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C30H28O4, triclinic, P1‾ $P\overline{1}$ (no. 2), a = 9.473(14) Å, b = 9.775(14) Å, c = 14.43(2) Å, α = 100.354(17)°, β = 91.053(17)°, γ = 94.062(17)°, V = 1310(1) Å3, Z = 2, R gt(F) = 0.0517, wR ref(F 2) = 0.1803, T = 296(2) K.

C26H28N2O6, monoclinic, P21/c (no. 14), a = 15.962(9) Å, b = 14.828(8) Å, c = 9.929(5) Å, β = 93.303°, V = 2346(2) Å3, Z = 4, R gt(F) = 0.0515, wR ref(F 2) = 0.1621, T = 296(2) K.

Abstract The ribosomally synthesized and post-translationally modified peptide (RiPPs) class of natural products has undergone significant expansion due to the rapid growth in genome sequencing data. Using a bioinformatics approach, we identify the dehydrazoles, a novel class of hypermodified RiPPs that contain both side chain dehydration of Ser residues, and backbone heterocyclization at Ser, Thr, and Cys residues to the corresponding azol(in)es. Structure elucidation of the hypermodified peptide carnazolamide, a representative class member, shows that 18 post-translational modifications are installed by just five enzymes. Complete biosynthetic reconstitution demonstrates that dehydration is carried out by an unusual DUF4135 dehydration domain fused to a zinc-independent cyclase domain (CcaM). We demonstrate that CcaM only modifies Ser residues that precede an azole in the core peptide. As heterocyclization removes the carbonyl following the Ser residue, CcaM likely catalyzes dehydration without generating an enolate intermediate. Additionally, CcaM does not require the leader peptide, and this core-dependence effectively sets the order for the biosynthetic reactions. Biophysical studies demonstrate direct binding of azoles to CcaM consistent with this azole moiety-dependent dehydration. Bioinformatic analysis reveals more than 50 related biosynthetic gene clusters that contain additional catalysts that may produce structurally diverse scaffolds.

C28H32O6, orthorhombic, Pnma (no. 62), a = 7.752(2) Å, b = 29.959(8) Å, c = 10.176(3) Å, V = 2363.5(11) Å3, Z = 4, R gt(F) = 0.1145, wR ref(F 2) = 0.1076, T = 296(2) K.

Allopurinol (ALP) attenuates oxidative stress and diabetic cardiomyopathy (DCM), but the mechanism is unclear. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) following the disassociation with its repressor Keap1 under oxidative stress can maintain inner redox homeostasis and attenuate DCM with concomitant attenuation of autophagy. We postulated that ALP treatment may activate Nrf2 to mitigate autophagy over-activation and consequently attenuate DCM. Streptozotocin-induced type 1 diabetic rats were untreated or treated with ALP (100 mg/kg/d) for 4 weeks and terminated after heart function measurements by echocardiography and pressure-volume conductance system. Cardiomyocyte H9C2 cells infected with Nrf2 siRNA or not were incubated with high glucose (HG, 25 mmol/L) concomitantly with ALP treatment. Cell viability, lactate dehydrogenase, 15-F2t-Isoprostane and superoxide dismutase (SOD) were measured with colorimetric enzyme-linked immunosorbent assays. ROS, apoptosis, was assessed by dihydroethidium staining and TUNEL, respectively. The Western blot and qRT-PCR were used to assess protein and mRNA variations. Diabetic rats showed significant reductions in heart rate (HR), left ventricular eject fraction (LVEF), stroke work (SW) and cardiac output (CO), left ventricular end-systolic volume (LVVs) as compared to non-diabetic control and ALP improved or normalized HR, LVEF, SW, CO and LVVs in diabetic rats (all P

Objective To fabricate caffeic acid-grafted gelatin (CA-gel) hydrogels and investigate effects of the grafting ratios on the physicochemical properties of the hydrogels, and evaluate the antioxidant function of hydrogels. Methods CA-gel gelatin was synthesized by controlling the ratio of caffeic acid and gelatin, and the hydrogels were formed with laccase as the cross-linking agent. The molecular structure of caffeic acid-grafted gelatin was characterized by HPLC and 1H-NMR. The grafting degree of caffeic acid was determined by UV-Vis spectrophotometer and the gelation time of hydrogel was determined by vial-tilting method. The elastic modulus was measured by microsphere indentation method. The swelling ratio and degradation rate of the hydrogel were calculated according to mass change before and after swelling and degradation, and the scavenging effect on DPPH radical(DPPH·) was determined by the change of absorbance of DPPH radical solution. Cell counting kit-8 was used to evaluate the cytotoxicity of the hydrogels and the protective effect on fibroblasts in high oxidative stress microenvironment. Results Caffeic acid was grafted onto gelatin molecules with following respective parameters: grafting degrees were 33.0 μmol/g, 61.8 μmol/g and 74.4 μmol/g, the gelation time was 33 min, 42 min and 47 min, the swelling ratios of the hydrogels were 896.5%, 835.3% and 803.9%, the elastic modulus of the hydrogels were 7.2 kPa, 29.4 kPa and 34.5 kPa, and the scavenging effects on DPPH radical of the hydrogels were 38.5%, 41.9% and 49.8%, respectively. In addition, the degradation rate decreased with the increase of grafting degree. The hydrogels were non-cytotoxic and displayed protective effect on the fibroblasts in the peroxide-existing environment. Conclusions CA-gel hydrogels have adjustable gelation time, biodegradation rate, elastic modulus and free radical scavenging activity and show a significant protective effect against fibroblasts in high oxidative stress microenvironment as well.

Aiming at the requirements of data storage and sharing between side devices and among marketing distribution dispatching systems in cloud master station platform of power Internet of Things,a power data storage and sharing method based on blockchain and data lake is proposed. Firstly,the distributed power data storage architecture on edge layer is designed. Through ring signature and CryptoNote protocol,the data interaction between side device storage nodes is encrypted to realize the identity authentication of both parties,and the data sharing between nodes in power data security storage system is realized based on intelligent contract of blockchain. Then,the data sharing and access control model between the operation and dispatching platforms is constructed based on the data lake and the smart contract,in which the hash value of the data is stored in the blockchain,and the data is stored in the data lake,so as to realize the cross platform and cross domain secure sharing and access of data. Finally,an experimental platform is built to demonstrate the proposed method. The results show that the maximum storage delay time of the proposed method is short,and the throughput and security are also high,so it has a good application prospect.

C22H24I2N2, orthorhombic, Pbca (no. 33), a = 21.069(4) Å, b = 8.7963(17) Å, c = 23.757(5) Å, V = 4402.8(15) Å3, Z = 8, Rgt(F) = 0.0530, wRref(F2) = 0.1569, T = 296(2) K.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is a severe disease with high mortality, and is associated with poor prognosis and frequent lymphatic metastasis. Therefore, prognostic indicators for ESCC are urgently needed. A-kinase anchor-protein 8-like (AKAP8L) is a member of the A kinase anchor-protein (AKAPs) family and is overexpressed in many cancers. However, the role of AKAP8L in ESCC remains unclear. The aim of this study is to investigate the expression patterns and prognostic value of AKAP8L in ESCC. Methods The mRNA expression of AKAP8L was analyzed from the dataset of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry was applied to detect the AKAP8L expression in tissue microarray. Pearson’s chi-square test was carried out for the correlation analysis of clinicopathological features and AKAP8L expression. The prognostic significance of clinicopathological features and AKAP8L expression was determined by univariate and multivariate Cox hazard models. Kaplan–Meier survival curve was used for survival analysis. Results We found that the mRNA level of AKAP8L was higher in tumor tissues than in adjacent tissues in TCGA and GEO dataset. High AKAP8L expression was associated with poor overall survival (OS) in ESCC patients (p = 0.0039). Besides, AKAP8L expression was highly expressed in patients with lymph node metastasis detected by ESCC tissue microarray (p = 0.0014). The comparison of the different clinicopathological features of ESCC between high and low AKAP8L expression groups revealed that high AKAP8L expression was related to lymph node stage (p = 0.041). Kaplan–Meier survival analysis revealed that high AKAP8L expression indicates an unfavorable progression-free survival (PFS) and OS in ESCC patients (p

As the penetration rate of electric vehicles (EVs) increases, how to reasonably distribute the ensuing large charging load to various charging stations is an issue that cannot be ignored. This problem can be solved by developing a suitable charging guidance strategy, the development of which needs to be based on the establishment of a realistic EV charging behaviour model and charging station queuing system. Thus, in this paper, a guidance and pricing strategy for fast charging that considers different types of EV users' willingness to charge is proposed. Firstly, the EVs are divided into two categories: private cars and online ride-hailing cars. These categories are then used to construct charging behaviour models. Based on this, a charging decision model for EV users is constructed. At the same time, a first-come-first-served (FCFS) charging station queuing system is constructed to model the real-time charging situation in the charging station in a more practical way. Finally, a dynamic tariff updating model is used to obtain the optimal time-of-use tariff for each charging station, and then the tariffs are used to guide the fast-charging demand. By comparing the spatial and temporal distribution of charging demand loads at charging stations under different scenarios and considering whether the tariffs at each charging station play a guiding role, it is verified that the proposed strategy effectively optimises the balanced distribution of EV charging loads and alleviates the congestion at charging stations. [ABSTRACT FROM AUTHOR]

Objective: The Non-targeted metabolomics technology was used to analyze the metabolites in the serum and liver of mice with chronic alcoholic liver injury (ALD), to identify and screen out the differential metabolites related to alcoholic liver injury and construct its metabolic pathway, and to explore the protective mechanism of puerarin against alcoholic liver injury in mice. Methods: The mouse model of chronic alcoholic liver injury was established by intragastric administration of 52 liquor for 8 weeks. Meanwhile, the protective effects of puerarin on ALD mice were evaluated using biochemical indexes of liver function and pathological tissue sections. Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) metabonomics technique was used to analyze the metabolites of mouse liver and serum. Multivariate statistics were used to process the data, and the variable importance projection (VIP) of the first principal component was >1 and the t-test P<0.05 was used to screen out the differential metabolites. Metabolic pathways of differential metabolites using KEGG database. Results: Puerarin could significantly improve ALT and AST levels in alcohol-induced liver injury mice (P<0.05 or P<0.01). Furthermore, the pathological section results indicated that puerarin could improve liver inflammatory cell infiltration in ALD mice. Through multivariate statistics, 11 metabolites were found in serum metabolites between the model group and the blank group. Under puerarin intervention, the levels of 11 metabolites tended to blank group, mainly related to amino acid synthesis and metabolism, glutathione metabolism, porphyrin metabolism and chlorophyll metabolism. There were 32 different metabolites between the model group and blank group in liver metabonomics, and the levels of 31 different metabolites tended to blank group under puerarin intervention, which mainly involved the amino acid synthesis and metabolism, biosynthesis of primary bile acids, purine metabolism, phosphatidylinositol signalling system, steroid metabolism and other metabolic pathways. Conclusion: Puerarin has a protective effect on alcoholic liver injury in mice, and its mechanism may be through regulating the disorder of serum and liver metabolites, which provides a valuable reference for anti-alcoholism health food in the future. [ABSTRACT FROM AUTHOR]

C36H24F12N2P2, triclinic, P1‾$\overline{1}$ (no. 2), a = 8.218(7) Å, b = 10.384(9) Å, c = 19.908(17) Å, α = 96.402(12)°, β = 91.216(12)°, γ = 101.161(12)°, V = 1655(2) Å3, Z = 2, Rgt(F) = 0.0685, wRref(F2) = 0.2188, T = 296(2) K.

Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumor that seriously threatens human health and life. With increasing studies on the mechanism of tumor immune escape, programmed death receptor 1 (PD-1) and programmed death ligand receptor 1 (PD-L1) have been proven to be involved in tumor immune escape. The primary mechanism is that PD-1 recruits protein tyrosine phosphatase (SHP-2) to dephosphorylate downstream tyrosine kinase (SyK) and phosphatidylinositol 3-kinase (PI3K), thereby inhibiting downstream protein kinase B (AKT), extracellular regulated protein kinases (ERK) and other important signaling pathways, ultimately inhibiting T cell activation. In recent years, PD-1/PD-L1 inhibitors have become popular immunotherapies. Pembrolizumab and nivolumab have been approved for HNSCC patients by the U.S. Food and Drug Administration. Both durvalumab and atezolizumab are still in clinical trials, and published data show that both have certain safety and efficacy but still need much clinical data to support them. Meanwhile, the combination of PD-1/PD-L1 inhibitors with radiotherapy, chemotherapy and immunotherapy is still controversial in terms of clinical efficacy and adverse events, and further research is needed. However, serious immune-related adverse reactions limit the clinical application of PD-1/PD-L1 inhibitors, despite promising curative effects. Therefore, developing novel inhibitors and investigating stable and effective biomarkers and upstream and downstream signaling mechanisms are urgent issues.

Abstract Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis, with an unfavorable response to palliative chemotherapy. Unfortunately, there are few effective therapeutic regimens. Therefore, we require novel treatment strategies with enhanced efficacy. The present study aimed to investigate the antitumor efficacy of APG-1252-M1, a dual inhibitor of BCL-2/BCL-XL, as a single agent and combined with gemcitabine. We applied various apoptotic assays and used subcutaneous transplanted NPC model to assess the in vitro and in vivo antitumor activity. Moreover, phospho-tyrosine kinase array was used to investigate the combined therapy’s potential synergistic mechanism. In addition, further validation was performed using immunohistochemistry and western blotting. In vitro, we observed that APG-1252-M1 had moderate antitumor activity toward NPC cells; however, it markedly improved gemcitabine’s ability to promote NPC cell apoptosis and suppress invasion, migration, and proliferation. Specifically, APG-1252 plus gemcitabine exhibited even remarkable antitumor activity in vivo. Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.

The architecture of aeroengine air-cooling system channels is notably intricate, with impingement heat transfer standing out as a critical process amidst the complexity. This study delves into the casing annular cavity's structure, examining the influence of flow and structural parameters on heat transfer characteristics. Experimental findings have revealed a trend towards more uniform temperature distributions across the impingement target plate as the relative impingement distance (H/d) increases, under a constant impingement Reynolds number (Rej). Notably, an impingement angle (β) of 90° yields optimal heat transfer effects on the target surface. Furthermore, a higher impingement hole consistency (Is) correlates with a lower and more uniform temperature distribution across the target plate. Additionally, escalating the crossflow ratio (mc/m) results in a decline in the temperature at the impingement stagnation point and a corresponding rise in the heat transfer coefficient. [ABSTRACT FROM AUTHOR]

Aims: Comorbid anxiodepressive‐like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain. Methods: After chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open‐field test, and elevated plus maze test to evaluate their anxiodepressive‐like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms. Results: Evident anxiodepressive‐like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive‐like behaviors. Conclusion: Our results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up‐regulation of HCN2 isoforms. [ABSTRACT FROM AUTHOR]

In the future, the active load of the distribution network side will be dominated by electric vehicles (EVs), showing that the charging power demand of electric vehicles will change with the change in charging electricity price. With the popularity of electric vehicles in the distribution network, their aggregation operators will play a more prominent role in pricing management and charging behavior, and setting an appropriate charging price can achieve a win–win situation for operators and electric vehicle users. At the same time, the proportion of scenery in the distribution network is relatively high, and the uncertainty of self-output has a certain impact on the pricing strategy of operators and the charging behavior of electric vehicle users, which has become an important research topic. Based on the above background, an EV operator pricing strategy considering the landscape uncertainty is proposed, a Stackelberg game model is established to maximize the respective benefits of operators and EV users, and the two-layer model is further transformed into a single-layer model through the Karush–Kuhn–Tucker (KKT) condition and duality theorem. Finally, the IEEE 33 system is simulated with the CPLEX solver, and the global optimal pricing strategy is obtained. Simulation results prove that electric vehicle operators experience a maximum profit increase of 2.6% due to the impact of maximum capacity of energy storage equipment and the uncertainty of renewable energy output can result in electric vehicle operators losing approximately 20% of their profits at most. [ABSTRACT FROM AUTHOR]