A kinase-cGAS cascade to synthesize a therapeutic STING activator.

The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence1-3. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents4,5. Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic6,7 (ClinicalTrials.gov study NCT04220866 ). From two non-natural nucleotide monothiophosphates, MK-1454 is assembled diastereoselectively in a one-pot cascade, in which two thiotriphosphate nucleotides are simultaneously generated biocatalytically, followed by coupling and cyclization catalysed by an engineered animal cyclic guanosine-adenosine synthase (cGAS). For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules.

The MksG nuclease is the executing part of the bacterial plasmid defense system MksBEFG.

Cells are continuously facing the risk of taking up foreign DNA that can compromise genomic integrity. Therefore, bacteria are in a constant arms race with mobile genetic elements such as phages, transposons and plasmids. They have developed several active strategies against invading DNA molecules that can be seen as a bacterial 'innate immune system'. Here, we investigated the molecular arrangement of the Corynebacterium glutamicum MksBEFG complex, which is homologous to the MukBEF condensin system. We show here that MksG is a nuclease that degrades plasmid DNA. The crystal structure of MksG revealed a dimeric assembly through its C-terminal domain that is homologous to the TOPRIM domain of the topoisomerase II family of enzymes and contains the corresponding ion binding site essential for DNA cleavage in topoisomerases. The MksBEF subunits exhibit an ATPase cycle in vitro and we reason that this reaction cycle, in combination with the nuclease activity provided by MksG, allows for processive degradation of invading plasmids. Super-resolution localization microscopy revealed that the Mks system is spatially regulated via the polar scaffold protein DivIVA. Introduction of plasmids results in an increase in DNA bound MksG, indicating an activation of the system in vivo.

Explosive Leidenfrost-Droplet-Mediated Synthesis of Monodispersed High-Entropy-Alloy Nanoparticles for Electrocatalysis.

High-entropy-alloy nanoparticles (HEA NPs) exhibit promising potential in various catalytic applications, yet a robust synthesis strategy has been elusive. Here, we introduce a straightforward and universal method, involving the microexplosion of Leidenfrost droplets housing carbon black and metal salt precursors, to fabricate PtRhPdIrRu HEA NPs with a size of ∼2.3 nm. The accumulated pressure within the Leidenfrost droplet triggers an intense explosion within milliseconds, propelling the carbon support and metal salt rapidly into the hot solvent through explosive force. The exceptionally quick temperature rise ensures the coreduction of metal salts, and the dilute local concentration of metal ions limits the final size of the HEA NPs. Additionally, the explosion process can be fine-tuned by selecting different solvents, enabling the harvesting of diverse HEA NPs with superior electrocatalytic activity for alcohol electrooxidation and hydrogen electrocatalysis compared to commercial Pt (Pd) unitary catalysts.

Reasonable Design and Deep Insight of Efficient Integrated Photorechargeable Li-Ion Batteries by Using a Cu/CuO/Cu2S Electrode.

Herein, Cu-foam-supported CuO nanowire arrays covered with Cu2S nanosheet substrates (Cu/CuO/Cu2S) are adopted as efficient photoelectrodes for photorechargeable lithium-ion batteries (PR-LIBs). The assembled PR-LIB exhibits remarkable solar energy conversion efficiency alongside superior lithium storage capabilities. Without an electrical power supply, the photocharged PR-LIB sustained a discharge process for 63.0 h under a constant current density of 0.05 mA cm-2. The corresponding solar-to-electrical energy conversion efficiency is 4.50%, which is an impressive achievement among recently reported contemporary technologies. Mechanism investigation shows that the Cu/CuO/Cu2S photogenerated carriers augment the extraction and insertion of Li+ according to different oxidation and reduction reactions in the charging and discharging reactions. This research delineates a refined model system and proposes innovative directions for developing efficient heterojunction photoelectrodes, significantly propelling the development of PR-LIB technology.

Confinement-Modulated Clusterization-Triggered Time-Dependent Phosphorescence Color from Xylan-Carbonized Polymer Dots.

Achieving time-dependent phosphorescence color (TDPC) in organic materials is attractive but extremely challenging due to the nonradiative decay and modulation puzzle of triplet state. Herein, xylan, a hemicellulose waste from the paper mill, was used to construct carbonized polymer dots (CPDs) with clusterization-triggered room-temperature phosphorescence (RTP). CPDs were endowed with tuneable triplet energy levels by through-space conjugation of heteroatom groups, which could be confined in silica to simultaneously activate surface oxide-related low-energy and cross-linked core N-related high-energy emissive centers. Thus, the blue emissive center with a lifetime of 425.6 ms and green emissive center with a longer lifetime of 1506 ms coexisted in the confined CPDs; the former was the dominant contribution to RTP at first, and the latter became dominant over time, leading to a typical TDPC evolution with large color contrast from blue to blue-green and then to green. Meanwhile, the TDPC could remain unobstructed after the confined CPDs were soaked in water for more than a month. The CPDs were successfully applied in location and deformation imaging of hydrogel and advanced dynamic information encryption and anticounterfeiting. The work may shed new light on the design of TDPC materials and broaden the high-value use of paper-mill waste xylan.

Catalyst Selection over an Electrochemical Reductive Coupling Reaction toward Direct Electrosynthesis of Oxime from NOx and Aldehyde.

Aqueous electrochemical coupling reactions, which enable the green synthesis of complex organic compounds, will be a crucial tool in synthetic chemistry. However, a lack of informed approaches for screening suitable catalysts is a major obstacle to its development. Here, we propose a pioneering electrochemical reductive coupling reaction toward direct electrosynthesis of oxime from NOx and aldehyde. Through integrating experimental and theoretical methods, we screen out the optimal catalyst, i.e., metal Fe catalyst, that facilitates the enrichment and C-N coupling of key reaction intermediates, all leading to high yields (e.g., ∼99% yield of benzaldoxime) for the direct electrosynthesis of oxime over Fe. With a divided flow reactor, we achieve a high benzaldoxime production of 22.8 g h-1 gcat-1 in ∼94% isolated yield. This work not only paves the way to the industrial mass production of oxime via electrosynthesis but also offers references for the catalyst selection of other electrochemical coupling reactions.

The mechanism of lovastatin in suppressing the proliferation of esophageal squamous cell carcinoma based on proteomics.

BACKGROUND: Lovastatin, a type of statin usually considered as a lipid-lowering drug that lowers blood cholesterol and low-density lipoprotein cholesterol levels, has been rediscovered to have anticancer activity. Fewer studies exist regarding the effect of lovastatin on esophageal squamous cell carcinoma (ESCC). METHODS: Here, we report that lovastatin shows anticancer effect on ESCC By affecting the mitochondrial autophagy pathway. Moreover, based on proteomics and computer molecular simulations found that RAB38 and RAB27A may be a target of lovastatin. RESULTS: We observed that autophagy of mitochondria is inhibited by lovastatin, affecting esophageal squamous cell proliferation. There is a possible link between the expression of RAB38, RAB27A and immune cell invasion in esophageal cancer. CONCLUSIONS: These results demonstrate the huge potential of lovastatin as an RAB38, RAB27A inhibitor in esophageal cancer chemotherapy and chemoprevention.

Novel co-delivery of oridonin and docetaxel nanoliposome for an enhanced antitumor effect on esophageal cancer.

INTRODUCTION: Esophageal cancer is one of the major cancers in China. Most patients with esophageal cancer are diagnosed at an advanced stage, and the 5 year survival rate is discouraging. Combined chemotherapy is a common method for the treatment of esophageal cancer. METHODS: In this study, distearoyl phosphatidyl ethanolamine polyethylene glycol 2000 (DSPE-PEG2000) nanoliposomes (NLPs) encapsulating the anticancer drugs docetaxel (DOX) and oridonin (ORD) were prepared, and their ability to enhance the release of anticancer drugs was determined. The NLP system was characterized by transmission electron microscopy, particle size and encapsulation efficiency. In addition, the release characteristics and pharmacodynamics of these drugs were also studied in detail. RESULTS: When the DOX/ORD ratio was 2:1, the higher proportion of DOX led to a stronger synergy effect. DOX/ORD NLPs were prepared by the high-pressure homogenization method and had a uniform spherical morphology. The mean particle size and polydispersity index were determined to be 246.4 and 0.163, respectively. The stability results showed that no significant change was observed in particle size, zeta potential, Encapsulation efficiency and dynamic light scattering for DOX/ORD NLPs during the observation period. The results of in vitro release illustrated that the acidic environment of tumor might be beneficial to drug release. The three-dimensional tumorsphere showed that DOX/ORD NLPs can reach the interior of tumor spheres, which destroys the structure of cells, resulting in irregular spherical tumor spheres. The in vivo study results indicated that DOX/ORD NLPs had an obvious targeting effect on subcutaneous tumors and have the potential to actively deliver drugs to tumor tissues. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to detect apoptosis. The results showed that DOX/ORD NLP treatment could significantly induce apoptosis and inhibit tumor growth. CONCLUSION: The DOX/ORD NLPs prepared in this study can enhance the anti-tumor activity, and are expected to be a promising co-delivery platform for the treatment of esophageal cancer.

Modulation of π-Electron Density in Ultrathin 2D Layers of Graphite Carbon Nitride for Efficient Photocatalytic Hydrogen Production.

The rational design and synthesis of novel semiconductor nano-/quantum materials have been ambitiously pursued in the field of photocatalysis as the technology is promising and critical for attaining future energy and environmental sustainability. Herein, the integrity of aromatic carbon into graphitic carbon nitride (CN) at the same molecular plane with a few 2D layers is achieved by using modulated precursors of CN, forming carbon regulated ultrathin CN (CUCN) with improved charge transfer kinetics and photocatalytic hydrogen production. The grafted graphite rings adjacent to carbon nitride frameworks induce a significant rearrangement and relocalization of the overall framework, and form conjugated sp2 hybridized interfaces and internal electric fields that drive the separation and directional transfer of photogenerated electrons from CN sheets towards intralayer graphite regions, where the photocatalytic hydrogen evolution reaction occurs extensively, yielding largely increased HER rate of 2231.8 µmol g-1 h-1 by 8.2 times relative to CN, as well as a remarkable apparent quantum yield of 2.93% under monochromatic light at 420 nm. The high physicochemical stability and low synthesis cost of CUCN make it a potential benchmark photocatalyst that can be readily modified via element doping, heterojunction introduction, defect engineering, and so on, to further enhance its HER performance.

Bifunctional Ni Foam Supported TiO2 @Ni3 S2 core@shell Nanorod Arrays for Boosting Electrocatalytic Biomass Upgrading and H2 Production Reactions.

Replacing traditional oxygen evoltion reaction (OER) with biomass oxidation reaction (BOR) is an advantageous alternative choice to obtain green hydrogen energy from electrocatalytic water splitting. Herein, a novel of extremely homogeneous Ni3 S2 nanosheets covered TiO2 nanorod arrays are in situ growth on conductive Ni foam (Ni/TiO2 @Ni3 S2 ). The Ni/TiO2 @Ni3 S2 electrode exhibits excellent electrocatalytic activity and long-term stability for both BOR and hydrogen evolution reaction (HER). Especially, taking glucose as a typical biomass, the average hydrogen production rate of the HER-glucose oxidation reaction (GOR) two-electrode system reached 984.74 µmol h-1 , about 2.7 times higher than that of in a common HER//OER two-electrode water splitting system (365.50 µmol h-1 ). The calculated power energy saving efficiency of the GOR//HER system is about 13% less than that of the OER//HER system. Meanwhile, the corresponding selectivity of the value-added formic acid produced by GOR reaches about 80%. Moreover, the Ni/TiO2 @Ni3 S2 electrode also exhibits excellent electrocatalytic activity on a diverse range of typical biomass intermediates, such as urea, sucrose, fructose, furfuryl alcohol (FFA), 5-hydroxymethylfurfural (HMF), and alcohol (EtOH). These results show that Ni/TiO2 @Ni3 S2 has great potential in electrocatalysis, especially in replacing OER reaction with BOR reaction and promoting the sustainable development of hydrogen production.