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Ketotic dairy cows exhibit a state of negative energy balance (NEB) characterized by elevated circulating levels of β-hydroxybutyrate (BHB) and fatty acids. Impaired hepatic insulin signaling in dairy cows occurs frequently during the transition into lactation, but its role on liver function during this period is not well known. In nonruminants, endoplasmic reticulum (ER) stress is a causal factor contributing to impaired insulin signaling in the liver. Thus, the aim of this study was to investigate the status of hepatic insulin and ER stress signaling and whether ER stress contributes to impaired insulin signaling in dairy cows with ketosis. Healthy (control cows, n = 10, BHB ≤0.6 mM) and ketotic (ketotic cows, n = 10, BHB ≥1.2 mM) cows at 3 to 10 d in milk were selected for liver biopsy and blood sampling before feeding. In vitro experiments were conducted with isolated hepatocytes from 5 healthy calves (1 d old, fasted female, 30-40 kg of body weight). Treatments included BHB (0, 0.9, 1.8, 3.6 mM), tauroursodeoxycholic acid (TUDCA, a canonical inhibitor of ER stress), and different incubation times (0.5, 1, 2, 3, 5, 7, 9, or 12 h). Ketotic cows had lower daily milk yield (median: 29.50 vs. 23.00 kg), higher plasma nonesterified fatty acid (NEFA) (median: 0.33 vs. 1.17 mM), BHB (median: 0.43 vs. 3.22 mM), aspartate aminotransferase (median: 70.58 vs. 155.70 U/L), alanine aminotransferase (median: 18.31 vs. 37.90 U/L), lower plasma glucose (median: 4.32 vs. 2.37 mg/dL), and revised quantitative insulin sensitivity check index (median: 0.39 vs. 0.37) compared with healthy cows. Increased abundance of phosphorylated insulin receptor substrate-1 (IRS1) and decreased abundance of phosphorylated protein kinase B (AKT) and glycogen synthase kinase-3β (GSK3β) in ketotic cows indicated a state of insulin resistance. In addition, abundance of phosphorylated protein kinase RNA-like ER kinase (PERK) and inositol requiring protein-1α (IRE1α), and cleavage of activating transcription factor-6 (ATF6) were greater in the liver of ketotic cows. In vitro, at the early stages of incubation, treatment with BHB upregulated abundance of phosphorylated of IRE1α, PERK, and the cleavage of ATF6, as well as several unfolded protein response genes [X-box-binding protein-1 (XBP1), 78 kDa glucose-regulated protein (GRP78), and C/EBP homologous protein (CHOP)]. Furthermore, in response to increasing doses of BHB, the phosphorylation level of PERK, IRE1α, and the cleavage of ATF6, and the abundance of XBP1, GRP78, and CHOP increased. In addition, BHB treatment increased phosphorylation of IRS1 and decreased phosphorylation of AKT and GSK3β, and upregulated abundance of gluconeogenic genes (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase). Importantly, these changes were reversed by inhibiting ER stress with TUDCA treatment. Overall, the present study indicated that reversing ER stress during ketosis might help alleviate hepatic insulin resistance. Targeting ER stress may represent a potential therapeutic target for controlling the negative aspects of ketosis on liver function.

Free fatty acids (FFA)-induced hepatic inflammation agravates liver injury and metabolic dysfunction in dairy cows with ketosis or fatty liver. Under stressful conditions, autophagy is generally considered as a cell protection mechanism, but whether the FFA-induced inflammatory and stress effect on hepatocytes involves an autophagy response is not well known. Thus, the objective of this study was to investigate the effects of FFA on autophagy and the role of autophagy in the activation of NF-κB (nuclear factor kappa B) signaling and NLRP3 (NLR family pyrin domain containing 3) inflammasome in calf hepatocytes. Calf hepatocytes were isolated from 3 healthy Holstein female new-born calves (1 d of age, 30-40 kg) and exposed to various concentrations of FFA (0, 0.3, 0.6, or 1.2 mM) after treatment with or without the autophagy inhibitor chloroquine (CQ) or the autophagy activator rapamycin. Expression of autophagy markers, LC3 (microtubule-associated protein 1 light chain 3) and p62 (sequestosome 1), NF-κB signaling, and NLRP3 inflammasome-related molecules were analyzed via western blot and quantitative real-time PCR. Results revealed that 0.6 and 1.2 mM FFA activated NF-κB signaling and NLRP3 inflammasome as indicated by an elevated ratio of p-NF-κB/NF-κB, protein abundance of NLRP3 and CASP1 (caspase 1), activity of CASP1, and mRNA abundance of IL1B and IL18. In addition, hepatocyte treated with 0.6 and 1.2 mM FFA or autophagy inhibitor CQ displayed increased protein abundance of p62 and LC3-II. Moreover, there was no difference in protein abundance of p62 and LC3-II between calf hepatocytes treated with 1.2 mM FFA and 1.2 mM FFA plus CQ, indicating that FFA inhibits autophagic activity in calf hepatocytes. Treatment with CQ led to overactivation of NF-κB signaling and NLRP3 inflammasome. Furthermore, CQ plus 1.2 mM FFA aggravated FFA-induced inflammation. In contrast, induction of autophagy by rapamycin ameliorated the FFA-activated NF-κB signaling and NLRP3 inflammasome as demonstrated by a lower ratio of p-NF-κB/NF-κB, protein abundance of NLRP3 and CASP1, activity of CASP1, and mRNA abundance of IL1B and IL18. Overall, inhibition of autophagy exacerbated, whereas induction of autophagy alleviated, FFA-induced inflammatory processes in calf hepatocytes, suggesting that impairment of autophagy might be partly responsible for hepatic inflammation and subsequent liver injury in dairy cows with ketosis or fatty liver. As such, regulation of autophagy may be an effective therapeutic strategy for controlling overt inflammatory responses in vivo.

Sulfur corrosion has been proven to significantly decrease the insulation performance of oil-immersed transformer and the addition of benzotriazole passivator (BTA) to insulating oil has been widely used to control the sulfur corrosion. However, the relevant studies indicate that the addition of metal passivator to oil can cause abnormal generation of dissolved gases in oil. Thus, this study further explores the effects of metal passivator degradation on the dissolved gas characteristics of oil in oil-immersed transformers. Several accelerated aging experiments on oil-paper insulations with and without BTA are conducted. The results indicate that the addition of BTA lead to the generation of abnormal dissolved gases in the oil along with an increase of stray gases, especially the increase of H 2 , CO and CO 2 . Moreover, an abnormal production of the total hydrocarbon fraction is found, which may interfere with the DGA results. Finally, the degradation of BTA related to abnormal production of stray gases in the insulating oil was preliminarily analyzed and discussed.

Using the waste basalt powder, ferric chloride (FeCl3·6H2O), ferrous sulfate (FeSO4·7H2O), 3-aminotrimethoxysilane (3-TMSPT) and Chitosan (CTS) as raw materials, through hydrothermal synthesis, in-situ synthesis, cross-linking and grafting methods, the amino-modified chitosan/magnetic zeolite composite (NH2-CTS/MZ) was prepared. The samples were characterized by SEM, XRD, VSM, BET, FTIR and XPS. The removal ability and adsorption mechanism of U(VI) in an aqueous solution by NH2-CTS/MZ were systematically studied. The results showed that under the conditions of 308 K and pH = 5, NH2-CTS/MZ reached adsorption equilibrium within 180 min, and the equilibrium adsorption capacity was 749.5 mg·g−1. The adsorption isotherm conforms to the Langmuir isotherm model (R2 = 0.998), and the adsorption kinetics conforms to the quasi-secondary kinetic model (R2 = 0.987). The adsorption behaviour is a spontaneous endothermic process. This study shows that NH2-CTS/MZ has a good application prospect in the removal of uranyl ions.

Disruption of endoplasmic reticulum (ER) homeostasis, a condition termed "ER stress," contributes to the development of liver injury in nonruminants. Because liver injury is a prominent pathological feature associated with overproduction of ketone bodies in dairy cows with ketosis, understanding the ER stress state and its functional consequences on liver injury is of particular interest. Here, 30 multiparous cows (within 3 wk postpartum) classified based on blood β-hydroxybutyrate (BHB) as healthy (n = 15, BHB0.6 mM) or clinically ketotic (n = 15, BHB3.0 mM) were used. Compared with healthy cows, ketotic cows had greater levels of serum fatty acids and activities of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ-glutamyl transferase, and glutamate dehydrogenase but lower serum glucose. Furthermore, dairy cows with ketosis had greater protein abundance of ER stress markers in liver tissue, including protein kinase RNA-like ER kinase (PERK), inositol-requiring protein-1α (IRE1α), and cleaved activating transcription factor-6 (ATF6). Cows with ketosis also had higher mRNA levels of hepatic 78-kDa glucose-regulated protein (GRP78) and spliced X-box binding protein 1 (sXBP1). These data confirmed an enhanced ER stress state in clinically ketotic cows. To explore whether enhanced hepatic ER stress was induced by elevated ketone bodies and the possible contribution of ER stress to liver injury, in vitro experiments were then performed using isolated primary calf hepatocytes treated with incremental concentrations of BHB (0, 0.6, 1.2, 3.0, and 4.8 mM) for 12 h with or without overexpression of GRP78 (the master regulator of unfolded protein response). Phosphorylation levels of PERK and IRE1α proteins, level of cleaved ATF6 protein, and mRNA abundance of GRP78 and sXBP1 in hepatocytes increased after treatment with high (3.0 and 4.8 mM) BHB, indicating a mechanistic link between excessive BHB and enhanced hepatic ER stress. Furthermore, treatment with 3.0 and 4.8 mM BHB markedly elevated activities of aspartate aminotransferase and alanine aminotransferase in cell supernatant, indicating exacerbated hepatocyte damage after ER stress was enhanced. Overexpression of GRP78 attenuated both BHB-induced ER stress and the ensuing cellular damage, suggesting that hepatocyte damage caused by excessive BHB can be mediated via enhanced ER stress. Overall, the present study revealed that ER stress may exacerbate liver injury development in clinically ketotic cows, underscoring the biological relevance of this pathway in the context of liver injury.

Sodium (Na) and potassium (K) ion batteries are promising for the next-generation energy storage equipment, but compared with lithium (Li) ion battery, their requirements for suitable host materials are much tougher, due to their large ions. 2D accordion-like MXene materials have been studied a lot as electrode materials for Na/K ion battery for their vast interlamellar spacing, but they suffer from layers’ restacking. Herein, a sandwich-like N-doped carbon nanotube@Nb2C (N-CNT@Nb2C) has been synthesized, where N-CNT fibers are sandwiched between MXene layers to fix the whole structure, enhance electrical conductivity, and increase interlamellar spacing. After nitrogen doping, carbon nanotubes own higher conductivity and sites to penetrate N-CNT walls. Consequently, N-CNT@Nb2C shows excellent electrochemical performance in Li, Na, K batteries, such as steady cycling performance for more than 500 cycles. We also test its performance with liquid K–Na alloy as anode of K ion battery. Due to the dendrite-free character of liquid anode, it exhibits better electrochemical performance than with solid K anode. The N-CNT@Nb2C promotes the finding of more suitable electrode materials for alkali ion batteries, deepens understanding of their inner mechanisms, and facilitates their commercialization.

Aim: Ivosidenib is a potent and selective small molecule inhibitor of mutant isocitrate dehydrogenase 1. Accurate measurement of ivosidenib is the key to ivosidenib pharmacokinetics in clinical trials. Materials & methods: Quantitation of ivosidenib was conducted by using a stable isotope labeled compound (ivosidenib-d4) as the internal standard. Results: This assay was validated and successfully applied to support multiple clinical trials. Selected clinical samples were also tested by a chiral LC–MS/MS method against four ivosidenib isomer standards to exclude the possibility of in vivo racemization of ivosidenib. Conclusion: A robust LC–MS/MS method was validated for ivosidenib in human plasma. This is the first time for ivosidenib bioanalytical method in any human matrix to be reported.

A low adsorption clay-resistant polycarboxylate superplasticizer (KN-PC) was synthesized using acrylic acid and isopentenol polyoxyethylene ether as the main reaction materials. The structural characterization and clay-resistant mechanism of the KN-PC were explored using Fourier transform infrared spectroscopy and X-ray diffraction, and the effect of the KN-PC on the performance of composite paste with various montmorillonite (MMT) contents was analyzed. Compared with ordinary polycarboxylate superplasticizer (PC), the KN-PC has a low sensitivity to the MMT. By the action of the MMT, the adsorption dosage of the KN-PC on the MMT is much smaller than that of the PC.

Ketosis is a common metabolic disorder in high-producing dairy cows during the peripartal period. Negative energy balance leads to increased circulating levels of nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHB), consequently increasing the risk of ketosis. It is well-known that NEFA and BHB can induce lipotoxicity and oxidative stress in bovine tissues/organs including the liver and adipose tissue. Although the mammary gland is one important site for NEFA and BHB metabolism, whether an overload in their concentrations within mammary cells causes oxidative stress during ketosis remains unclear. Thus, the present study compared oxidative stress status and mitochondrial function in mammary tissues harvested by biopsy from healthy (n = 15) and clinically ketotic (n = 15) dairy cows within 2 to 3 wk postpartum. Compared with healthy cows, ketotic cows had depressed daily milk yield (median: 28.92 vs. 21.56 kg) and dry matter intake (median: 22.36 vs. 19.92 kg/d), accompanied by elevated plasma NEFA (median: 0.32 vs. 1.26 mM), BHB (median: 0.52 vs. 3.69 mM), and lower plasma glucose (median: 4.55 vs. 2.13 mM). As detected by a commercial kit, a greater level of reactive oxygen species in mammary epithelial cells of ketotic cows, and greater oxidant indices including hydrogen peroxide and malondialdehyde coupled with lower antioxidant indices including glutathione peroxidase, catalase, and superoxide dismutase activities as detected by the respective biochemical kits in the homogenate of mammary tissue of ketotic cows indicated increased oxidative stress status. Lower citrate synthase activity and ATP production as detected by the respective commercial kits coupled with lower mRNA and protein abundance of mitochondrial respiratory chain oxidative phosphorylation complexes I-V (CO I-V) in ketotic cows suggested an impairment of mitochondrial function. This was supported by lower mRNA and protein abundance of nucleus-derived mitochondrial function regulators including peroxisome proliferator activated receptor gamma coactivator 1 α, mitofusin 2, nuclear respiratory factor 1, and mitochondrial transcription factor A. Lower mitochondrial membrane potential evaluated via the tetraethylbenzimidazolylcarbocyanine iodide (JC-1) labeling method and swollen mitochondria in mammary epithelial cells of ketotic cows suggested the existence of mitochondrial damage. Overall, the present study revealed extensive mitochondrial dysfunction and oxidative stress in the mammary gland of clinically ketotic cows. As such, data suggest that reduced milk yield in cows with ketosis is partly due to enhanced oxidative stress along with mitochondrial dysregulation in the mammary gland.

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML. The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance.

In order to solve the problem of lack of resistance of active microorganisms to the complex ion environment in the treatment of uranium-containing wastewater, the Deino-flr-2 radiation-resistant genetically engineered bacteria containing flr-2 fluorine-resistant gene was constructed and characterized. Utilizing the reductase activity of Deinococcus radiodurans (DR) itself and the enrichment of U(VI) by the surface active functional groups of the bacteria, the treatment of simulated low-concentration uranium-containing wastewater will be realized. In the most favorable conditions, accounting for approximately 90% of U(VI) was removed. The calculated data disclosed that the enrichment process of U(VI) by Deino-flr-2 well fit with the pseudo-second-order kinetic and Freundlich isotherm model.

Background: Based on the theory of “five Zang-organs corresponding to the seasons” in traditional Chinese medicine (TCM), physiological functions including emotions vary with the seasons. We aimed to investigate the seasonal photoperiod effects of melatonin (MT) released from the pineal gland on the MT receptor (MTR)-Gs/Gi-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding protein (CREB) signaling pathway in the hippocampus. Methods: Rats were divided into three groups: control, operation (surgery with pineal gland removal), and pseudo-operation groups (same surgery as operation group but without removing pineal gland), and fed at specific time across the four seasons. The levels of MTR, adenylate cyclase (AC), cAMP, PKA, and CREB in the hippocampus were analyzed using ELISA. The concentrations of Gs and Gi were analyzed using Western blot. The expression of CREB mRNA was detected by PCR. Results: For intragroup comparisons, compared with spring, the levels of Gs/Gi in the control group were higher in summer, autumn, and winter (P = .009 in summer; P

The anthocyanin synthetic pathway is regulated centrally by an MYB-bHLH-WD40 (MBW) complex. Anthocyanin pigmentation is an important fruit quality trait in red-fleshed kiwifruit; however, the underlying regulatory mechanisms involving the MBW complex are not well understood. In this study, one R2R3MYB (AcMYBF110 expressed in fruit characteristically), one bHLH (AcbHLH1), two upstream regulators of AcbHLH1 (AcbHLH4 and AcbHLH5), and one WDR (AcWDR1) are characterized as being involved in the regulation of anthocyanin synthesis in kiwifruit. AcMYBF110 plays an important role in the regulation of anthocyanin accumulation by specifically activating the promoters of several anthocyanin pathway genes including AcCHS, AcF3'H, AcANS, AcUFGT3a, AcUFGT6b, and AcGST1. Coexpression of AcbHLH1, AcbHLH4, or AcbHLH5 together with AcMYBF110 induces much greater anthocyanin accumulation in both tobacco leaves and in Actinidia arguta fruit compared with AcMYBF110 alone. Moreover, this activation is further enhanced by adding AcWDR1. We found that both AcMYBF110 and AcWDR1 interact with all three AcbHLH factors, while AcMYBF110 also interacts with AcWDR1 to form three different MBW complexes that have different regulatory roles in anthocyanin accumulation of kiwifruit. The AcMYBF110-AcbHLH1-AcWDR1 complex directly targets the promoters of anthocyanin synthetic genes. Other features of the regulatory pathways identified include promotion of AcMYBF110, AcbHLH1,and AcWDR1 activities by this MBW complex, providing for both reinforcement and feedback regulation, whereas the AcMYBF110-AcbHLH4/5-AcWDR1 complex is indirectly involved in the regulation of anthocyanin synthesis by activating the promoters of AcbHLH1 and AcWDR1 to amplify the regulation signals of the first MBW complex.

Polyhedral oligomeric silsesquioxanes (POSS) and γ-glycidoxy propyl trimethoxy silane (KH560) were applied to modify boron nitride (BN) and boron nitride whisker (BNw), and modified BN (m-BN) and m...

In this study, the antiglycation potential and mechanisms of vitexin were explored in vitro by multispectroscopy, microscope imaging, high-resolution mass spectrometry, and computational simulations. Vitexin was found to show much stronger antiglycation effects than aminoguanidine. The inhibition against the fluorescent advanced glycation end products was more than 80% at 500 μM vitexin in both bovine serum albumin (BSA)-fructose and BSA-methylglyoxal (MGO) models. Treated with 100 and 200 μM vitexin for 24 h, the contents of MGO were reduced to 4.97 and 0.2%, respectively, and only one vitexin-mono-MGO adduct was formed. LC-Orbitrap-MS/MS analysis showed that vitexin altered the glycated sites and reduced the glycation degree of some sites. The mechanisms of vitexin against protein glycation were mainly through BSA structural protection, MGO trapping, and alteration of glycation sites induced by interaction with BSA. These findings provided valuable information about the functional development of vitexin as a potential antiglycation agent.

Purpose: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight Results: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. Conclusions: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients. See related commentary by Pinato et al., p. 908

Metal oxides are more inexpensive and abundant as plasmonic materials compared with noble metals. This report shows that chemically reduced WO₃–ₓ nanosheets exhibit a localized surface plasmon resonance (LSPR) band centered at 540 nm and photocatalytic activity toward degradation of methyl orange. The methyl orange is decomposed via the reaction with plasmonic hot holes and superoxide radicals from excitation of LSPR. This work has provided evidence that plasmonic hot holes from oxides can directly react with methyl orange and play a significant role in photocatalysis. In contrast, it is well-known that plasmonic hot holes in metals are seldom reported for involvement of photocatalysis.

A symmetric battery composed of a single electrode material as both the anode and cathode is a model battery configuration owing to its distinctive advantages over the existing asymmetric ones in terms of cost, production process and safety issues. However, the limited choice of suitable electrode materials limits the practical application of high-performance symmetric batteries. Herein, we report a novel Li-rich β-Li2IrO3 (LIO) symmetric electrode material with a reversible capacity of >200 mA h g−1 between 3.0 and 4.8 V (LIO-cathode) and >300 mA h g−1 between 0.1 and 3.0 V (LIO-anode), respectively. The synthesized LIO materials manifested a unique three dimensionally (3D) ordered hyperhoneycomb-like structure that endows the material with enhanced structural integrity and stability, leading to an outstanding cycle life of both the LIO-cathode and anode. Additionally, the symmetric full lithium ion battery (LIB) using LIO as both the anode and cathode exhibited a high reversible capacity of 160 mA h g−1 between 2.0 and 4.5 V with a high working potential of 3.5 V.

Background To synthesize acetylated low anticoagulant low molecular weight heparin (ALMWH) and to detect its antineoplastic activity. Methods We obtained Low anticoagulant low molecular weight heparin (LMWH) by splitting unfractionated heparin (UFH) with sodium periodate oxidation and sodium borohydride reduction, then the LMWH was subjected to acetylate catalyzed by dicyclohexylcarbodiimide and dimethylaminopyridine to produce ALMWH. The anti-proliferative activities were determined on MDA-MB-231 human breast cancer cells in vitro. Results ALMWH exhibited stranger anti-proliferative activity Compared with LMWH, In the MDA-MB-231 cell line, the growth of MDA-MB-231 cells with IC50 of 22.16 µM at 48 h in a concentration-dependent and time-dependent manner, ALMWH produced stronger inhibitory effects especially when it was used in low concentrations. By the use of bulky catalysts, the acetylation site in the molecular chain of low molecular weight heparin with a high selectivity, the synthesis process of Low anticoagulant low molecular weight heparin can be easily controlled. Therefore, large scale industrial production can be carried out. Conclusions The synthesized ALMWH possesses a high anti-proliferative activity, Chemical modification of structure can endow LMWH with a high antiproliferative activities. ALMWH is expected to enter clinical trials due to its high druggability. Simultaneously, this study provides a basic method for screening of antineoplastic drug with low toxicity.

Introduction: Intrahepatic cholangiocarcinoma (ICC), which is difficult to diagnose and is usually fatal due to its late clinical presentation and a lack of effective treatment, has risen over the past decades but without much improvement in prognosis. Objective: The study aimed to investigate the role of apatinib that targets vascular endothelial growth factor receptor-2 (VEGFR2) in ICC. Methods: MTT assays, cell scratch assays, and tube formation assays were used to assess the effect of apatinib on human ICC cell line (HuCCT-1) and RBE cells proliferation, migration, and angiogenic capacity, respectively. Expression of vascular endothelial growth factor (VEGF), VEGFR2, signal transducer and activator of transcription factor 3 (STAT3), pSTAT3, and hypoxia inducible factor 1 subunit alpha (HIF-1α) pathway proteins was assessed using Western blotting and mRNA expression analysis in HuCCT-1 was performed using RT-qPCR assays. The pcDNA 3.1(-)-VEGFR2 and pcDNA 3.1(-)-HIF-1α were transfected into HuCCT-1 and RBE cells using Lipofectamine 2,000 to obtain overexpressed HuCCT-1 and RBE cells. Results: We found that apatinib-inhibited proliferation, migration, and angiogenesis of HuCCT-1 and RBE cells in vitro in a dose-dependent manner. We also proved that apatinib effectively inhibits angiogenesis in tumor cells by blocking the expression of VEGF and VEGFR2 in these cells. In addition, we demonstrated that apatinib regulates the expression of STAT3 phosphorylation by inhibiting VEGFR2. Finally, we showed that apatinib regulates ICC angiogenesis and HIF-1α/VEGF expression via STAT3. Conclusions: Based on the above findings, we conclude that apatinib inhibits HuCCT-1 and RBE cell proliferation, migration, and tumor angiogenesis by inhibiting the VEGFR2/STAT3/HIF-1α axis signaling pathway. Apatinib can be a promising drug for ICC-targeted molecular therapy.

Nuciferine (NF) has received extensive attention due to its medicinal value in the treatment of metabolic diseases, such as obesity; however, to date, the effects of NF on obesity-related intestinal permeability, autophagy and the gut microbiota have not been investigated. Herein, C57BL/6J mice were fed either a chow or a high-fat diet (HFD) with or without NF for 8 weeks. The results showed that NF supplement reduced weight gain, fat accumulation and intestinal permeability in the HFD mice accompanied by improved autophagy. Subsequently, an in vitro experiment was performed using Caco-2 and HT-29 cells, which showed that NF supplement not only promoted the formation of autophagosomes and autophagolysosomes, but also alleviated LPS-increased intestinal permeability. Importantly, NF supplement protected from LPS-induced paracellular permeability impairment after the administration of autophagy-related gene (Atg) 5 small-interfering RNA (siRNA). These results demonstrate that NF exerts beneficial effects on the intestinal permeability by improving autophagy. Furthermore, we also found that NF supplement lowered the abundance of Butyricimonas and increased the abundance of Akkermansia, an anti-obesity bacterium. Thus, overall, we demonstrated that NF supplement confers reduced intestinal permeability by improving autophagy and alters the composition of the gut microbiota in HFD-fed mice, thereby producing an anti-obesity effect.

Yolk-shelled silicon/carbon materials (YS-Si/C) are the most promising anode candidates to further improve the energy density of commercial lithium-ion batteries. Yet, limited conductive promotion and low tap density resulting from hollow spaces, and complex fabrication processes caused by employing various templating methods, are still critical issues for practical applications of YS-Si/C. In this work, a suite of YS-Si/C anode materials with confined Si-yolks by the C-shell without and with carbon nanotubes (each confines a Co3O4 nanoparticle on its tip) on the outer, inner and both sides of the C-shell were facilely and controllably synthesised. The best YS-Si/C anode with carbon nanotubes on both sides of the C-shell can achieve an excellent reversible capacity of 220 mAh g-1 under 40.0 A g-1 with 100% reversible capacity retention after 1200 cycles. Importantly, an electrochemical transmission electron microscope measurement system was assembled and applied for the concurrent in operando quantification of the exerted mechanical force and real-time structural responses of YS-Si/C during lithiation/delithiation and Li dendrite formation/dissolution processes, which can be used to gain new insights into the phenomenological structural changes, providing valuable guidance for the rational structural design of high-performance electrode materials.

Planewave density functional theory (DFT-PW91) calculations are employed to study the methanol synthesis through CO2 and CO hydrogenation, as well as the two side reactions: the water gas shift (WGS) reaction and formic acid formation, on Ni(110). For the WGS reaction on Ni(110), we find that the redox mechanism is favored over the carboxyl-mediated mechanism. We show that the formate pathway is the dominant one for formic acid formation. For methanol synthesis through CO2 and CO hydrogenation on Ni(110), our results reveal that the formic-acid- and dioxymethylene-mediated pathways coexist, in contrast to methanol synthesis on Cu(111) where the formic-acid-mediated pathway dominates. We also find that on Ni(110), hydrogenation of CH2O* to CH3O* and that to CH2OH* both contribute to MeOH synthesis. Based on the derived energetics, we ascertain that CH3O* hydrogenation to CH3OH* is likely the rate-determining step along the CH3O* pathway on Ni(110). Remarkably, CH3O* hydrogenation can be facilitated by the presence of HCO*, demonstrating the promotional effect of CO. We further show that CO also participates in methanol synthesis directly via its hydrogenation to HCO* and further to CH2O*. Additional microkinetic modeling by considering feed composition and reaction conditions would provide further mechanistic insights into methanol synthesis on Ni(110).

A novel adsorbent magnetic functionalized m-carboxyphenyl azo calix[4]arene symmetrical sulfide derivative (Fe3O4/M-CCSSD) was fabricated by a series of simple reactions and characterized by FT-IR and SEM. The effects on U (VI) adsorption process were investigated at several conditions. The calculated data disclose that the adsorption process of U (VI) by Fe3O4/M-CCSSD is an endothermic spontaneous process, which well fits with the pseudo-second-order kinetic and Freundlich isotherm model. In the most favorable conditions, accounting for approximately 89% of U (VI) was removed. In addition, Fe3O4/M-CCSSD showed high selectivity for U (VI) and exceptional reusability.

We present a well-designed, low-cost, and simple synthetic approach to realizing the hybrid composites of Ag nanoparticle-decorated bacterial nanocellulose (denoted as Ag-NPs@BNC) as a three-dimensional (3D) flexible surface-enhanced Raman scattering (SERS) substrate with ultrahigh SERS sensitivity, excellent signal reproducibility, and stability. The homogeneous Ag-NPs with high density were in situ grown on the networked BNC fibers by the controlled silver mirror reaction and volume shrinkage treatment, which created uniformly distributed SERS "hot spots" in the 3D networked hybrid substrate. Attributed to these unique 3D hot spots, the as-presented Ag-NPs@BNC substrates exhibited ultrahigh sensitivity and good spectral reproducibility. Moreover, the hydrophilic BNC exhibits good permeability and adsorption performances, which could capture the target molecules in the highly active hot spot areas to further improve the SERS sensitivity. As a result, not only dye molecules (rhodamine 6G) but also toxic organic pollutants such as 2-naphthalenethiol and thiram have been detected using the hybrid substrates as SERS substrates, with sensitivities of 1.6 × 10-8 and 3.8 × 10-9 M, respectively. The good linear response of the intensity and the logarithmic concentration revealed promising applications in the rapid and quantitative detection of toxic organic pollutants. Besides, this self-supported Ag-NPs@BNC substrate demonstrated good stability and flexibility for varied detection conditions. Therefore, the 3D networked, flexible, ultrasensitive, and stable Ag-NPs@BNC substrate shows potential as a versatile SERS substrate in the rapid identification of various organic molecules.

This communication describes the facile and surfactant-free synthesis of Pt3Pd icosahedral nanocrystals through propionic acid (PA)–assisted solvothermal method. The complexes of N,N-dimethylformamide (DMF) and PA play critical roles in stabilizing the icosahedral shape with {111} surfaces. Icosahedral Pt3Pd nanocrystals exhibit an impressive methanol oxidation activity and durability. The enhanced electrochemical performance is attributed to the electron effects induced by the surface strain and some steps or kinks enclosed by high energy plane of {533}, {553}, and {554}.

Aim: 2-Hydroxyglutarate (2-HG) is a target engagement biomarker in patients after treatment with inhibitors of mutated isocitrate dehydrogenase (mIDH). Accurate measurement of 2-HG is critical for monitoring the inhibition effectiveness of the inhibitors. Materials & methods: Human plasma samples were spiked with stable isotope labelled internal standard, processed by protein precipitation, and analyzed using LC–MS/MS. This method was validated following regulatory guidance and has been successfully applied in a clinical study for mIDH inhibition. Results: An LC–MS/MS method with a surrogate analyte approach was developed and validated to measure 2-HG in human plasma with acceptable intra- and inter-assay accuracy and precision. Conclusion: A sensitive and robust LC–MS/MS method was developed and validated for measuring 2-HG in human plasma.

Background Prostate cancer is characterized by aberrant lipid metabolism, including elevated fatty acid oxidation. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate-limiting step of fatty acid oxidation. This study aimed to determine if CPT1B has a critical role in prostate cancer progression and to identify its regulatory mechanism. Methods CPT1B expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases was compared with patient survival data. A tissue microarray was constructed with 60 samples of prostate cancer and immunohistochemically stained for CPT1B. Castration-resistant prostate cancer (CRPC) cell lines 22RV1 and C4-2 in which CPT1B expression had been stably knocked down were established; and cell proliferation, cell cycle distribution, and invasion were investigated by Cell Counting Kit-8 (CCK-8) and colony formation assays, flow cytometry, and Transwell assays, respectively. To examine the impact of androgen receptor (AR) inhibition on CPT1B expression, JASPAR CORE was searched to identify AR-binding sites in CPT1B. Dual luciferase and ChIP assays were performed to confirm CPT1B activity and AR binding, respectively. Differentially expressed genes (DEGs) in prostate cancer underwent gene set enrichment analysis (GSEA). Enzalutamide-resistant C4-2 cells were generated and the mechanism of enzalutamide resistance and downstream signaling pathway changes of CPT1B to C4-2 was explored through CCK-8 test. Results CPT1B expression was upregulated in human prostate cancer compared with normal prostate tissue and was associated with poor disease-free survival and overall survival. Silencing of CPT1B resulted in downregulated cell proliferation, reduced S-phase distribution, and lower invasive ability, whereas the opposite was observed in CRPC cells overexpressing CPTB1. DEGS in prostate cancer were correlated with G-protein-coupled receptor signaling, molecular transducer activity, and calcium ion binding. AR may regulate CPT1B expression and activity via specific binding sites, as confirmed by dual luciferase and ChIP assays. The CCK-8 experiment demonstrated that CPT1B overexpression in C4-2 cells did not significantly increase the ability of enzalutamide resistance. However, overexpression of CPT1B in C4-2R cells significantly increased the enzalutamide resistance. Upregulation of CPT1B expression increased AKT expression and phosphorylation. Conclusions CPT1B is upregulated in prostate cancer and is correlated with poor prognosis, indicating its potential as a biomarker. AR inhibits the transcription of CPT1B. In the CRPC cell line, overexpression of CPT1B alone cannot promote enzalutamide resistance, but in the drug-resistant line C4-2R, overexpression of CPT1B can promote the resistance of C4-2R to enzalutamide.

Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is a key regulator of energy metabolism in the liver. In nonruminants, the hepatic abundance of SIRT3 is decreased in individuals with nonalcoholic fatty liver diseases, and recovery of SIRT3 alleviates hepatic triacylglycerol (TG) deposition. However, the level of SIRT3 expression and its effects on lipid metabolism in dairy cows have not been characterized. Here we studied the hepatic expression of SIRT3 in cows with fatty liver and the role of SIRT3 in fatty acid metabolism in bovine hepatocytes. This in vivo study involved 10 healthy cows and 10 cows with fatty liver, from which we collected samples of liver tissue and blood. Primary hepatocytes were isolated from Holstein calves and treated with 0, 0.5, or 1.0 mM nonesterified fatty acids (NEFA) for 24 h or transinfected with SIRT3 overexpression adenovirus (Ad-SIRT3)/SIRT3-short interfering (si)RNA for 48 h. Cows with fatty liver displayed lower serum glucose concentrations but higher serum NEFA and β-hydroxybutyrate concentrations relative to healthy cows. Cows with fatty liver also had significant lower mRNA and protein abundance of hepatic SIRT3. Incubation of primary hepatocytes with NEFA reduced SIRT3 abundance in primary hepatocytes in a dose-dependent manner. Fatty acid (1 mM) treatment also markedly increased the abundance of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) but significantly decreased the abundance of carnitine palmitoyltransferase I (CPT1A), carnitine palmitoyltransferase II (CPT2), and acyl-CoA oxidase (ACO). Knockdown of SIRT3 by SIRT3-siRNA downregulated the mRNA abundance of CPT1A, CPT2, and ACO. In contrast, overexpression of SIRT3 by Ad-SIRT3 upregulated the mRNA abundance of CPT1A, CPT2, and ACO; downregulated the mRNA abundance of ACC1 and FAS; and consequently, decreased intracellular TG concentrations. Overexpression of SIRT3 ameliorated exogenous NEFA-induced TG accumulation by downregulating the abundance of ACC1 and FAS and upregulating the abundance of CPT1A, CPT2, and ACO in calf hepatocytes. Our data demonstrated that cows with fatty liver had lower hepatic SIRT3 contents, and an increase in SIRT3 abundance by overexpression mitigated TG deposition by modulating the expression of lipid metabolism genes in bovine hepatocytes. These data suggest a possible role of SIRT3 as a therapeutic target for fatty liver disease prevention in periparturient dairy cattle.

Background Small extracellular vesicles (sEV) secreted by mesenchymal stem cells (MSC) derived from human induced pluripotent stem cells (iPSC, iMSC-sEV) are considered to have great potential in treating ischemic diseases. Angiogenesis play an important role in post-stroke recovery. However, no studies have yet been conducted to systemically examine the effect and the underlying mechanism of iMSC-sEV on angiogenesis under brain ischemia conditions. Methods Ischemic stroke model was performed in rats induced by middle cerebral artery occlusion (MCAO), and the pro-angiogenic capacity of iMSC-sEV was measured. The in vitro effects of iMSC-sEV on the migration and tube formation of endothelial cells were investigated, respectively. Autophagy and autophagy-related signaling pathway were detected in vivo and in vitro. Results We found that iMSC-sEV significantly reduced infarct volume, enhanced angiogenesis, and alleviated long-term neurological deficits in rats after stroke. We also demonstrated that iMSC-sEV increased migration and tube formation of endothelial cells in vitro. A further mechanism study revealed that the pro-angiogenic effect of iMSC-sEV was correlated with a reduction in autophagy. Furthermore, iMSC-sEV significantly activated signal transducer and activator of transcription 3 (STAT3), and suppression of STAT3 abolished iMSC-sEV-induced inhibition of autophagy and promotion of angiogenesis in vivo and in vitro. Conclusions Taken together, our data indicate that iMSC-sEV promote angiogenesis after ischemic stroke, potentially, by inhibiting autophagy, a process that is partially dependent on STAT3 activation.

Background and purpose Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism. Experimental approach Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks. In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study. Key results C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism. Conclusion and implications These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment.

Ketosis is a metabolic disease of dairy cows often characterized by high concentrations of ketone bodies and fatty acids, but low milk protein and milk production. The Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) and the mechanistic target of rapamycin (mTOR) signaling pathways are central for the regulation of milk protein synthesis. The effect of high levels of fatty acids on these pathways and β-casein synthesis are unknown in dairy cows with clinical ketosis. Mammary gland tissue and blood samples were collected from healthy (n = 15) and clinically-ketotic (n = 15) cows. In addition, bovine mammary epithelial cells (BMEC) were treated with fatty acids, methionine (Met) or prolactin (PRL), respectively. In vivo, the serum concentration of fatty acids was greater (P > 0.05) and the percentage of milk protein (P > 0.05) was lower in cows with clinical ketosis. The JAK2-STAT5 and mTOR signaling pathways were inhibited and the abundance of β-casein was lower in mammary tissue of cows with clinical ketosis (P > 0.05). In vitro, high levels of fatty acids inhibited the JAK2-STAT5 and mTOR signaling pathways (P > 0.05) and further decreased the β-casein synthesis (P > 0.05) in BMEC. Methionine or PRL treatment, as positive regulators, activated the JAK2-STAT5 and mTOR signaling pathways to increase the β-casein synthesis. Importantly, the high concentration of fatty acids attenuated the positive effect of Met or PRL on mTOR, JAK2-STAT5 pathways and the abundance of β-casein (P > 0.05). Overall, these data indicate that the high concentrations of fatty acids that reach the mammary cells during clinical ketosis inhibit mTOR and JAK2-STAT5 signaling pathways, and further suppress β-casein synthesis.

Cisplatin resistance is one of the main obstacles in the treatment of advanced nasopharyngeal carcinoma (NPC). AKR1C1 is a member of the Aldo‐keto reductase superfamily (AKRs), which converts aldehydes and ketones to their corresponding alcohols and has been reported to be involved in chemotherapeutic resistance of multiple drugs. The expression and function of AKR1C1 in NPC have not been reported until now. The aim of this research was to investigate the expression of AKR1C1 and it is role in cisplatin resistance in NPC. AKR1C1 protein expression was detected by immunohistochemistry in human NPC tissues and by Western blot assays in NPC and immortalized nasopharyngeal epithelial cells. The effects of AKR1C1 knock‐down by siRNA on proliferation, migration and invasion in NPC cells were evaluated by CCK8, wound healing and transwell assays. To evaluate the effects of AKR1C1 silencing on cisplatin sensitivity in NPC cells, CCK8 assays were used to detect cell proliferation, flow cytometry was used to detect cell cycle distribution, and flow cytometry and DAPI staining were used to detect cell apoptosis. AKR1C1 down‐regulation was associated with advanced clinicopathological characters such as larger tumor size, more lymphatic nodes involvement, with metastasis and later clinical stages, while AKR1C1 down‐regulation was a good prognostic factor for overall survival (OS) in NPC patients. In vitro study showed that AKR1C1 was not directly involved in the malignant biological behaviours such as proliferation, cell cycle progression and migration of NPC cells, whereas AKR1C1 knock‐down could enhance cisplatin sensitivity of NPC cells. These results suggest that AKR1C1 is a potential marker for predicting cisplatin response and could serve as a molecular target to increase cisplatin sensitivity in NPC.

Non‐alcohol fatty liver disease (NAFLD) is a common disease which causes serious liver damage. Geniposide (GEN), a kind of iridoid glycoside extracted from Gardenia jasminoides fruit, has many biological effects, such as resistance to cell damage and anti‐neurodegenerative disorder. Lipid accumulation was obvious in tyloxapol‐induced liver and oil acid (OA) with palmitic acid (PA)‐induced HepG2 cells compared with the control groups while GEN improved the increasing conditions. GEN significantly lessened the total cholesterol (TC), the triglyceride (TG), low‐density lipoprotein (LDL), very low‐density lipoprotein (VLDL), myeloperoxidase (MPO), reactive oxygen species (ROS) and increased high‐density lipoprotein (HDL), superoxide dismutase (SOD) to response the oxidative stress via activating nuclear factor erythroid‐2–related factor 2 (Nrf2), haeme oxygenase (HO)‐1 and peroxisome proliferator‐activated receptor (PPAR)α which may influence the phosphorylation of adenosine 5’‐monophosphate–activated protein kinase (AMPK) signalling pathway in mice and cells. Additionally, GEN evidently decreased the contents of sterol regulatory element‐binding proteins (SREBP)‐1c, phosphorylation (P)‐mechanistic target of rapamycin complex (mTORC), P‐S6K, P‐S6 and high mobility group protein (HMGB) 1 via inhibiting the expression of phosphoinositide 3‐kinase (PI3K), and these were totally abrogated in Nrf2−/− mice. Our study firstly proved the protective effect of GEN on lipid accumulation via enhancing the ability of antioxidative stress and anti‐inflammation which were mostly depend on up‐regulating the protein expression of Nrf2/HO‐1 and AMPK signalling pathways, thereby suppressed the phosphorylation of mTORC and its related protein.

Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839). Patients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4β-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity. Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72–138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4β-hydroxycholesterol/cholesterol ratios of 119–168% at 500-mg QD ivosidenib. Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation. ClinicalTrials.gov NCT02074839.

Contamination of 99TcO4–, a problematic radioactive anion in the nuclear fuel cycle, in groundwater has been observed in a series of legacy nuclear sites, representing a notable radiation hazard an...

Hyperketonemia is a metabolic disease in dairy cows, associated with negative nutrition balance (NNB) induced by low dry matter intake (DMI) and increased nutrient requirements. Hyperketonemia could induce metabolic stress, which might indirectly affect mammary tissue. Autophagy is a highly conserved physiological process that results in the turnover of intracellular material, and is involved in maintaining cellular homeostasis under the challenge of metabolic stress induced by NNB. The aim of this study was to investigate the autophagy status and autophagy-related pathways AMP-activated kinase α (AMPKα) and mechanistic target of rapamycin (mTOR) in the mammary glands of dairy cows with hyperketonemia. Cows with hyperketonemia [CWH, n = 10, blood β-hydroxybutyrate (BHB) concentration 1.2 to 3.0 mmol/L] and cows without hyperketonemia (CWOH, n = 10, BHB1.2 mmol/L) from 3 to 12 DIM were randomly selected from the herd. The mammary tissue and blood samples were collected from these cows between 0630 and 0800 h, before feeding, at 3 to 12 d in milk. Serum concentrations of glucose, BHB, and fatty acids were determined using an autoanalyzer with commercial kits between 0630 and 0800 h, before feeding. Concentrations of fatty acids, BHB (median and interquartile range: CWH, 2.44 and 1.3, 2.82 mM; CWOH, 0.49 and 0.41, 0.57 mM), and milk fat were greater in CWH. The DMI, glucose concentration, milk production, and milk protein levels were lower in CWH. The mRNA abundance of autophagosome formation-related gene, beclin 1 (BECN1), phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), autophagy-related gene (ATG) 5, ATG7, ATG12, microtubule-associated protein 1 light chain 3 (MAP1LC3, also called LC3) and sequestosome-1 (SQSTM1, also called p62) were greater in the mammary glands of CWH. The protein abundance of LC3-II and phosphorylation level of Unc-51-like kinase 1 (ULK1) were greater in CWH, but the total ubiquitinated proteins and protein abundance of p62 were lower. Transmission electron microscopy showed an increased number of autophagosomes in the mammary glands of CWH. Furthermore, the phosphorylation of AMPKα was greater, but the phosphorylation of mTOR was lower in the mammary glands of CWH. These results indicate that activity of mTOR pathways and autophagy activity, and upregulation of AMPKα, may be response mechanisms to mitigate metabolic stress induced by hyperketonemia in the mammary glands of dairy cows.

Manganese dioxide (MnO2) with high theoretical capacity (1380 F g−1), high natural abundance and low cost has been considered as one of the most competitive active materials for preparing the electrode of supercapacitors. However, the poor electrical conductivity limits its broad applications. To solve this problem, we design a hierarchical Cu(OH)2@MnO2 core-shell nanorods array on copper foam (CF), in which the one-dimensional (1D) Cu(OH)2 nanorod core provides the scaffold for the growth of MnO2 nanosheets and a short ion and electronic diffusion pathway and the two-dimensional (2D) MnO2 nanosheets shell provides enormous active sites due to their large surface area. The obtained Cu(OH)2@MnO2/CF nanorods array displays an excellent areal capacitance of 708.62 mF cm−2 at the current density of 2 mA cm−2 (283.45 F g−1 at 0.8 A g−1). Additionally, the assembled Cu(OH)2@MnO2/CF//activated carbon (AC) asymmetric supercapacitor shows an outstanding energy density of 18.36 Wh kg−1 at a power density of 750 W kg−1. Two such capacitors connected in series can light up a red LED bulb for over fifteen minutes.

A composite biosorbent (AC-TFR) prepared by encapsulating tannin-formaldehyde resin (TFR) into calcium alginate (AC) beads was used to remove Cr(VI) from an aqueous solution. Various influencing factors, such as TFR dosage, pH, initial Cr(VI) concentration, contact time, temperature and presence of co-ions in the medium, were investigated. The structures and adsorption performances of the adsorbents were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Compared with other AC-TFR adsorbents, AC-TFR-2 (mass ratio of AC:TFR = 1:1) showed an excellent adsorption capacity based on the efficiency of Cr(VI) removal. The kinetic data fitted to pseudo-second-order and intra-particle diffusion models suggested that the adsorption process was subject to a rate-controlling step. The equilibrium adsorption data fitted well to the Langmuir isotherm model, and the maximum adsorption capacities of AC-TFR-2 were 145.99, 167.22 and 174.52 mg/g at 288, 298, and 308 K, respectively. The thermodynamic parameters revealed that Cr(VI) removal by AC-TFR-2 was endothermic and spontaneous, and the process was chemical adsorption. The mechanism of Cr(VI) removal consisted first of reduction to Cr(III), which has a low toxicity, and then chelation onto AC-TFR-2 via ion exchange.

Thermoviscosifying polymers (TVPs) are a class of promising materials for chemically enhanced oil recovery (EOR) because of their unique viscosity increment with increasing temperature. However, pr...

A novel material called m-carboxyphenyl azo calix[4]arene amine oxime derivatives (M-CCAOD) was synthesized by diazotization-coupling reaction and substitution reaction. Then the composite consisting of Fe3O4 and M-CCAOD was prepared through a facile self-assembly method. The as-synthesized Fe3O4/M-CCAOD composite was used to remove U(VI) from aqueous solutions under different conditions. The calculated data indicate that the adsorption process of uranium by Fe3O4/M-CCAOD is an exothermic spontaneous process, which well fits with the pseudo-second-order and Freundlich model. More significantly, the composite showed high selectivity for uranium and excellent reusability, demonstrating that Fe3O4/M-CCAOD may be a potential uranium adsorbent material.

Current studies on carbonate soils are mostly directed at carbonate sands rather than widely distributed carbonate gravels. In this study, a series of large-scale direct shear tests were conducted to evaluate the parameters that affect the mechanical behaviours of carbonate gravels, including the particle size, gradation, relative density and normal stress. Simultaneously, several tests on quartz gravels with similar gradations were conducted for a comparison. The experimental results showed that a large cohesion, which is defined as the interlocking cohesion in this paper, appears in carbonate gravels and it increases as the average particle size and relative density increase. The strength envelope of the carbonate gravel with an average particle size greater than or equal to 3.9 mm could be expressed as a broken-line with two straight lines in the stress range of 0–1600 kPa, but for quartz gravel, the broken-line mode appears when the average particle size reaches 7.7 mm. This result could be related to the breakage of the particles. Therefore, a certain number of gravel particles with different sizes and different shapes were coloured to trace the breakage mode of the particles. At the same time, it could be found that the strength of the carbonate gravel is not always greater than that of the quartz gravel with a similar gradation.

Chicoric acid is polyphenol of natural plant and has a variety of bioactivity. Caused by various kinds of stimulating factors, acute liver injury has high fatality rate. The effect of chicoric acid in acute liver injury induced by Lipopolysaccharide (LPS) and d‐galactosamine (d‐GalN) was investigated in this study. The results showed that CA decreased the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum and reduced the mortality induced by LPS/d‐GalN. CA can restrain mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB) to alleviate inflammation. Meanwhile, the results indicated CA can active nuclear factor‐erythroid 2‐related factor 2 (Nrf2) pathway with increasing the level of AMP‐activated protein kinase (AMPK). And with the treatment of CA, protein levels of autophagy genes were obvious improved. The results of experiments indicate that CA has protective effect in liver injury, and the activation of AMPK and autophagy may make sense.

Environmentally harmful and high-priced initiators such as azodiisobutyronitrile, perchloric acid and butyllithium are usually essential for most of the polymerization technologies such as radical, cationic and anionic polymerizations. Besides, it is also troublesome to achieve complete separation of initiators from the obtained polymers. Herein, a recyclable catalytic system for the generation of hydroxyl radicals by catalyzing hydrogen peroxide based on bi-nano-bionic enzymes (refers to the bionic enzymes constructed from two kinds of enzymes, Fe3O4@Au NPs) was successfully constructed. The magnetic and flower-like Fe3O4 NPs provided a recyclable and well-dispersed scaffold for immobilization of Au NPs, leading to enhanced catalytic activity of Au bionic enzymes. The designed catalytic system showed excellent catalytic activity for hydroxyl radical generation under various working conditions (pH 7–11, 15–100 °C). Impressively, the catalytic system was then employed as a novel initiating system (Fe3O4@Au NPs/H2O2) for reversible addition–fragmentation chain transfer (RAFT) polymerization of a wide range of functional monomers using different RAFT agents in both aqueous and organic solvents. The established initiating system provided an effective method for RAFT polymerization with a real-time control feature in a recyclable way by magnetic separation. It was found that over 93.9% catalytic activity of Fe3O4@Au was still retained after 4 consecutive operations of RAFT polymerization.