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The clinical success of T-cell receptor (TCR)-based immunotherapy depends on the efficacy and specificity of TCRs. Naturally occurring TCRs have limited anti-tumor potency due to their low affinity for tumor antigens. Affinity enhancement is a promising strategy to generate highly potent TCRs. However, it is concerned that affinity-enhanced TCRs are prone to lose specificity. We isolated low affinity TCRs specific for NY-ESO-1157-165/HLA-A*02:01 from peripheral blood mononuclear cells of healthy donors. An affinity-enhanced TCR candidate with optimal affinity and specificity was generated using phage display and an extensive set ofin vitroandin vivoassays. Alanine scanning mutagenesis showed that the TCR candidate retained specificity by making extensive contacts to the side chains of NY-ESO-1157-165peptide. Adoptive transfer of T cells engineered with this candidate (termed TAEST16001) significantly inhibited tumor growth in subcutaneous, metastatic, and patient-derived xenograft (PDX) mouse tumor models. This study demonstrates that sophisticated engineering and screening techniques can be utilized to generate a clinical candidate TCR with potent anti-tumor activity without losing specificity. TAEST16001 was approved by the Center for Drug Evaluation (CDE) as the first TCR-based immunotherapy clinical trial in China (ClinicalTrials.govIdentifier:NCT03159585).

Transition metal oxides have shown an extraordinary potential for lithium-storage capability to date. However, it remains enormous challenge to gain high capacities, good rate performance and cyclability due to their inferior conductivity. To address this issue, oxygen vacancies (VOs) implanted ultrathin WO3 nanorods (the diameter around 5 nm and the length less than 100 nm) composed with reduced graphene oxide (namely WO3-x/rGO), were synthesized by proposing a logical design. For the sake of better showing the outcome of such configuration, holy nanosheets of pure WO3 anode were proposed to compare with nanorods WO3-x/rGO one in terms of electrochemical properties, and they were obtained via annealing H2WO4/rGO precursor in air and argon atmosphere with the same annealing ramp, respectively. By contrast, both electron paramagnetic resonance and X-ray photoelectron spectroscopic characterizations demonstrate the existence of VOs in WO3-x/rGO composite. The generation of VOs together with the reserve of rGO, the conductivity of WO3-x/rGO anode is distinctly enhanced, which is then verified by the compared electrochemical performance in this work. It is clearly shown that the WO3-x/rGO nanocomposite displays a capacity of 745 mAh g−1 at a current density of 0.1 A g−1 after 200 cycles and excellent cycling stability up to 1000 cycles with capacity of 428 mAh g−1 at 1 A g−1. These findings exhibit that nanorods WO3-x/rGO nanocomposite is a promising candidate for high-performance Li-ion battery anode.

Glycoside hydrolases (GHs) have attracted special attention in research aimed at modifying natural products by partial removal of sugar moieties to manipulate their solubility and efficacy. However, these modifications are challenging to control because the low substrate specificity of most GHs often generates undesired by-products. We previously identified a GH2-type fungal β-glucuronidase from Aspergillus oryzae (PGUS) exhibiting promiscuous substrate specificity in hydrolysis of triterpenoid saponins. Here, we present the PGUS structure, representing the first structure of a fungal β-glucuronidase, and that of an inactive PGUS mutant in complex with the native substrate glycyrrhetic acid 3-O-mono-β-glucuronide (GAMG). PGUS displayed a homotetramer structure with each monomer comprising three distinct domains: a sugar-binding, an immunoglobulin-like β-sandwich, and a TIM barrel domain. Two catalytic residues, Glu414 and Glu505, acted as acid/base and nucleophile, respectively. Structural and mutational analyses indicated that the GAMG glycan moiety is recognized by polar interactions with nine residues (Asp162, His332, Asp414, Tyr469, Tyr473, Asp505, Arg563, Asn567, and Lys569) and that the aglycone moiety is recognized by aromatic stacking and by a π interaction with the four aromatic residues Tyr469, Phe470, Trp472, and Tyr473. Finally, structure-guided mutagenesis to precisely manipulate PGUS substrate specificity in the biotransformation of glycyrrhizin into GAMG revealed that two amino acids, Ala365 and Arg563, are critical for substrate specificity. Moreover, we obtained several mutants with dramatically improved GAMG yield (>95%). Structural analysis suggested that modulating the interaction of β-glucuronidase simultaneously toward glycan and aglycone moieties is critical for tuning its substrate specificity toward triterpenoid saponins.

A Cu(I)-catalyzed cross-coupling reaction of bis(trimethylsilyl)diazomethane and benzoxazoles/oxazoles is reported. A wide range of functional groups can be tolerated in this transformation. This reaction provides a new method to directly introduce a 1,1-bis(trimethylsilyl)methyl group into heteroaromatic C–H bonds. Subsequent transformations of 1,1-bis(trimethylsilyl)-methylated heteroaromatic compounds are also presented.