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Addressing the delicate balance between the energy and sensitivity of energetic materials has been a prominent research focus. Here, 7,8-dinitropyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (ICM-104) is assembled with oxidizer ions through coulombic interactions, achieving an increase in energy while maintaining relatively low sensitivity. X-ray diffraction results indicated that the two energetic salts have a layered structure different from that of ICM-104, and have high densities of 1.89 and 1.95 g cm−3, which are higher than most other energetic salts. Both have excellent thermal detonation velocity (8813 and 8857 m s−1) and detonation pressure (33.2 and 35.7 GPa), higher than 1,3,5-trinitro-1,3,5-triazacyclohexane (RDX) (D: 8795 m s−1, P: 34.9 GPa). Moreover, compound 1 exhibits low mechanical sensitivities (FS > 360 N, IS > 40 J), which has great potential as an insensitive energetic material. In addition, two energetic salts have favorable laser-ignited combustion and propulsion performances, which provide new strategies for the formulation design of solid propellants. [ABSTRACT FROM AUTHOR]

Although numerous non-metallic pentazolate (cyclo-N5−) salts have been synthesized and investigated, no cyclo-N5− salt containing cage-like cations has been reported to date. To identify how cage-like cations impact the structures and properties of cyclo-N5− salts, we synthesized and examined two cyclo-N5− salts (C10H18N6 and C6H14N12) based on cage-like cations. Furthermore, the structures and performances of these cyclo-N5− salts were compared. The results suggest that the cyclo-N5− salts based on cage-like cations possess good insensitivity (IS > 40 N, FS > 360 J), which provides a good idea for developing new energetic salts with low sensitivity. Furthermore, we compared C6H14N12 with chain-like cationic pentazolate salt based on a similar structure and reported that C6H14N12 demonstrated improved density and detonation performance. This result indicates that selecting cage-like cations as antagonistic ions to cyclo-N5− anions may be an improved choice compared to chain-like cations having similar structures. [ABSTRACT FROM AUTHOR]

Dinitroimidazole (DNI) and dinitropyrazole (DNP), along with their congeners, possess similar molecular structures but exhibit distinct melting points. To analyse and elucidate the fundamental reasons for property differences from the perspective of intermolecular interactions, we proposed a simplified approach named binding energy in clusters (BEC) in computing weak interactions within complex crystal systems. Based on the results of the symmetry-adapted perturbation theory (SAPT) calculations, an approximate estimation of the melting point range can be derived by taking into account the cumulative effect (energy of electrostatic, dispersion and induction terms) and repulsive effect (energy of exchange term) values. We have also proposed a formula for calculating the specific melting point, which indicates that stronger intermolecular interactions have a major impact on the melting point, while the distribution of weak interactions also affects the melting point. This work would provide an effective reference for molecular design and structure–performance analysis. [ABSTRACT FROM AUTHOR]

With the increase in the demand for high‐performance composite explosives, the search for advanced energetic melt‐castable compounds has attracted increasing attention in the field of energetic materials. Herein, two new energetic materials with nitromethyl and azidomethyl substituents (1‐(nitromethyl)‐3,4‐dinitro‐1H‐pyrazole (NMDNP) and 1‐(azidomethyl)‐3,4‐dinitro‐1H‐pyrazole (AMDNP) were prepared by the substituent modification of a potential melt‐castable molecule ((3,4‐dinitro‐1H‐pyrazol‐1‐yl) methyl nitrate, MC‐4), respectively. NMDNP exhibited a suitable melting point (90 °C), good thermal stability (Td: 185 °C) and excellent detonation performance (8484 m s−1) and impact sensitivity (25 J), thereby demonstrating promise as an energetic melt‐castable material. Simultaneously, compared with the nitrato‐methyl and azidomethyl substituents, the nitromethyl substituent exhibited greater advantages in regulating performance. [ABSTRACT FROM AUTHOR]

Machine learning (ML) is an emerging approach for predicting molecular properties. The prediction of the properties of energetic molecules by ML is still in its infancy. In order to improve the accuracy of ML‐based predictions, it is important to pay attention to aspects such as data preparation, model selection, and hyperparameter tuning. In this work, we focused on the influence of different featurization methods and algorithms on predicting the enthalpy of formation (EOF) of energetic compounds. We manually extracted a dataset consisting of 649 EOF values of energetic materials from the literature and compared different combinations of featurization methods and algorithms. The experimental results confirmed that ML can effectively map the relationship between molecular structure and EOF. Custom descriptor sets were found to perform best in featurization with a mean absolute error of 90.10 kJ mol−1, after training by kernel ridge regression algorithm. [ABSTRACT FROM AUTHOR]

Simple Summary: The anti-tumor role of Fasudil in EGFR-mutation NSCLC as well as its mechanism are largely unknown. Here, we show that Fasudil could effectively inhibit EGFR-mutation cell growth and enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib by suppressing intracellular lipid accumulation. Mechanistic investigations showed that Fasudil could reverse gefitinib-induced SCD1 expression by suppressing AMPK activity, and combination therapy had a greater inactivation effect on the EGFR/PI3K/AKT pathway than either treatment alone. These findings highlight the clinical significance of Fasudil in EGFR mutation NSCLC therapy. Tyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest analysis, and apoptosis analysis show that Fasudil treatment effectively suppressed the growth and induced apoptosis of the EGFR-mutant NSCLC cells. Furthermore, Fasudil in combination with gefitinib showed a synergistic anti-tumor effect in gefitinib-resistant NSCLC cells. RNA-seq analysis and immunoblotting indicated that Fasudil treatment significantly inhibited intracellular lipid accumulation and EGFR/PI3K/AKT pathway activation. Mechanistic investigations showed that Fasudil regulated lipogenic gene expressions via AMPK signal pathway. In vivo, Fasudil and gefitinib co-administration significantly attenuated the growth of H1975 nude mouse xenograft models, suggesting that Fasudil treatment combined with gefitinib can be applied as a therapy for gefitinib-resistant NSCLC cells. [ABSTRACT FROM AUTHOR]

Cyclic nitramine explosives including RDX, HMX and CL-20 have drawn extensive attention due to their wide applications and excellent performance. However, these three nitramine explosives exhibit obviously different properties (such as density and thermostability) even though they share similar compositions and structures. Here, applying static calculations, we analyzed and disclosed the root of property differences from views of monomolecular parameters, intermolecular interactions and crystal packing. A high-precision method named binding energy in cluster (BEC) is proposed to analyze intermolecular interactions for molecules in a crystal. The polymorph and its effect on crystal density is discussed and the rationality of the BEC method is verified through comparing BECs in different polymorphs. This work may provide effective references for molecular design and structure–performance relationship analysis. [ABSTRACT FROM AUTHOR]

Energetic isomers often exhibit different properties. To understand the effect of arrangement and connection of isomers on energetic properties and sensitivity, in this study, we designed and synthesized a series of oxadiazole nitramine compounds including N-(5-(5-(nitramino)-1,3,4-oxadiazol-2-yl)-1,2,4-oxadiazol-3-yl)nitramide (NOON) and its ionic derivatives. NOON exhibits comparable performance (D = 8888 m s−1, P = 34.1 GPa) to highly explosive RDX. A comparative study of detonation properties, sensitivity, and thermal stability of the three oxadiazole nitramine isomers (NOON, ICM-101, and DNBO) is carried out. The results show that due to the proton transformation, strong intramolecular hydrogen bonding interaction, and formation of six-membered ring conformation, the 2-nitramino-1,3,4-oxadiazole building block exhibits better detonation properties and higher thermal stability than its isomer 2-nitramino-1,2,4-oxadiazole. [ABSTRACT FROM AUTHOR]

With the growth of chemical data, computation power and algorithms, machine learning-assisted high-throughput virtual screening (ML-assisted HTVS) is revolutionizing the research paradigm of new materials. Herein, a combined ML-assisted HTVS and experimental approach was applied to accelerate the search for energetic melt-castable materials with promising properties. The ML-assisted HTVS system is composed of high-throughput molecular generation (in a heuristic enumeration method) and five machine learning-based property prediction models (including density, melting point, decomposition temperature, detonation velocity, and detonation pressure). Using this system, we rapidly targeted 136 promising candidates from a generated molecular space containing 3892 molecules. With extensive efforts on experimental synthesis, eight new energetic melt-castable materials (MC-1 to MC-8) were obtained, and their measured properties were in good agreement with the predicted results. This work verifies the effectiveness of the combined ML-assisted HTVS and experimental approach for the accelerated discovery of energetic melt-castable materials. [ABSTRACT FROM AUTHOR]

Background: It remains unclear whether discharged COVID-19 patients have fully recovered from severe complications, including the differences in the post-infection metabolomic profiles of patients with different disease severities. Methods: COVID-19-recovered patients, who had no previous underlying diseases and were discharged from Wuhan Union Hospital for 3 months, and matched healthy controls (HCs) were recruited in this prospective cohort study. We examined the blood biochemical indicators, cytokines, lung computed tomography scans, including 39 HCs, 18 recovered asymptomatic (RAs), 34 recovered moderate (RMs), and 44 recovered severe/ critical patients (RCs). A liquid chromatography-mass spectrometry-based metabolomics approach was employed to profile the global metabolites of fasting plasma of these participants. Results: Clinical data and metabolomic profiles suggested that RAs recovered well, but some clinical indicators and plasma metabolites in RMs and RCs were still abnormal as compared with HCs, such as decreased taurine, succinic acid, hippuric acid, some indoles, and lipid species. The disturbed metabolic pathway mainly involved the tricarboxylic cycle, purine, and glycerophospholipid metabolism. Moreover, metabolite alterations differ between RMs and RCs when compared with HCs. Correlation analysis revealed that many differential metabolites were closely associated with inflammation and the renal, pulmonary, heart, hepatic, and coagulation system functions. Conclusion: We uncovered metabolite clusters pathologically relevant to the recovery state in discharged COVID-19 patients which may provide new insights into the pathogenesis of potential organ damage in recovered patients. [ABSTRACT FROM AUTHOR]

It has been reported that melatonin can relieve the symptoms of chronic obstructive pulmonary disease (COPD) by improving sleep quality, that is to say, the pineal secreted hormone melatonin has a protective effect in the pathogenesis of COPD, but its underlying mechanism remains unclear. In this study, we recruited 73 people into control (n = 22), stable COPD (n = 20), and acute exacerbation of COPD (n = 31) groups to detect the serum melatonin levels. Then, through the mouse model, we employed a systematic study based on the metabolomic and transcriptomic analyses to investigate the molecular mechanisms involved in the progression of the disease. Circulating melatonin in acute exacerbation of COPD patients was decreased compared with that in healthy donors and stable COPD patients. The serum melatonin level was positively correlated with lung function parameters, such as FEV1, FEV1/FVC, and FEV1% predicted in acute exacerbation of COPD patients. Animal experiments showed that melatonin can not only alleviate chronic lipopolysaccharide (LPS)-induced mouse lung destruction and chronic lung inflammation but also reduce necroptosis (RIP1/RIP3/MLKL), a programmed cell death process in bronchial epithelial cells. The protective effect of melatonin on chronic lung inflammation was further suggested to be dependent on targeting its membrane receptor MT1/MT2. In addition, transcriptomic and metabolomic profiling in the lungs of mice indicated that LPS can induce perturbations of the mainstream metabolites associated with amino acid and energy metabolism. Melatonin may reduce the necroptosis by modifying the disordered pathways of alanine, aspartate, and glutamate metabolism caused by LPS. This study suggests that melatonin may act as a potential therapeutic agent for alleviating the chronic inflammation associated with COPD. [ABSTRACT FROM AUTHOR]

This retrospective study examined changes in fasting blood glucose (FBG) levels during hospitalization and their effect on risk of death for Coronavirus disease 2019 (COVID-19) patients without previously diagnosed diabetes. A model with low- and high-stable pattern trajectories was established based on a longitudinal change in FBG levels. We analyzed FBG trajectory-associated clinical features and risk factors for death due to COVID-19. Of the 230 enrolled patients, 44 died and 87.83% had a low-stable pattern (average FBG range: 6.63–7.54 mmol/L), and 12.17% had a high-stable pattern (average FBG range: 12.59–14.02 mmol/L). There were statistical differences in laboratory findings and case fatality between the two FBG patterns. Multivariable logistic regression analysis showed that increased neutrophil count (odds ratio [OR], 25.43; 95% confidence interval [CI]: 2.07, 313.03), elevated direct bilirubin (OR, 5.80; 95%CI: 1.72, 19.58), elevated creatinine (OR, 26.69; 95% CI: 5.82, 122.29), lymphopenia (OR, 8.07; 95% CI: 2.70, 24.14), and high-stable FBG pattern (OR, 8.79; 95% CI: 2.39, 32.29) were independent risk factors for higher case fatality in patients with COVID-19 and hyperglycemia but no history of diabetes. FBG trajectories were significantly associated with death risk in patients with COVID-19 and no diabetes. [ABSTRACT FROM AUTHOR]

A novel H2O2 adduct of ammonium cyclopentazolate, NH4N5·½H2O2, was readily synthesized by a simple and effective method. This adduct, as determined by single-crystal X-ray diffraction, has a cyclo-N5− anion, an ammonium ion and ½H2O2 molecule in the asymmetric unit. In this structure, H2O2 molecules are incorporated into the crystal lattices of NH4N5, forming an interesting three-dimensional (3D) network structure in which cyclo-N5− ions are stacked layer by layer and NH4+ ions are intercalated into the layers and connected the layers through hydrogen bonds. This novel solvate, NH4N5·½H2O2, has a high oxygen balance (−22.86% based on CO2), high calculated detonation velocity and pressure (8938 m s−1 and 26.37 GPa) and an impressive specific impulse (259.97 s) much higher than that of anhydrous NH4N5. Moreover, the combustion products of this solvate mainly include nontoxic N2, H2 and H2O. This simple and effective strategy of combining NH4N5 with H2O2 is highly desirable for future studies on the development of disruptive energetic materials. [ABSTRACT FROM AUTHOR]

Deep eutectic solvents (DESs) are emerging as green and sustainable solvents for the efficient extraction of bioactive compounds. In this study, a series of DESs was prepared using choline chloride with natural, renewable organic acids, polyalcohols, or sugars. The physicochemical properties of their aqueous solutions were investigated. Subsequently, evaluation of the extraction of bioactive berberine and palmatine from a traditional Chinese herb, Phellodendri amurensis cortex (PAC), using these DES aqueous solutions was performed in an ultrasound-assisted environment. The morphologies of the raw and treated PAC samples were observed using scanning electron microscopy to determine the extraction efficiency of the ultrasonic bath using different solvents. Antioxidant capacities of PAC extract solutions were investigated by FRAP and ABTS assays. Furthermore, the extraction conditions were statistically optimized using a response surface methodology to improve the yields of the alkaloids, and the antioxidant capacities of the resultant solutions. This study demonstrates that DES aqueous solutions are suitable, green solvents for the efficient extraction of bioactive compounds from Chinese herbs with the aid of ultrasound. The use of DES aqueous solutions can eliminate the requirement of volatile organic compounds, which would reduce the damage to the environment. [ABSTRACT FROM AUTHOR]

Energetic materials with a graphite-like crystal structure always demonstrate better energy-sensitivity balance than the common ones. However, the knowledge on how to design a graphite-like energetic material is still limited and a rational design procedure for graphite-like energetic materials is much desired. Here, a set of systematic methods for discovering new graphite-like energetic materials is presented. We analyzed the intermolecular self-assembled behavior of graphite-like energetic materials and proposed a combined method of coplanar configuration searching (CCS) and point-chain-plane progressive intermolecular assembly (pcp-PIA) to predict and screen new graphite-like energetic materials. Furthermore, with a self-established high-throughput design system, we rapidly focused on a potential graphite-like energetic molecule (namely, 2-azido-5-nitropyrimidine-4,6-diamine, DANAP) from 426 candidates and finally experimentally verified its graphite-like crystal structure. We believe that the method presented here will have potential applications in guiding the crystal engineering of graphite-like energetic materials, thereby accelerating the discovery of new energetic materials with promising properties. [ABSTRACT FROM AUTHOR]

A new design strategy for zwitterionic energetic materials was developed, and two gem-dinitromethyl functionalized 5-amino-1,3,4-oxadiazolate inner salts were synthesized and characterized. Compared with common energetic salt analogues, both zwitterionic energetic compounds exhibited higher densities, better detonation performances, and comparable mechanical sensitivities. This design strategy may stimulate the development of additional zwitterionic energetic materials. [ABSTRACT FROM AUTHOR]

In the development of advanced high-energy-density materials (HEDMs), the traditional strategy of integrating oxidant and fuel components into an organic molecule makes it very difficult to balance the energy and safety of materials. Herein, we present an intermolecular host–guest inclusion strategy for constructing advanced HEDMs with well-balanced energy and safety. By gradually introducing high-energy oxidants into the supramolecular voids of the deliberately selected energetic host crystal, three host–guest inclusion HEDMs (i.e., HGI-1, HGI-2 and HGI-3) were prepared, which show detonation performances separately comparable to those of three classical HEDMs, namely RDX, HMX and ε-CL-20, but with mechanical sensitivities that are much superior to those of these classical HEDMs. In addition, these self-assembled HEDMs have excellent combustion properties and exhibit great potential as high-energy low signature propellants. This presented host–guest inclusion strategy shows enormous potential for tailoring the energy and sensitivity of energetic materials and will accelerate the development of advanced HEDMs in the future. [ABSTRACT FROM AUTHOR]