiation. In particular, this operationally simple strategy provides an appropriate approach to the synthesis of diverse and valuable diarylmethane motifs. Mechanistic studies and DFT calculations have provided insights into the detailed mechanism of the photoinduced HAT pathway. This research suggests a general platform that could popularize promising uranyl photocatalytic performance.