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Abstract The beginning of human settlement in the Hami Basin, located in the eastern part of Xinjiang, has been a focal question for the academic community in China. In particular, the thesis that the immigrating population from the Hexi Corridor since the late Neolithic founded the Tianshanbeilu culture has riveted the attention of scholars. Pottery wares, abundantly discovered at the synonymous cemetery of this culture, have played a key role in extrapolating population migration and cultural interaction. This paper aims to test the thesis by characterizing the chemical composition, painting pigment, and carburizing technique of 70 pottery samples from the cemetery with various scientific methods. It shows that the chemical compositions of the coarse pottery in the three colors of red, yellow, and gray, painted and unpainted alike, are remarkably different from those of fine pottery in black and red, indicating that the raw materials for the coarse and fine pottery samples are possibly procured from different sources; the pigments of the red slip and black paint are derived from hematite, black manganese ore, and carbon black; carburizing and polishing techniques are further applied to the gray coarse pottery; In combination with the compositional data of pottery samples from the Yaer cemetery also in the Hami Basin and the Xichengyi settlement in the Hexi Corridor, this paper finds that some pottery wares of the Tianshanbeilu culture were exchanged within the Hami Basin, but each site had its own production facility. No direct exchange of pottery wares with Xichengyi is attested; the similar style of pottery wares between the two sites may have resulted from population migration and technological exchange.

Abstract Inlay celadon was a type of high-end ceramics of the Koryŏ dynasty (918–1392 AD) produced in the Korean Peninsula. It was conveyed to China during the Yuan dynasty (1279–1368 AD) as tribute or trade goods. In this study, the authors analyzed six samples of inlay celadon recently discovered at the prosperous Taicang Port of the Yuan and Ming dynasties in the lower Yangtze River, China. With scanning electron microscopy coupled with energy dispersive spectroscopy (SEM–EDS) and X-ray diffraction (XRD), the authors investigated the production technique, and compositional characteristics of these samples for the purpose of tracking their provenances. While the bodies are made of porcelain stone, the glazes are of porcelain stone and calcium-rich flux. The white inlay material in these samples is kaolinite-dominant, and the black one is made of quartz with high Fe content or a compound of quartz and raw materials with high Fe content. The results link the samples uncovered at the Taicang Port to the Samhǔngni Kiln in Kangjin-gun and the Uch'ǒlli and Chinsǒri Kilns in Buan-gun in Southern Korea. The products from these kilns were shipped to China in several shipments.

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Importance: Drug-likeness of a compound is an overall assessment of its potential to succeed in clinical trials, and is essential for economizing research expenditures by filtering compounds with unfavorable properties and poor development potential. To this end, a robust drug-likeness prediction method is indispensable. Various approaches, including discriminative rules, statistical models, and machine learning models, have been developed to predict drug-likeness based on physiochemical properties and structural features. Notably, recent advancements in novel deep learning techniques have significantly advanced drug-likeness prediction, especially in classification performance. Highlights: In this review, we addressed the evolving landscape of drug-likeness prediction, with emphasis on methods employing novel deep learning techniques, and highlighted the current challenges in drug-likeness prediction, specifically regarding the aspects of generalization and interpretability. Moreover, we explored potential remedies and outlined promising avenues for future research. Conclusion: Despite the hurdles of generalization and interpretability, novel deep learning techniques have great potential in drug-likeness prediction and are worthy of further research efforts.

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound 42 (IC50 = 0.79 μmol/L) was finally obtained. Compound 42 selectively inhibited ANO1 without affecting ANO2 and intracellular Ca2+ concentration. Subsequently, the analgesic effect was investigated by intragastric administration in pain models. Compound 42 significantly attenuated allodynia which was induced by formalin and chronic constriction injury. Through homology modeling and molecular dynamics, the binding site was predicted to be located near the calcium-binding region between α6 and α8. Our study validates ANO1 inhibitors having a significant analgesic effect by intragastric administration and also provides selective molecular tools for ANO1-related research.

Novel antibacterial agents are urgently needed to address the infections caused by multi-drug resistant bacteria. Urinary tract infections are common infectious diseases in clinical. Most of these infections are caused by drug-resistant uropathogenic Escherichia coli. PPK1 is an essential kinase for bacterial motility, biofilm formation, quorum sensing, and virulence factors in the expression of uropathogenic E. coli. In the present study, two small molecules potentially targeting PPK1 were discovered through virtual screening and biological assays. The in vitro and in vivo results suggested that the interaction of these compounds with PPK1 can disrupt biofilm formation of uropathogenic E. coli and reduce invasive ability and resistance to oxidative stress of this strain. Moreover, the compounds exhibit good antibacterial bacterial activity in the mice with urinary tract infection. Taken together, our findings could provide a new chemotype for the development of antibacterials targeting PPK1.

Summary: SARM1, an NAD-utilizing enzyme, regulates axonal degeneration. We show that CZ-48, a cell-permeant mimetic of NMN, activated SARM1 in vitro and in cellulo to cyclize NAD and produce a Ca2+ messenger, cADPR, with similar efficiency as NMN. Knockout of NMN-adenylyltransferase elevated cellular NMN and activated SARM1 to produce cADPR, confirming NMN was its endogenous activator. Determinants for the activating effects and cell permeability of CZ-48 were identified. CZ-48 activated SARM1 via a conformational change of the auto-inhibitory domain and dimerization of its catalytic domain. SARM1 catalysis was similar to CD38, despite having no sequence similarity. Both catalyzed similar set of reactions, but SARM1 had much higher NAD-cyclizing activity, making it more efficient in elevating cADPR. CZ-48 acted selectively, activating SARM1 but inhibiting CD38. In SARM1-overexpressing cells, CZ-48 elevated cADPR, depleted NAD and ATP, and induced non-apoptotic death. CZ-48 is a specific modulator of SARM1 functions in cells. : Biochemistry; Enzymology; Biochemical Mechanism Subject Areas: Biochemistry, Enzymology, Biochemical Mechanism

Traditional Chinese medicine (TCM) has been developed for thousands of years with its various biological activities. The interest in TCM in tumor prevention and treatment is rising with its synergistic effect on tumor cells and tumor immunosuppressive microenvironment (TIM). Characteristic of TCM fits well within the whole system and multi-target cancer treatment. Herein we discuss the underlying mechanisms of TCM actions in TIM via regulating immunosuppressive cells, including restoring the antigen presentation function of dendritic cells, enhancing NK cells-mediated killing activity, restraining the functions of myeloid cell-derived suppressor cells, and inhibiting cancer-associated fibroblasts. TCM also regulates tumor progression through enhancing immune response, preventing immune escape and inducing cell death of tumor cells, which triggers immune response in nearby cells. In addition, we discuss TCM in clinical applications and the advantages and disadvantages of TCM in cancer prevention and treatment, as well as current therapeutic challenges and strategies. It might be helpful for understanding the therapeutic potential of TCM for cancer in clinic.

Hemorrhagic stroke accounts for 10-15% of all strokes and is strongly associated with mortality and morbidity worldwide, but its prevention and therapeutic interventions remain a major challenge. Here, we report the identification of miconazole as a hemorrhagic suppressor by a small-molecule screen in zebrafish. We found that a hypomorphic mutant fn40a, one of several known β-pix mutant alleles in zebrafish, had the major symptoms of brain hemorrhage, vessel rupture and inflammation as those in hemorrhagic stroke patients. A small-molecule screen with mutant embryos identified the anti-fungal drug miconazole as a potent hemorrhagic suppressor. Miconazole inhibited both brain hemorrhages in zebrafish and mesenteric hemorrhages in rats by decreasing matrix metalloproteinase 9 (MMP9)-dependent vessel rupture. Mechanistically, miconazole downregulated the levels of pErk and Mmp9 to protect vascular integrity in fn40a mutants. Therefore, our findings demonstrate that miconazole protects blood vessels from hemorrhages by downregulating the pERK-MMP9 axis from zebrafish to mammals and shed light on the potential of phenotype-based screens in zebrafish for the discovery of new drug candidates and chemical probes for hemorrhagic stroke.

Summary: cADPR is a well-recognized signaling molecule by modulating the RyRs, but considerable debate exists regarding whether cADPR can bind to and gate the TRPM2 channel, which mediates oxidative stress signaling in diverse physiological and pathological processes. Here, we show that purified cADPR evoked TRPM2 channel currents in both whole-cell and cell-free single-channel recordings and specific binding of cADPR to the purified NUDT9-H domain of TRPM2 by surface plasmon resonance. Furthermore, by combining computational modeling with electrophysiological recordings, we show that the TRPM2 channels carrying point mutations at H1346, T1347, L1379, S1391, E1409, and L1484 possess distinct sensitivity profiles for ADPR and cADPR. These results clearly indicate cADPR is a bona fide activator at the TRPM2 channel and clearly delineate the structural basis for cADPR binding, which not only lead to a better understanding in the gating mechanism of TRPM2 channel but also shed light on a cADPR-induced RyRs-independent Ca2+ signaling mechanism. : Yu et al. demonstrate that cADPR, which was thought to be an intracellular calcium messenger by modulating function of the ryanodine receptors (RyRs), also activates the TRPM2 channel. Their results suggest that cADPR regulates intracellular calcium release through multiple pathways. Keywords: cADPR, NUDT9-H domain, TRPM2 channel

Multidrug resistance protein 4 (MRP4/ABCC4) is an ATP-binding cassette (ABC) transporter. It is associated with multidrug resistance (MDR), which is becoming a growing challenge to the treatment of cancer and infections. In the context of several types of cancer in which MRP4 is overexpressed, MRP4 inhibition manifests striking effects against cancer progression and drug resistance. In this study, we combined ligand-based and structure-based drug design strategy, by searching the SPECS chemical library to find compounds that are most likely to bind to MRP4. Clustering analysis based on a two-dimensional fingerprint was performed to help with visual selection of potential compounds. Cell viability assays with potential inhibitors and the anticancer drug 6-MP were carried out to identify their bioactivity. As a result, 39 compounds were tested and seven of them reached inhibition above 55% with 6-MP. Then compound Cpd23 was discovered to improve HEK293/MRP4 cell sensibility to 6-MP dramatically, and low concentration Cpd23 (5 μM) achieved the equivalent effect of 50 μM MK571. The accumulation of 6-MP was determined by validated high-performance liquid chromatography methods, and pretreatment of the HEK293/MRP4 cells with 50 μM MK571 or Cpd23 resulted in significantly increased accumulation of 6-MP by approximately 1.5 times. This compound was first reported with a novel scaffold compared with previously known MRP4 inhibitors, which is a hopeful molecular tool that can be used for overcoming multidrug resistance research.

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Target fishing often relies on the use of reverse docking to identify potential target proteins of ligands from protein database. The limitation of reverse docking is the accuracy of current scoring funtions used to distinguish true target from non-target proteins. Many contemporary scoring functions are designed for the virtual screening of small molecules without special optimization for reverse docking, which would be easily influenced by the properties of protein pockets, resulting in scoring bias to the proteins with certain properties. This bias would cause lots of false positives in reverse docking, interferring the identification of true targets. In this paper, we have conducted a large-scale reverse docking (5000 molecules to 100 proteins) to study the scoring bias in reverse docking by DOCK, Glide, and AutoDock Vina. And we found that there were actually some frequency hits, namely interference proteins in all three docking procedures. After analyzing the differences of pocket properties between these interference proteins and the others, we speculated that the interference proteins have larger contact area (related to the size and shape of protein pockets) with ligands (for all three docking programs) or higher hydrophobicity (for Glide), which could be the causes of scoring bias. Then we applied the score normalization method to eliminate this scoring bias, which was effective to make docking score more balanced between different proteins in the reverse docking of benchmark dataset. Later, the Astex Diver Set was utilized to validate the effect of score normalization on actual cases of reverse docking, showing that the accuracy of target prediction significantly increased by 21.5% in the reverse docking by Glide after score normalization, though there was no obvious change in the reverse docking by DOCK and AutoDock Vina. Our results demonstrate the effectiveness of score normalization to eliminate the scoring bias and improve the accuracy of target prediction in reverse docking. Moreover, the properties of protein pockets causing scoring bias to certain proteins we found here can provide the theory basis to further optimize the scoring functions of docking programs for future research.

Nicotinamide adenine dinucleotide (NAD), one of the most important coenzymes in the cells, is a substrate of the signaling enzyme CD38, by which NAD is converted to a second messenger, cyclic ADP-ribose, which releases calcium from intracellular calcium stores. Starting with 2′-deoxy-2′-fluoroarabinosyl-β-nicotinamide adenine dinucleotide (ara-F NAD), a series of NAD analogues were synthesized and their activities to inhibit CD38 NAD glycohydrolase (NADase) were evaluated. The adenosine-modified analogues showed potent inhibitory activities, among which 2′-deoxy-2′-fluoroarabinosyl-β-nicotinamide guanine dinucleotide (ara-F NGD) was the most effective one. The structure-activity relationship of NAD analogues was also discussed.

CD38 is a multifunctional enzyme/receptor expressed in a variety of mammalian tissues, regulating a wide range of physiological functions. Beginning with the previously reported compound 1, an inhibitor of human CD38 NADase, we synthesized a series of indole-based NH-substituted derivatives with modifications on alkyl chains, changes in substituent groups on aromatic rings, and differences in carbon chain lengths. Compounds 10, 13, 16 and 34 exhibited moderate inhibition of human CD38 NADase. Analysis of the structure-activity relationships showed that the phenylpropionyl moiety was very important for the inhibitory activity. This study provides information for the rational design of CD38 inhibitors.