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Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and PXR/CAR knockout (KO) HepaRG cells, as well as a PXR reporter gene assay, were used to investigate the mechanism of CYP3A4 and CYP2B6 induction by prototypical substrates and a group of compounds from the Merck KGaA oncology drug discovery pipeline. The basal and inducible gene expression of CYP3A4 and CYP2B6 of nuclear hormone receptor (NHR) KO HepaRG relative to control HepaRG was characterized. The basal expression of CYP3A4 was markedly higher in the PXR (10-fold) and CAR (11-fold) KO cell lines compared with control HepaRG, whereas inducibility was substantially lower. Inversely, basal expression of CYP3A4 in PXR/CAR double KO (dKO) was low (10-fold reduction). Basal CYP2B6 expression was high in PXR KO (9-fold) cells which showed low inducibility, whereas the basal expression remained unchanged in CAR and dKO cell lines compared with control cells. Most of the test compounds induced CYP3A4 and CYP2B6 via PXR and, to a lesser extent, via CAR. Furthermore, other non-NHR-driven induction mechanisms were implicated, either alone or in addition to NHRs. Notably, 5 of the 16 compounds (31%) that were PXR inducers in HepaRG did not activate PXR in the reporter gene assay, illustrating the limitations of this system. This study indicates that HepaRG is a highly sensitive system fit for early screening of cytochrome P450 (P450) induction in drug discovery. Furthermore, it shows the applicability of HepaRG NHR KO cells as tools to deconvolute mechanisms of P450 induction using novel compounds representative for oncology drug discovery. SIGNIFICANCE STATEMENT: This work describes the identification of induction mechanisms of CYP3A4 and CYP2B6 for an assembly of oncology drug candidates using HepaRG nuclear hormone receptor knockout and displays its advantages compared to a pregnane X receptor reporter gene assay. With this study, risk assessment of drug candidates in early drug development can be improved.

The 1T phase of MoS2 has been widely reported to be highly active toward the hydrogen evolution reaction (HER), which is expected to restrict the competitive nitrogen reduction reaction (NRR). However, in this work, a prototype of active sites separation over 1T‐MoS2 is proposed by DFT calculations that the Mo‐edge and S atoms on the basal plane exhibit different catalytic NRR and HER selectivity, and a new role‐playing synergistic mechanism is also well enabled for the multistep NRR, which is further experimentally confirmed. More importantly, a self‐sacrificial strategy using g‐C3N4 as templates is proposed to synthesize 1T‐MoS2 with an ultrahigh 1T content (75.44%, named as CNMS, representing the composition elements of C, N, Mo, and S), which yields excellent NRR performances with an ammonia formation rate of 71.07 µg h–1 mg–1cat. at −0.5 V versus RHE and a Faradic efficiency of 21.01%. This work provides a promising new orientation of synchronizing the selectivity and activity for the multistep catalytic reactions.

Multiple myeloma (MM) is a B-cell malignancy for which new treatments are urgently needed. Redirecting the activity of T cells by bispecific antibodies against tumor cells is a potent approach. The B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein and therefore is an ideal therapeutic target for T-cell redirecting therapies. The main objective of this work is to target the BCMA by generating BCMA-specific murine monoclonal antibody and construct a cluster of differentiation 3 (CD3)/BCMA-directed tandem diabodies (Tandab). In brief, using standard hybridoma technology, we developed a novel BCMA-specific monoclonal antibody (clone 69G8), that specifically bind with BCMA+ cell lines and MM patient sample; whereas BCMA- cells were not recognized. For T cells by bispecific antibodies application, we constructed a Tandab (CD3/BCMA) simultaneously targeting both CD3 and BCMA and our studies demonstrated that Tandab (CD3/BCMA) was functional with specific binding capability both for CD3+ cells and BCMA+ cells. It induced selective, dose-dependent lysis of BCMA+ cell lines, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA- cells were not affected. Furthermore, we demonstrated that Tandab activity correlates with BCMA expression, with higher potency observed in highly BCMA expressing tumor cells. In vivo, the purified Tandab (CD3/BCMA) significantly inhibited the tumor growth in a subcutaneous NCI-H929 xenograft model. Taken together, these results show that the Tandab (CD3/BCMA) displays potent and selective anti-MM activities and represents a promising immunotherapeutic for the treatment of MM.

Electrocatalytic N2 reduction reaction (NRR) serves as a promising approach for converting N2 to NH3 in a sustainable way to replace the energy-intensive Haber-Bosch process. MoS2-based electrocatalysts hold great potentials in catalyzing N2 reduction due to their similarity with active MoFe-co in biological nitrogenase. In this work, we reported a sulfur vacancy-rich MoS2 as an excellent electrocatalyst for NRR, where the sulfur vacancies (SVs) were easily controlled by regulating the amount of P dopants. MoS2 with abundant SVs (P-M-1) achieved a large NH3 yield rate of 60.27 µg h−1 mg−1cat. and high Faradaic efficiency of 12.22% towards NRR. Further mechanistic study revealed that P dopants not only created SVs as the active centers but also modulated the electronic structure for the enhanced adsorption and activation of N2 molecules, thus immensely promoting the catalytic performance of NRR.

Excessive ammonium (NH4+) and phosphate (PO43−) in aquatic environments can cause serious eutrophication. Agricultural waste is an efficient adsorbent for nutrients removal and has good potential for comprehensive utilisation of resources. In this study, two Chinese medicinal herbal residues, Rhizoma Typhonium Gigantei (ZB) and Radix Glycyrrhizae Preparata (ZG), were implemented to simultaneously remove NH4+ and PO43− from water. Parameters such as adsorbent dosage, solution pH, contact time and initial concentration that influenced the adsorption process onto adsorbents, along with removal mechanism and practical performance were investigated. The microstructure of ZB was irregular with numerous spherical particles, while ZG displayed an uneven flaky structure with few rough grooves. The nutrients adsorption was significantly influenced by pH. The maximum adsorption capacity by ZB was 91.84 N mg g−1 and 71.81 P mg g−1. In addition, the maximum adsorption capacity recorded by ZG was 100.86 N mg g−1 and 89.51 P mg g−1 (pH, 8.0; dosage, 0.2 g L−1; initial concentration, 60 mg L−1; and contact time, 180 min, for both the herbal residues). The adsorption of NH4+ and PO43− was well described by the pseudo-second-order and intra-particle diffusion models, respectively. The Langmuir isotherm model is the best fit model for the adsorption equilibrium data, suggesting monolayer adsorption of NH4+ and PO43− by the two adsorbents. In addition, NH4+ was predominantly adsorbed by electrostatic attraction, ion exchange and complexation, whereas PO43− was predominantly adsorbed by intra-particle diffusion and ligand exchange. Practical application analysis demonstrated that ZG could remove and recover more NH4+ and PO43− from swine wastewater than ZB. Therefore, ZG exhibited a more significant potential to simultaneously remove and recover NH4+ and PO43− from wastewater.

The NH3 is generally synthesized by the traditional Haber–Bosch method, which is energy-consuming and releases a lot of CO2. Electrocatalytic fixation of N2 is highlighted as a carbon-free route to generate NH3 by the nitrogen reduction reaction (NRR), but strongly demands highly efficient and durable electrocatalysts. Herein, we propose the multiphasic 1T@2H-MoSe2 as a highly active NRR catalyst for the first time, which exhibits excellent activity for the NRR with a NH3 yield of 19.91 ± 0.89 μg h−1 mgcat.−1 and a FE of 2.82% ± 0.1% at −0.6 V in 0.1 M Na2SO4. Moreover, a good durability is also demonstrated.