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The composition of natural gas can vary considerably across different oil and gas fields. Such compositional variation is primarily reflected in the distinctive physical properties of natural gas. However, during practical application in an oil and gas field, a refrigeration temperature drop in a vortex tube is often observed because vortex tubes generally have low intrinsic refrigeration efficiencies. When vortex tubes are applied in oil and gas fields, the utilization of the oil pressure of a natural gas wellhead is often desirable to avoid excessive energy usage from external devices. In this study, a numerical model of a vortex tube was developed, executed, and validated through laboratory experiments. The refrigeration temperature drop values of 12 gases with distinctive physical properties at a total inlet pressure of 0.3 MPa, an inlet temperature of 300 K, and a cooling mass flow ratio of 0.5 were analyzed. The importance of different physical properties was ranked based on the gray correlation method. Additionally, the synergetic effects of the physical properties on the refrigeration temperature drop were analyzed via regression fitting. The results indicate a significant impact of the gas physical properties on the refrigeration temperature drop in the vortex tube. The maximum and minimum refrigeration temperature drop obtained for different gases can differ by up to 16 K. Furthermore, the refrigeration temperature drop in the vortex tube does not change monotonically with any physical property. Instead, it depends on the synergetic effect from the physical properties, which have different levels of influence on it.

Herein, two series of HDAC/tubulin dual inhibitors via introducing the key pharmacophore of HDAC inhibitor into the skeletons of 2,6-diarylpyridine and 2'-arylchalcone were synthesized. Among them, 2,6-diarylpyridine-based hydroxamic acid 10a exhibited good inhibitory activity against HDAC8 (IC

In response to the long-term potential toxicity concerns of tubulin destabilizer, an enzyme-responsive prodrug therapy for triple-negative breast cancer was developed based on the different β-glucuronidase levels between tumor and normal tissues in this study. All the prodrugs synthesized herein showed remarkable stability in phosphate buffer and bovine serum solution, among which 17a was found to be more susceptible to enzymatic cleavage. 17a exhibited excellent selectivity between the in vitro antiproliferative activities against β-glucuronidase-pretreated and -untreated cancer cells (IC

KBQA is a task that requires to answer questions by using semantic structured information in knowledge base. Previous work in this area has been restricted due to the lack of large semantic parsing dataset and the exponential growth of searching space with the increasing hops of relation paths. In this paper, we propose an efficient pipeline method equipped with a pretrained language model. By adopting beam search algorithm, the searching space will not be restricted in subgraph of 3 hops. Besides, we propose a data generation strategy, which enables our model to generalize well from few training samples. We evaluate our model on an open-domain complex Chinese question answering task CCKS2019 and achieve F1-score of 62.55% on the test dataset. In addition, in order to test the few-shot learning capability of our model, we randomly select 10% of the primary data to train our model, and the result shows that our model can still achieves F1-score of 58.54%, which verifies the capability of our model to process KBQA task and the advantage in few-shot learning.

Microtubule is one of the important targets for cancer treatment. A novel class of diaryl substituted imidazo[4,5-c]pyridin-2-ones and imidazo[4,5-c]pyridines were designed based on combination principles by merging the structures of β-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo[4,5-c]pyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule.

A diverse of chiral β-lactam bridged analogues of combretastatin A-4 (CA-4), 3-substituted 1,4-diaryl-2-azetidinones, were asymmetrically synthesized and biologically evaluated, leading to identify a number of potent anti-proliferative compounds represented by 14b and 14c with IC50 values of 0.001-0.021 μM, against four human cancer cell lines (A2780, Hela, SKOV-3 and MDA-MB-231). Structure-activity relationship (SAR) studies on all stereoisomers of 14b and 14c revealed that the absolute configurations of the chiral centers at 3- and 4-position were critically important for the activity and generally a trans configuration between the "A" and "B" rings is optimal. In addition, 14b and 14c displayed less cytotoxicity on normal human oviduct epithelial cells than malignant cells indicating good selectivity in vitro. Further biochemical evaluation and cocrystal structures with tubulin demonstrated that both compounds disrupted tubulin polymerization through interacting at the colchicine-binding site, suppressed angiogenesis in vitro and in vivo, blocked cell cycle progression at mitotic phase and induced cellular apoptosis. The in vivo assays verified that both compounds inhibited xenograft tumor growth in nude mice with acceptable therapeutic window, showing promising potentials for further clinical development.

A series of novel hydantoin-bridged analogues of combretastatin A-4 (CA-4) were designed, synthesized and evaluated for antiproliferative activities in vitro and in vivo . The most potent compound 8d , showed potent cytotoxicity against four human cancer cell lines with IC 50 values of 0.186–0.279 μM, and possessed the efficacy of inhibiting tubulin polymerization, disrupting in vitro vascularization, blocking cell cycle in G 2 /M phase and inducing cell apoptosis. In the nude mice xenograft model, 8d significantly inhibited the tumor growth and showed low toxicity. Further chiral separation proved ( R )-(−)- 8d to be the preferential enantiomer with IC 50 values of 0.081–0.157 M. These results indicated that the hydantoin derivatives merit further investigation as potential anticancer agents that inhibit tubulin polymerization.

A novel class of diaryl substituted azetidin-2-one derivatives were designed, asymmetrically synthesized, and evaluated for antiproliferative activities. The in vitro antitumor assay revealed that among the 4-aryl-substituted 1-(3,4,5-trimethoxyphenyl)azetidin-2-ones (B series), most possessed moderate to strong activities, with compound B7c that bears a 2-naphthyl substituent being the most potent one (IC50 0.16–0.40 μM) against a panel of human cancer cell lines. In contrast, none of the 3-(arylmethylene)-substituted 1-(3,4,5-trimethoxyphenyl)azetidin-2-ones (L series) showed significant activities in the assay. Further studies indicated that B7c inhibited tubulin polymerization, disrupted in vitro vascularization, blocked cell cycle progression at G2/M phase, induced cell apoptosis, decreased mitochondrial membrane potential, and increased the intracellular reactive oxygen species level in a dose-dependent way. Compound B7c also inhibited significantly tumor growth in a xenograft mice model with no obvious drop in the mice body weights. Collectively, these results suggested that B7c and its analogues should merit further investigation as new promising antitumor agents.

In order to discover novel hypoxia-inducible factor 1 (HIF-1) inhibitors for the cancer metastasis treatment, 68 new aryl carboxamide compounds were synthesized and evaluated for their inhibitory effect by dual luciferase-reporter assay. Based on five rounds of investigation on structure-activity relationships step by step, compound 30m was discovered as the most active inhibitor (IC50 = 0.32 μM) with no obvious cytotoxicity (CC50 > 50 μM). It effectively attenuated hypoxia-induced HIF-1α protein accumulation and reduced transcription of vascular epidermal growth factor in a dose-dependent manner, which was further demonstrated by its inhibitory potency on capillary-like tube formation, angiogenesis of zebrafish as well as cellular migration and invasion. Importantly, compound 30m exhibited antimetastatic potency in breast cancer lung metastasis in the mice model, indicating its promising therapeutic potential for prevention and treatment of tumor metastasis. These results definitely merit attention for further rational design of more efficient HIF-1 inhibitors in the future.

A series of chiral β-lactam bridged analogues (3-substituted 1,4-diaryl-2-azetidinones) of combretastatin A-4 (CA-4) were synthesized asymmetrically, and their antitumor activities were evaluated in vitro and in vivo. The cocrystal structure of tubulin in complex with compound 9 was determined by X-ray crystallography, which showed that 9 binds to the same site as colchicine with similar binding mode, and the absolute configuration of its C-4 was first identified and demonstrated to be critically important for their antiproliferative activities.

Inhibition of tubulin polymerisation with small molecules has been clinically validated as a promising therapy for multiple solid tumours. Herein, a series of chiral azetidin-2-ones were asymmetrically synthesised and biologically evaluated for antitumour activities. Among them, a chiral fluorinated azetidin-2-one, 18, was found to exhibit the most potent activities against five cancer cell lines, including a drug-resistant cell line, with IC50 values ranging from 1.0 to 3.6 nM. Further mechanistic studies revealed that the compound 18 worked by disrupting tubulin polymerisation, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis, and suppressing angiogenesis. Additionally, 18 exhibited higher human-microsomal metabolic stability and aqueous solubility compared to those of combretastatin A-4. Finally, 18 was also found to effectively inhibit tumour growth in a xenograft mice model with low toxicity and thus might be a promising lead for further clinical development.