Here, we described the structural modification of previously identified μ opioid receptor (MOR) antagonist NAN, a 6α-N-7′-indolyl substituted naltrexamine derivative, and its 6β-N-2′-indolyl substituted analogue INTA by adopting the concept of “bivalent bioisostere”. Three newly prepared opioid ligands, 25 (NBF), 31, and 38, were identified as potent MOR antagonists both in vitro and in vivo. Moreover, these three compounds significantly antagonized DAMGO-induced intracellular calcium flux and displayed varying degrees of inhibition on cAMP production. Furthermore, NBF produced much less significant withdrawal effects than naloxone in morphine-pelleted mice. Molecular modeling studies revealed that these bivalent bioisosteres may adopt similar binding modes in the MOR and the “address” portions of them may have negative or positive allosteric modulation effects on the function of their “message” portions compared with NAN and INTA. Collectively, our successful application of the “bivalent bioisostere concept” identified a promising lead to develop novel therapeutic agents toward opioid use disorder treatments.

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Nalfurafine, a moderately selective kappa opioid receptor (KOR) agonist, is used in Japan for treatment of itch without causing dysphoria or psychotomimesis. Here we characterized the pharmacology of compound 42B, a 3-dehydroxy analogue of nalfurafine and compared with that of nalfurafine. Nalfurafine and 42B acted as full KOR agonists and partial μ opioid receptor (MOR) agonists, but 42B showed much lower potency for both receptors and lower KOR/MOR selectivity, different from previous reports. Molecular modeling revealed that water-mediated hydrogen-bond formation between 3-OH of nalfurafine and KOR accounted for its higher KOR potency than 42B. The higher potency of both at KOR over MOR may be due to hydrogen-bond formation between nonconserved Y 7.35 of KOR and their carbonyl groups. Both showed modest G protein signaling biases. In mice, like nalfurafine, 42B produced antinociceptive and antiscratch effects and did not cause conditioned place aversion (CPA) in the effective dose ranges. Unlike nalfurafine, 42B caused motor incoordination and hypolocomotion. As both agonists showed G protein biases, yet produced different effects on locomotor activity and motor incoordination, the findings and those in the literature suggest caution in correlating in vitro biochemical data with in vivo behavior effects. The factors contributing to the disconnect, including pharmacodynamic and pharmacokinetic issues, are discussed. In addition, our results suggest that among the KOR-induced adverse behaviors, CPA can be separated from motor incoordination and hypolocomotion.

It is of soaring demand to develop statistical analysis tools that are robust against contamination as well as preserving individual data owners' privacy. In spite of the fact that both topics host a rich body of literature, to the best of our knowledge, we are the first to systematically study the connections between the optimality under Huber's contamination model and the local differential privacy (LDP) constraints.In this paper, we start with a general minimax lower bound result, which disentangles the costs of being robust against Huber's contamination and preserving LDP. We further study three concrete examples: a two-point testing problem, a potentially-diverging mean estimation problem and a nonparametric density estimation problem. For each problem, we demonstrate procedures that are optimal in the presence of both contamination and LDP constraints, comment on the connections with the state-of-the-art methods that are only studied under either contamination or privacy constraints, and unveil the connections between robustness and LDP via partially answering whether LDP procedures are robust and whether robust procedures can be efficiently privatised. Overall, our work showcases a promising prospect of joint study for robustness and local differential privacy.

2D metal−organic frameworks (MOFs) are promising 2D materials with a wide range of applications due to their unique physical and chemical properties. However, 2D MOFs are prone to stacking due to their ultrathin thickness, and the high-yield preparation method of 2D MOFs is highly demanded. In this work, a rapid and scalable method is novelistically presented to prepare 2D MOFs with highly colloidal stability and high yield through coordination modulation at room temperature. A well-ordered CuBDC-MBA nanosheet (BDC, 1,4-benzenedicarboxylic; MBA, 4-methoxybenzoic acid) fabricated by introducing MBA as a modulator exhibits extremely stable colloid suspension for 6 months and the yield of well-dispersed CuBDC-MBA is higher than 88.6%. As MBA successfully participates in synthetic coordination of CuBDC-MBA and is presumably installed on the edge of 2D MOFs with low MBA content due to anisotropic growth, CuBDC-MBA and CuBDC are similar with respect to nanosheet morphology, integrated crystal structure, and porosity. Moreover, well-dispersed CuBDC-MBA shows higher catalytic effectiveness for the cycloaddition reaction of CO 2 with 1.5 times higher yield than CuBDC. Thus, this method can provide a new idea based on coordination modulation to directly fabricate 2D MOFs with purposeful properties.

: Photodynamic Therapy (PDT), as a clinically approved modality for the treatment of various disordered diseases including cancer, has received great advances in recent years. By preferentially accumulating non-toxic Photosensitizers (PSs) in the pathological area, and in situ generation of cytotoxic reactive oxygen species (ROS) under local irradiation by a light source with appropriate wavelength, PDT works in a dual-selective manner. Over the past decades, numerous studies and reviews on PDT mainly focused on activable PSs and the newly emerging PSs in PDT. However, to the best of our knowledge, there are few articles on the systematic introduction of light sources and limited reports about targeted strategies in PDT. This review comprehensively summarizes various light sources applied in PDT together with typical enhanced targeting strategies, and outlines their advantages and disadvantages, respectively. The clinical applications and future perspectives in light sources are also partly presented and discussed.

The search for selective opioid ligands with desired pharmacological potency and improved safety profile has always been an area of interest. Our previous effort yielded a potent opioid modulator, NAN, a 6α-N-7′-indolyl-substituted naltrexamine derivative, which exhibited promising pharmacological activities both in vitro and in vivo. However, significant human ether-a-go-gorelated gene (hERG) liability limited its further development. Therefore, a systematic structural modification on NAN was conducted in order to alleviate hERG toxicity while preserving pharmacological properties, which led to the discovery of 2′methylindolyl derivative compound 21. Compared to NAN, compound 21 manifested overall improved pharmacological profiles. Follow-up hERG channel inhibition evaluation revealed a seven-fold decreased potency of compound 21 compared to NAN. Furthermore, several fundamental drug-like property evaluations suggested a reasonable ADME profile of 21. Collectively, compound 21 appeared to be a promising opioid modulator for further development as a novel therapeutic agent toward opioid use disorder treatments.

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