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The Regge-Teitelboim formulation of gravity, which utilizes dynamical embeddings in a background space, effectively introduces source terms in the standard Einstein equations that are not attributable to the energy-momentum tensor. We show that for a simple class of embeddings of the Robertson-Walker metric, these source terms naturally generate cosmic acceleration., 11 pages, 3 figures

Marine gravimetry provides high-quality gravity measurements, particularly in coastal areas. After the update of new sensors in GFZ’s air-marine gravimeter Chekan-AM, gravimetry measurements showed a significant improvement from the first new campaign DENEB2017 with an accuracy of 0.3/2=0.21 mGal @ 1 km along the tracks, which is at the highest accuracy level of marine gravimetry. Then, these measurements were used to assess gravity data derived from satellite altimetry (about 3 mGal) and a new finding is that a bias of −1.5 mGal exists in the study area. Additionally, ship soundings were used to assess existing seafloor topography models. We found that the accuracy of SRTM model and SIO model is at a level of 2 m, while the accuracy of the regional model EMODnet reaches the lever of sub-meters. Furthermore, a bias of 0.7 m exists and jumps above 5 m in the SRTM model near the coast of Sweden. Finally, new combined gravity anomalies with sounding data are used to reveal the fine structure of ocean topography. Our estimated seafloor topography model is more accurate than existing digital elevation data sets such as EMODnet, SRTM and SIO models and, furthermore, shows some more detailed structure of seafloor topography. The marine gravimetry and sounding measurements as well as the estimated seafloor topography are crucial for future geoid determination, 3D-navigation and resource exploration in the Baltic Sea.

With the development of network technology and the encouragement of national policies, education tends to be student-centered wisdom teaching. The use of data mining technology can extract meaningful and valuable teaching and learning information from educational big data resources, and apply the extracted information to education and teaching according to the actual teaching situation, so as to adjust the teaching plan and meet the goal of students’ intelligent learning. Based on this, this paper first briefly introduces five kinds of technologies commonly used in education big data mining, and then gives examples of smart education application system cases that have applied data mining and analytics technologies, as well as specific technologies, framework environments, toolkit and platforms, and analyzes the significance and role of data mining technology in wisdom teaching. Finally, it points out the challenges of data security, data collection and collation, data mining, large data need for colleges and universities on scale, and the tendency of big data to mystify.

Aberrant signaling from tropomyosin receptor kinases (TRKs) has been identified as the oncogenic driver in a large variety of cancers, suggesting that inhibition of TRK may be an attractive strategy of attack for anticancer therapeutics. Despite the encouraging therapeutic response to the first-generation TRK inhibitor Larotrectinib (1), the emergence of drug-resistant secondary mutations within its ATP-binding pocket cause relapse in cancer patients. A next-generation inhibitor that overcomes multiple Larotrectinib-resistant mutations is still a major “unmet clinical need”. In this study, the progressive exploration of the structure-activity relationship (SAR) through scaffold hopping, flexibilization, and fluoroalkoxy substitutions produced modifications on the reported compound 1 that led to the discovery of a superior derivative 7g. Compound 7g is a novel, orally available TRK inhibitor that showed excellent in vitro potency on a panel of Larotrectinib-resistant mutants both in biochemical and cellular assays. Compound 7g also exhibited improved in vivo antitumor efficacy in TRK wild type and mutant fusion-driven tumor xenograft models compared to the efficacy of Larotrectinib and Selitrectinib (3). These encouraging results suggest that compound 7g is a promising drug candidate to pursue for development of a TRK inhibitor to overcome clinically acquired resistance to Larotrectinib.

Fatty liver is a common metabolic disorder afflicting dairy cows during the periparturient period and is closely associated with endoplasmic reticulum (ER) stress. The onset of ER stress in humans and mice alters hepatic lipid metabolism, but it is unknown if such event contributes to fatty liver in dairy cows soon after parturition. ORAI calcium release-activated calcium modulator 1 (ORAI1) is a key component of the store-operated Ca2+ entry mechanism regulating cellular Ca2+ balance. The purpose of this study was to investigate the role of ORAI1 on hepatic lipidosis via ER stress in dairy cows. Liver tissue biopsies were collected from Holstein cows diagnosed as healthy (n = 6) or with hepatic lipidosis (n = 6). Protein and mRNA abundance of ER stress-related targets, lipogenic targets, or the transcription regulator SREBP1 and ORAI1 were greater in cows with lipidosis. In vitro, hepatocytes were isolated from four healthy female calves and used for culture with a 1.2 mM mixture of fatty acids (oleic, linoleic, palmitic, stearic, and palmitoleic acid) for various times (0, 3, 6, 9, or 12 h). As incubation time progressed, increases in concentration of Ca2+ and abundance of protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α), and activating transcription factor-6 (ATF6) protein in response to exogenous fatty acids underscored a mechanistic link among Ca2+, fatty acids, and ER stress. In a subsequent study, hepatocytes were transfected with small interfering RNA (siORAI1) or the ORAI1 inhibitor BTP2 for 48 h or 2 h followed by a challenge with the 1.2 mM mixture of fatty acids for 6 h. Compared with control group, silencing or inhibition of ORAI1 led to decreased abundance of fatty acid synthesis (FASN, SREBP1, and ACACA) and ER stress-related proteins in bovine hepatocytes. Overall, data suggested that NEFA through ORAI1 regulate intracellular Ca2+ signaling, induce ER stress, and lead to lipidosis in isolated hepatocytes.

The evaporation of a hexane lens on a distilled water surface was experimentally and theoretically studied. The formation of the hexane lens was recorded by a high-speed camera from the side to observe the variations of the contact diameters and contact angles. The experimental results showed that the shape variation of the hexane lens experienced the spreading stage and the evaporation stage. The spreading stage lasted for about 6% of the lens lifetime. For most time of the evaporation stage, the square of the lens contact radius decreased linearly with time, while the contact angle remained almost unchanged. During the final rapid evaporation stage (about 2% of the lens lifetime), the shape of the hexane lens changed and the lens shrank rapidly until it disappeared. A theoretical model based on diffusion-controlled evaporation under the constant contact angle mode was developed to describe the evaporation of the hexane lens on the water surface. In terms of geometry, the model assumes that a lens is composed of upper and lower spherical caps, and the apparent contact angle is defined based on the intersection of the two caps. The results calculated using the model were found to be in good agreement with the experimental data. Finally, the effects of initial lens volume, water temperature, and water surface deformation on lens evaporation were discussed through calculations. The results showed that increase in the water temperature and deformation of the water surface accelerated the evaporation process.

Introduction Differential metabolites (DMs) between cows with inactive ovaries (IO) and oestrous (E) cows were screened and metabolic pathways of DMs associated with IO were determined. Material and Methods Cows at 50 to 60 days (d) postpartum from an intensive dairy farm were randomly selected and allocated into an E group (n = 16) or an IO group (n = 16) according to a pedometer and rectal examinations. Their plasma samples were analysed by liquid chromatography–mass spectrometry (LC–MS) to compare plasma metabolic changes between the E and IO groups. Multivariate pattern recognition was used to screen the DMs in the plasma of IO cows. Results Compared with normal E cows, there were abnormalities in 20 metabolites in IO cows, including a significantly decreased content (VIP > 1, P < 0.05) of cholic acid, p-chlorophenylalanine, and arachidonic acid, and a significantly increased content (VIP > 1, P < 0.05) of tyramine, betaine, L-phenylalanine, L-glutamate, D-proline, L-alanine, and L-pyrophosphate. Five DMs (cholic acid, D-proline, L-glutamate, L-alanine, and L-pyroglutamic acid) with higher variable importance in projection (VIP) values between groups were validated by ELISA with blind samples of re-selected cows (IO, 50 to 60 d postpartum) and the validated results were consistent with the LC–MS results. Conclusion The 20 DMs in IO cows during the peak of lactation indicated that the pathogenesis of IO was involved in complex metabolic networks and signal transduction pathways. This study provides a basis for further exploration of the pathogenesis and prevention of IO in cows in the future.

To screen differentially expressed proteins in the blood dairy cows with inactive ovaries caused by a negative energy balance and to determine the roles of the identified proteins in the development of inactive ovaries.Holstein cows at 14 to 21 days postpartum in an intensive dairy farm were examined for their energy balance (EB) status by blood β-hydroxybutyrate (BHBA) and assigned to the inactive ovary (IO) group (n = 50) and the normal oestrus control (CON) group (n = 50) at 60 to 90 days postpartum by means of the oestrus manifestation, rectal examination and B-ultrasound examination. Fourteen differentially expressed proteins from 61 proteins in the plasma of dairy cows with IOs were identified by iTRAQ/LC-MS/MS and GO, KEGG, and PATHWAY analysis. Eleven expressed proteins were upregulated, and 3 expressed proteins were downregulated. Among the 10 differentially expressed proteins verified by Western blot or ELISA, the relative expression levels of ALDOB, IGFBP2, ITIH3 and LDHB in mixed samples and single samples were consistent with the proteomic protein results. PKM2, GPX3, ALDOB, RBP4 and AHSG were significantly different between the two groups (P P > 0.05) but were still downregulated in the ovarian resting group. This study confirmed that 14 plasma differential proteins in the inactive ovaries of postpartum dairy cows were associated with follicular development, and these findings provide a foundation for further research on the mechanism and prevention of inactive ovaries in dairy cows.

Disturbances in lipid metabolism are at the core of several health issues facing modern society, including fatty liver and obesity. The sterol regulatory element-binding protein 1 (SREBP-1) is one important transcription factor regulating lipid metabolism, but the relevant mechanism still remains unknown. The present study determined the transcriptional regulation of SREBP-1 and its target genes (including acetyl-CoA carboxylase α (accα), fatty acid synthase (fas) and stearoyl-CoA desaturase 1 (scd1)) in a freshwater teleost, grass carp Ctenopharyngodon idella. We cloned and characterised the 1988 bp, 2043 bp, 1632 bp and 1889 bp sequences of srebp-1, accα, scd1 and fas promoters, respectively. A cluster of putative binding sites of transcription factors, such as specific protein, yin yang 1, nuclear factor Y, sterol response elements (SRE) and enhancer box (E-box) element, were predicted on their promoter regions. Overexpression of nSREBP-1 reduced srebp-1 promoter activity, increased scd1 and fas promoter activity but did not influence accα promoter activity. The site-mutation and electrophoretic mobility shift assay analysis indicated that srebp-1, fas and scd1 promoters, but not accα promoter, possessed SRE. In Ctenopharyngodon idella kidney (CIK) cells of grass carp, nSREBP-1 overexpression significantly reduced srebp-1 mRNA expression and up-regulated miR-29 mRNA expression. The 3′UTR of srebp-1 possessed the potential miR-29 binding site and miR-29 up-regulated the luciferase activity of srebp-1 3′UTR and srebp-1 mRNA expression, implying a self-activating loop of SREBP-1 and miR-29 in grass carp. Based on the above-mentioned results, we found two novel transcriptional mechanisms for SREBP-1 in grass carp: (1) the auto-regulation sited on the SREBP-1 promoter regions was suppressive and (2) there was a self-activating loop of SREBP-1 and miR-29.

Photocatalysis has received tremendous attention among researchers due to its practical usage of solar energy in the field of degradation of toxic pollutants and energy harvesting. In this work, we reported an AgIn5S8/gC3N4 composite as visible light active photocatalyst for hydrogen production and toxic pollutants degradation. Furthermore, the synthesized composites were properly investigated by X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV–visible diffuse reflectance spectroscopy (UV–vis DRS) and electrochemical impedance spectroscopy (EIS) measurement. The visible light photocatalytic performance was investigated through the degradation of a cationic dye Rhodamine B (RhB) dye from aqueous solution. The photocatalytic hydrogen production results show that AgIn5S8 loaded with 25% of g-C3N4 exhibited higher hydrogen production rate than pure AgIn5S8 and g-C3N4. All the obtained outputs showed that the combination of AgIn5S8 and gC3N4 could exhibit excellent visible light response and better charge separation behaviour, which leads to better photocatalytic performance in AgIn5S8/gC3N4 composite system. Furthermore, AgIn5S8/gC3N4 composite photocatalyst retains good stability in the performance of consecutive cycle usage. The plausible mechanism of the photocatalytic reactions was also studied and explained.

Hypocalcemia in dairy cows is often associated with inflammation-related disorders such as metritis and mastitis. The protein encoded by the Ca2+ release-activated calcium modulator 1 (ORAI1) gene is a membrane Ca2+ channel subunit that is activated when Ca2+ stores are depleted. Polymorphonuclear neutrophils (PMNL) have a crucial role in the defense against infection through migration, adhesion, chemotaxis, phagocytosis, and reactive oxygen species (ROS) production in response to pathogens. Whether hypocalcemia affects the activity of PMNL and if ORAI1 is involved remains unknown. To address this, PMNL were isolated at 3 d of calving from dairy cows diagnosed as clinically healthy (n = 20, CONTROL) or with plasma concentration of calcium < 2.0 mmol/L as a criterion for diagnosis of subclinical hypocalcemia (n = 20, HYPOCAL). PMNL isolated from both groups of cows were treated with or without the sarcoendoplasmic Ca2+ ATPase inhibitor thapsigargin, Ca2+ ionophore Ionomycin, and ORAI1 blocker 2APB. The intracellular Ca2+ concentration, ORAI1 abundance, ROS, phagocytosis rate, migration, and adhering capacity of treated PMNL were evaluated. Some of the in vitro assays also included use of small interfering ORAI1 RNA (siORAI1), 100 nM 1,25(OH)2D3, or 100 nM parathyroid hormone (PTH). Intracellular Ca2+ concentration was markedly lower in HYPOCAL. In addition, ORAI1 was detected in PMNL plasma membrane via FACS and was markedly lower in cows with HYPOCAL. Migration, adhesion capacity, and phagocytosis rate of PMNL were lower in response to HYPOCAL. Furthermore, plasma and PMNL concentration of nucleosome assembly protein (NAP2) and pro-platelet basic protein (CXCL7) was markedly lower with HYPOCAL. All these changes were associated with lower ROS production by PMNL. Thapsigargin and ionomycin treatment in vitro increased ORAI1 expression, migration of PMNL, adhering capacity, phagocytosis rate, and ROS production; conversely, those effects were abrogated by siORAI1 and ORAI1 inhibitor 2APB treatment. Also cytosolic Ca2+ concentration and ORAI1 abundance were increased by 1,25(OH)2D3 and PTH supplementation. Overall, the data indicate that failure of PMNL to uptake Ca2+ due to downregulation of ORAI1 during subclinical hypocalcemia is a factor contributing to impaired PMNL function. In addition, plasma PTH or 1,25(OH)2D3 could regulate ORAI1 and also participate in the regulation of PMNL activity.

This paper studies the distributional asymptotics of the slowly changing sequence of logarithms (log b n) with b ∈ 𝕅 \ {1}. It is known that (logb n) is not uniformly distributed modulo one, and its omega limit set is composed of a family of translated exponential distributions with constant log b. An improved upper estimate ( log N / N \sqrt {\log N} /N ) is obtained for the rate of convergence with respect to (w. r. t.)the Kantorovich metric on the circle, compared to the general results on rates of convergence for a class of slowly changing sequences in the author’s companion in-progress work. Moreover, a sharp rate of convergence (log N/N)w. r. t. the Kantorovich metric on the interval [0, 1], is derived. As a byproduct, the rate of convergence w.r.t. the discrepancy metric (or the Kolmogorov metric) turns out to be (log N/N) as well, which verifies that an upper bound for this rate derived in [Ohkubo, Y.—Strauch, O.: Distribution of leading digits of numbers, Unif. Distrib. Theory, 11 (2016), no.1, 23–45.] is sharp.

Ketosis is a major metabolic disorder of high-yielding dairy cows during the transition period. Although metabolic adaptations of the adipose tissue are critical for a successful transition, beyond lipolysis, alterations within adipose tissue during ketosis are not well known. The objective of this study was to investigate the adipose tissue proteome of healthy or ketotic postpartum cows to gain insights into biological adaptations that may contribute to disease outcomes. Adipose tissue biopsy was collected on 5 healthy and 5 ketotic cows at 17 (±4) d postpartum and ketosis was defined according to the clinical symptoms and serum β-hydroxybutyrate concentration. Morphology micrographs stained by hematoxylin–eosin showed that adipocytes were smaller in ketotic cows than in healthy cows. The isobaric tag for relative and absolute quantification was applied to quantitatively identify differentially expressed proteins (DEP) in the adipose tissue. We identified a total of 924 proteins, 81 of which were differentially expressed between ketotic and healthy cows (P < 0.05 and fold changes >1.5 or

A three-dimensional unstructured-grid Finite Volume Community Ocean Model was applied to investigate the principal dispersal patterns and intraseasonal variability of the Pearl River plume in summer (June–August) during 1999–2010. The favorable forcing conditions and underlying dynamics for the formation of plume patterns were also explored. The model was validated against a suite of water level, salinity and temperature observations collected during the simulation periods. The simulated results agree well with the observed data, indicating that the model reasonably reproduces the main hydrodynamic processes occurring in the Pearl River estuary. Using Self-Organizing Maps, we extracted eight typical dispersal patterns of the Pearl River plume from the multiyear simulated daily surface salinity fields and estimated the occurrence frequency of each pattern. The eight plume patterns were further categorized into five types based on the morphologies and extension distances of each pattern, namely, west alongshore spreading, fettered spreading, offshore bulge spreading, bidirectional spreading and east offshore spreading; these five types account for 26.3%, 9.8%, 11.5%, 29.1% and 23.3% of the total occurrence frequency, respectively. The pattern that is characterized by bidirectional spreading with a strong eastward extension has the largest occurrence frequency among the eight patterns. Through an analysis of the best matching units derived from Self-Organizing Maps and the corresponding river discharge and wind conditions, we find that both wind and river discharge can significantly affect the Pearl River plume patterns. The plume orientation is mainly modulated by the wind, while the plume area and eastward extension distance are mainly affected by the river discharge. Generally, the favorable forcing conditions and underlying dynamics are different for each plume pattern, and various combinations of river discharge and wind can generate different dynamics to form different plume patterns. The climatological surface salinity field in summer shows a bidirectional structure with the plume extending westward attaching to the coast and eastward detaching from the coast. The areas and eastward extension distances of the Pearl River plume gradually decrease from June to August, affected by the intraseasonal changes in river discharge and wind. The statistical results of the daily plume patterns for June–August show that east offshore spreading, bidirectional spreading and west alongshore spreading are the primary types occurring in June, July and August, respectively. Furthermore, the occurrence frequencies of the west alongshore spreading and offshore bulge spreading increase, while the occurrence frequency of the east offshore spreading decreases from June to August.

This paper investigates the problem of attitude synchronization tracking of multiple spacecraft in the presence of limited inter-spacecraft communication, model uncertainties and external disturbances. A distributed adaptive event-triggered control scheme for attitude synchronization tracking of multiple spacecraft is proposed. In the proposed control scheme, the controllers are updated in an aperiodic manner at the event-sampled instants when a defined event-triggered error exceeds a state-dependent threshold. The inter-spacecraft communication topology in the control scheme is assumed to be undirected. The stability of the resulting closed-loop systems can be guaranteed by application of the Lyapunov function, and no accumulation of triggering instants is also ensured. Finally, simulation results are given to illustrate the effectiveness of the proposed control scheme.

A new satellite-only gravity field model entitled HUST-GOGRA2018s is developed by the combination of GRACE and GOCE data in this study. The modified dynamic approach is applied for GRACE data processing, while the space-wise least square method with a cascade filter is utilized for GOCE data processing. The GRACE-only model HUST-Grace2016s and GOCE-only model HUST-GOCE2018s are then computed, respectively. Our new developed GRACE-only model HUST-Grace2016s performs better than AIUB-GRACE03S, GGM05S, Tongji-GRACE01S at higher degrees, and the quality of our GOCE-only model HUST-GOCE2018s is also better than that of GO_CONS_GCF_2_TIM_R2 and GO_CONS_GCF_2_SPW_R2. The combination is subsequently implemented by the superposition of GRACE and GOCE full normal equations. During the combination, the optimal weight is determined by the least-squares combined adjustment method with parametric covariance approach (LS-PCA) and the spectral combination method, respectively. The comparison result demonstrates that LS-PCA is more proper for the combination. As a result, the final HUST-GOGRA2018s model is developed. Validated by external gravity field models, the results demonstrate that the HUST-GOGRA2018s is dominated by GRACE data for the spherical harmonic coefficients lower than degree 60 and GOCE data for the spherical harmonic coefficients higher than degree 150, and its performance is better than that of GOCO01S.

During the transition into lactation, bovine mammary epithelial cells (bMECs) are likely subjected to altered redox balance due to the high metabolic rate associated with the onset of lactation. In non-ruminants, lycopene (LYC), a naturally occurring hydrocarbon carotenoid, has attracted considerable attention as a potential natural agent against oxidative stress. The aim of this study was to investigate whether LYC alleviates oxidative injury in bMECs induced by H2O2 and the underlying molecular mechanisms. The primary bMEC and bovine MEC line MAC-T cells were treated with H2O2 (500 μM) and/or LYC (0.5, 1 or 2 μM) for 24 h. The results showed that treatment with LYC decreased H2O2-induced accumulation of intracellular reactive oxygen species (ROS), inflammatory cytokine (TNF-α, IL-6, and IL-1β) expression and the apoptosis rate. These effects were associated with the activation of the NFE2L2-antioxidant response element (ARE) pathway coupled with inactivation of the nuclear factor-κB (NF-κB) inflammatory and caspase/Bcl2 apoptotic pathways. The bMECs were transfected with NFE2L2 siRNA for 48 h and/or treated with H2O2 (500 μM) and/or LYC (2 μM) for another 24 h. The fact that transfection with NFE2L2 siRNA abrogated the protection of LYC against H2O2-induced accumulation of intracellular ROS, inflammatory cytokine expression and apoptosis suggested that this antioxidant transcription factor is essential for the protective mechanism induced by LYC. These results suggest that LYC might be a potent antioxidant in vivo that could be administered to ruminant animals during stressful periods such as the transition into lactation.

A multilayer approach is set up for local gravity field recovery within the framework of multi-resolution representation, where the gravity field is parameterized as the superposition of multiple layers of Poisson wavelets located at different depths beneath the Earth's surface. The layers are designed to recover gravity signals at different scales, where the shallow and deep layers mainly capture the short- and long-wavelength signals, respectively. The depths of these layers are linked to the locations of different anomaly sources beneath the Earth's surface, which are estimated by wavelet decomposition and power spectrum analysis. For testing the performance of this approach, a gravimetric quasi-geoid model over the North Sea, QGNSea V1.0, is modeled and validated against independent control data. The results show that the multilayer approach fits the gravity data better than the traditional single-layer approach, particularly in regions with topographical variation. An Akaike information criterion (AIC) test shows that the multilayer model obtains a smaller AIC value and achieves a better balance between the goodness of fit of data and the simplicity of the model. Further, an evaluation using independent GPS/leveling data tests the ability of regional models computed from different approaches towards realistic extrapolation, which shows that the accuracies of the QGNSea V1.0 derived from the multilayer approach are better by 0.4, 0.9, and 1.1 cm in the Netherlands, Belgium, and parts of Germany, respectively, than that using the single-layer approach. Further validation with existing models shows that QGNSea V1.0 is superior with respect to performance and may be beneficial for studying ocean circulation between the North Sea and its neighboring waters.

We address the leader-following tracking consensus issue for a class of linear multi-agent systems (MASs) via dynamic event-triggered (DET) approaches in this paper. The DET communication mechanism is introduced by an additional internal dynamic variable, and is developed to schedule agents’ data transmission. State observers are also employed to tackle the scenario wherein inner information of follower agents are not available for measurement. And then, state-based and observer-based distributed control proposals are proposed on the basis of dynamic event-triggered mechanism (DETM), respectively. To avoid continuous measurement information monitor, we present a technical approach for generation of the combinational information from their own neighboring agents only at event instants. The stabilities of the resulting closed-loop systems, both state-feedback one and output-feedback one, are rigorously analyzed in theory, and it is proven that all signals in the closed-loop system are bounded and Zeno behavior is also excluded. Simulation examples are presented to illustrate the theoretical claims.

In this study, the mechanisms of environmentally relevant doses of Cu and Zn mixtures influencing lipid deposition and metabolism were investigated in freshwater teleost yellow catfish Pelteobagrus fulvidraco (2 months old, 4.95 (t0.01 g, mean ± SEM). Our study indicated that waterborne Cu exposure increased lipid content, while Zn activated lipophagic flux and alleviated Cu-induced lipid accumulation. Yellow catfish hepatocytes treated with Zn or Zn + Cu activated autophagy-specific lipophagy, decreased lipid storage, and increased nonesterified fatty acid (NEFA) release, suggesting a causal relationship between lipophagy and lipid droplet (LD) breakdown under Zn and Zn + Cu conditions. Our further investigation found that Beclin1 deacetylation by sirtuin 1 (SIRT1) was required for Zn- and Zn + Cu-induced lipophagy and lipolysis, and lysine residues 427 and 434 were key sites for Beclin1 deacetylation. Taken together, these findings show that the Zn-induced deacetylation of Beclin1 promotes lipophagy as an important pathway to alleviate Cu-induced lipid accumulation in fish, which reveals a previously unidentified mechanism for understanding the antagonistic effects of Cu and Zn on metabolism at their environmentally relevant concentrations. Our results highlight the importance of combined exposure when the biological effects of heavy metals are evaluated during environmental risk assessments.

In present study, we explored the effects and the underlying mechanisms of phospholipase C (PLC) mediating glucose-induced changes in intestinal glucose transport and lipid metabolism by using U-73122 (a PLC inhibitor). We found that glucose incubation activated the PLC signal and U-73122 pre-incubation alleviated the glucose-induced increase in plcb2, plce1 and plcg1 mRNA expression. Meanwhile, U-73122 pre-treatment blunted the glucose-induced increase in sodium/glucose co-transporters 1/2 mRNA and protein expressions. U-73122 pre-treatment alleviated the glucose-induced increase in TAG content, BODIPY 493/503 fluorescence intensity, lipogenic enzymes (glucose 6-phospate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), malic enzyme and fatty acid synthase (FAS)) activity and the mRNA expressions of lipogenic genes and related transcription factors (6pgd, g6pd, fas, acca, srebp1 and carbohydrate response element-binding protein (chrebp)) in intestinal epithelial cells of yellow catfish. Further research found that U-73122 pre-incubation mitigated the glucose-induced increase in the ChREBP protein expression and the acetylation level of ChREBP in HEK293T cells. Taken together, these data demonstrated that the PLC played a major role in the glucose-induced changes of glucose transport and lipid metabolism and provide a new perspective for revealing the molecular mechanism of glucose-induced changes of intestinal glucose absorption, lipid deposition and metabolism.

Accurate prediction of dissolved oxygen time series is important for improving the water environment and aiding water resource management. In this study, four stand-alone models including multiple linear regression (MLR), support vector machine (SVM), artificial neural network (ANN) and random forest (RF), and four hybrid models based on wavelet transform (WT) including WT-MLR, WT-SVM, WT-ANN and WT-RF were used to predict the daily dissolved oxygen (DO) at 1–5-day lead times in the Dongjiang River Basin, China. To make the prediction robust, the maximal information coefficient (MIC) was used to capture comprehensive information between DO and explanatory variables. The 5-fold cross validation grid search approach was used to optimize parameters of machine learning tools. Two types of frameworks of WT: direct framework (i.e., only the explanatory variables were decomposed) and multicomponent framework (i.e., both explanatory variables and target variables were decomposed) were used to construct hybrid models. The results show that MIC extracts four optimal explanatory variables: previous DO, water temperature, air temperature and air pressure. Four evaluation parameters including correlation coefficient (R), Nash-Sutcliffe efficiency (NSE), mean absolute error (MAE) and root mean square error (RMSE) indicate that the prediction accuracy decreases as the lead time changes from 1 to 5 days. In terms of the stand-alone models, MLR model outperforms the other three models with higher NSE values of 0.616–0.921, and lower RMSE values of 0.503–1.111. With regard to the hybrid models, WT-ANN and WT-MLR models exhibit higher performance, and multicomponent framework performs better than direct framework in all hybrid models. In general, the multicomponent framework of WT can improve the prediction accuracy of stand-alone models at a certain degree, while the direct framework shows no obvious advantage.

Aloin, a naturally occurring anthraquinone glycoside derived from the Aloe species, has antioxidant and anti-inflammatory activities, but its role in non-alcoholic steatohepatitis (NASH) remains unknown. This study was designed to investigate the anti-inflammatory, antioxidant, and anti-apoptotic effects of aloin and the underlying mechanisms during NASH. Wild-type or nuclear erythroid 2-related factor 2 (Nrf2) knock-out (KO) mice were fed a choline-deficient, l-amino acid-defined, high-fat (CDAAH) diet and treated with aloin (10, 20 or 40 mg per kg bw per day) by gavage for twelve weeks. Liver and blood samples were collected to evaluate liver function, protein abundance, and histopathological status. Supplementing aloin at 20 mg kg-1 was optimal for mitigating liver damage during NASH, as evidenced by reduced alanine transaminase and aspartate aminotransferase activity in serum. Supplementation with aloin significantly reduced serum concentration or liver protein abundance of malondialdehyde, tumor necrosis factor alpha, Interleukin (IL)-1β and IL-6. Aloin treatment enhanced hepatic superoxide dismutase activity, glutathione and serum IL-10 levels in mice with NASH. Furthermore, supplementation with aloin inhibited hepatocyte apoptosis caused by Bcl-2 up-regulation and cleaved caspase-3 and Bax down-regulation. Mechanistically, by using Nrf2 KO mice, the protective effects of aloin were associated with enhanced antioxidant, anti-inflammatory and anti-apoptotic activity, all of which were mediated by Nrf2/heme oxygenase-1 (HO-1) signaling activation. Data suggested that aloin activates the Nrf2/HO-1 pathway and has protective potential against liver injury during NASH. Therefore, aloin supplementation might contribute to the prevention and treatment of NASH via activation of the Nrf2/HO-1 pathway.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment. Hyperactivation of mTOR complex 1 (mTORC1) and subsequent impairment of the transcription factor EB (TFEB)-mediated autophagy–lysosomal pathway (ALP) are implicated in the development of NAFLD. Accordingly, agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD. The objective of this study was to investigate the effects of nuciferine, a major active component from lotus leaf, on NAFLD and its underlying mechanism of action. Here we show that nuciferine activated ALP and alleviated steatosis, insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner. Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases, thereby suppressing lysosomal localization and activity of mTORC1, which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance. Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORC1–TFEB–ALP axis could represent a novel pharmacological strategy to combat NAFLD.

Background: The outbreak of the novel coronavirus disease 2019 (COVID-19) has caused global transmission, and been spread all over the world. For those regions that are currently free of infected cases, it is an urgent issue to prevent and control the local outbreak of COVID-19 when there are sporadic cases. We aimed to evaluate the effects of non-pharmaceutical interventions, such as isolation, contact tracing, and physical distancing, against local transmission of COVID-19, and to forecast the epidemic dynamics after local outbreak of diseases under different control measures. Methods: For this computational modelling study, we developed an individual-based model (IBM) to simulate the transmission dynamics of COVID-19 from a microscopic perspective of individual-to-individual contacts and heterogenous among individuals. We simulated the effects of different levels of non-pharmaceutical interventions in controlling disease transmission after the appearance of sporadic cases. Through model simulations, we discussed the epidemic dynamics and evaluated the conditions of initiating different level responses in order to achieve better controls of the local transmission. Findings: Model simulations shown that isolation of infected cases and quarantine of close contacts alone would not eliminate the local transmission of COVID-19, and there is a risk of a second wave epidemics. Quarantine the second-layer close contacts can obviously reduce the size of outbreak. Moreover, to effectively eliminate the daily new infections in a short time, it is necessary to reduce the individual-to-individual contacts. Interpretation: IBM provides a numerical representation for the local transmission of infectious diseases, the model extends the compartmental models to include individual heterogeneity and the close contacts network. Through model simulation, we quantitatively analysis the transmission patterns of COVID-19 under different control measures. Combinations of self-isolation, quarantine of close contacts, and social distancing would be necessary to block the local transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Funding Statement: This work was supported by the National Natural Science Foundation of China under grant No.11971023 and No.11871371. Declaration of Interests: The authors declare that they do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

This article studies the distributed prescribed-time coordination problem for the attitude system of multiple spacecraft subject to actuator saturation under the communication topology containing a directed spanning tree. The prescribed-time coordination requires that every spacecraft in a formation reaches an agreement state in a preset time. This preset time is set by the user and independent of any other control parameters and the initial state of spacecraft. To achieve this goal, we first design a distributed prescribed-time observer for every follower spacecraft to estimate the state of leader spacecraft. Next, a prescribed-time attitude control law is proposed by utilizing the estimated state of the leader spacecraft. In the proposed control law, an adaptive compensation law is used to compensate the input saturation. Furthermore, the prescribed-time stability of multispacecraft system subject to input saturation under the proposed scheme is analyzed in theory and simulation. The simulation results show the high reliability and effectiveness of the scheme. This work was supported by the National Natural Science Foundation of China under Grant 61873312.

Although the scale of the express industry is large, it is difficult to achieve the function of fully intelligent receiving and sending express. In this paper, the intelligent express delivery system is proposed based on the image and video processing technology of OpenCV, the Faster R-CNN object detection algorithm and other technologies. Through the depth camera and electronic scale, it can identify the object category, volume and weight of the items placed on the scale by the sender and store the video of the objects packed into the cabinet. The overall framework of the system was constructed; key technologies were applied to realize the system; the function of the system was tested. The experimental results show that it achieves the intelligent automation of delivery and delivery through the integrated express delivery system of intelligent identification and information traceability, which promotes the development of express delivery industry.

High dietary carbohydrate intake leads to lipid accumulation in the intestinal tract, but the molecular mechanism remains unknown. In the present study, using yellow catfish (Pelteobagrus fulvidraco) as a model, we found that (1) high carbohydrate diets (HCD) and high glucose (HG) increased lipid deposition, up-regulated lipogenesis and fatty acid β-oxidation, activated autophagy and induced oxidative stress in the intestinal tissues and intestinal epithelial cells (IECs); (2) lipophagy alleviated HG-induced lipid accumulation via the up-regulation of fatty acid β-oxidation; (3) Akt interacted directly with Beclin1; (4) HG suppressed Akt1 phosphorylation, downregulated Akt1-mediated phosphorylation of Beclin1, activated lipophagy and alleviated the increment of TG deposition induced by HG with S87 and S292 being the key phosphorylation residues of Beclin1 in response to HG; (5) ROS generation mediated HG-induced activation of lipophagy and HG-induced suppression of AKT phosphorylation, activated AMPK and alleviated HG-induced increase of TG deposition. Our study provides mechanistic evidence that high carbohydrate- and glucose-induced lipophagy in intestine and IECs is associated with ROS-AKT-Beclin1-dependent activation of autophagy, which alleviates glucose-induced lipid accumulation. Our findings are important since the regulation of autophagy can be used as potential molecular targets for the prevention and treatment of lipotoxicity in the intestine of vertebrates, including humans.

Enrofloxacin (ENR), one representative of fluoroquinolones widely used in husbandry, poses potential threats to aquatic organisms. However, its toxicological effect remained largely unknown. Here, we explored the influences of environmentally relevant concentration of ENR exposure on the gills of yellow catfish Pelteobagrus fulvidraco, a well-known freshwater teleost. After 10-weeks of waterborne ENR exposure at environmentally relevant concentrations, the gill tissues were collected and subsequently used for histopathology, enzyme activity, protein and mRNA expression analysis in yellow catfish. Our study revealed that waterborne ENR exposure reduced Na+/K+-ATPase activity, tight junction genes' expression and cytokines secretion, activated oxidative stress and induced apoptosis in gills. ENR exposure also activated MAPK signaling in a concentration-dependent manner. Thus, we demonstrated that environmentally relevant concentration of ENR exposure activated oxidative stress and MAPK pathway, resulted in immune dysfunction and induced intrinsic apoptosis. These results elucidated that ENR, as an environmental pollutant, had more complex toxicological effects on gills of fish than previously assessed, which provided novel insight into ENR toxicology and the assessment of its environmental risks.

This study aimed to present the characteristics of and to predict subclinical hypocalcemia in dairy cows during the transition period using blood analytes. We examined fluctuations in plasma calcium (Ca), phosphorus (P), bone metabolic markers carboxy-terminal telopeptide of type I collagen (CTX), fibroblast growth factor (FGF23), 1,25(OH)2D3, parathyroid hormone, and other blood biochemical analytes from prepartum week 2 to postpartum day 14 in 116 multiparous high-producing Holstein cows from a free-stall barn dairy farm. With a plasma concentration of Ca 0 considered as an indication of increased risk of subclinical hypocalcemia after calving. The scoring rule had an accuracy of 79.3%, sensitivity of 76.9%, and specificity of 81.3%. The plasma concentrations of FGF23, CTX, and Ca were ideal predictors of postpartum subclinical hypocalcemia in dairy cows.

Inactive ovaries (IOs) affect the estrus cycle and timed artificial insemination (TAI) efficiency in dairy cows during early lactation. The objective of the experiment was to determine metabolic changes in the serum and milk whey of dairy cows with IO and estrus. Twenty-eight healthy postpartum Holstein cows in similar age, milk production, and body condition were selected at 30 days postpartum for tracking to 70 days postpartum, and estrus performance was recorded through Afi Farm® software. The ovarian status and follicular diameter of dairy cows were examined by an experienced breeder through B-ultrasound and rectal examination. Fourteen normal estrus cows were allocated to control group A and 14 cows with IO to group B, all at 30–70 days postpartum. The serum and milk whey in the two groups of cows at 70 days postpartum were used for non-targeted nuclear magnetic resonance (1H-NMR) analysis to measure the different metabolites of cows with IO. In group B compared with group A at 70 days postpartum, there was an increase in the milk whey of six different metabolites including succinate, creatine phosphate, glycine, myo-inositol, glycolate, and orotate and a decrease in the milk whey of seven metabolites, including alanine, creatinine, o-phosphorylcholine, lactose, taurine, galactose, and glucose-1-phosphate. There was an increase in the serum of group B cows of four differential metabolites, including 3-hydroxybutyrate, acetate, glutamine, and glycine and a decrease in the serum of nine differential metabolites, including alanine, succinate, citrate, creatinine, o-phosphocholine, glucose, myo-inositol, tyrosine, and histidine compared with group A. Group B cows with IO had decreased glucose metabolism and impaired tricarboxylic acid cycle, increased lipid mobilization, and abnormal amino acid metabolism. The study provides a potential prevention strategy for IO in dairy cows in future.

Coronavirus disease 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still a pandemic around the world. Currently, specific antiviral drugs to control the epidemic remain deficient. Understanding the details of SARS-CoV-2 structural biology is extremely important for development of antiviral agents that will enable regulation of its life cycle. This review focuses on the structural biology and medicinal chemistry of various key proteins (Spike, ACE2, TMPRSS2, RdRp and Mpro) in the life cycle of SARS-CoV-2, as well as their inhibitors/drug candidates. Representative broad-spectrum antiviral drugs, especially those against the homologous virus SARS-CoV, are summarized with the expectation they will drive the development of effective, broad-spectrum inhibitors against coronaviruses. We are hopeful that this review will be a useful aid for discovery of novel, potent anti-SARS-CoV-2 drugs with excellent therapeutic results in the near future.

We present a procedure for quantizing complex projective spaces CPp,q, q≥1, as well as construct relevant star products on these spaces. The quantization is made unique with the demand that it preserves the full isometry algebra of the metric. Although the isometry algebra, namely, su(p+1,q), is preserved by the quantization, the Killing vectors generating these isometries pick up quantum corrections. The quantization procedure is an extension of one applied recently to Euclidean two-dimensional anti–de Sitter space (AdS2), where it was found that all quantum corrections to the Killing vectors vanish in the asymptotic limit, in addition to the result that the star product trivializes to pointwise product in the limit. In other words, the space is asymptotically anti–de Sitter, making it a possible candidate for the AdS/CFT correspondence principle. In this article, we find indications that the results for quantized Euclidean AdS2 can be extended to quantized CPp,q, i.e., noncommutativity is restricted to a limited neighborhood of some origin, and these quantum spaces approach CPp,q in the asymptotic limit.

Background Bovine mammary epithelial cells after calving undergo serious metabolic challenges and oxidative stress both of which could compromise autophagy. Transcription factor EB (TFEB)-mediated autophagy is an important cytoprotective mechanism against oxidative stress. However, effects of TFEB-mediated autophagy on the oxidative stress of bovine mammary epithelial cells remain unknown. Therefore, the main aim of the study was to investigate the role of TFEB-mediated autophagy in bovine mammary epithelial cells experiencing oxidative stress. Results H2O2 challenge of the bovine mammary epithelial cell MAC-T increased protein abundance of LC3-II, increased number of autophagosomes and autolysosomes while decreased protein abundance of p62. Inhibition of autophagy via bafilomycin A1 aggravated H2O2-induced reactive oxygen species (ROS) accumulation and apoptosis in MAC-T cells. Furthermore, H2O2 treatment triggered the translocation of TFEB into the nucleus. Knockdown of TFEB by siRNA reversed the effect of H2O2 on protein abundance of LC3-II and p62 as well as the number of autophagosomes and autolysosomes. Overexpression of TFEB activated autophagy and attenuated H2O2-induced ROS accumulation. Furthermore, TFEB overexpression attenuated H2O2-induced apoptosis by downregulating the caspase apoptotic pathway. Conclusions Our results indicate that activation of TFEB mediated autophagy alleviates H2O2-induced oxidative damage by reducing ROS accumulation and inhibiting caspase-dependent apoptosis.

Cardamonin (CD), a naturally occurring chalcone derived from the Alpinia species, has been shown to exert antioxidant and anti-inflammatory activity, but its role in the prevention of acetaminophen- (APAP-) induced hepatotoxicity remains elusive. The objective of this study was to determine the protective effects of CD against APAP-induced acute liver injury (ALI) and the underlying mechanisms. Wild-type or transcription factor nuclear factor erythroid 2-related factor 2- (NFE2L2-) deficient mice were treated with CD (50 or 100 mg/kg, i.p.) or vehicle for 24 h. Subsequently, these mice were challenged with APAP (400 mg/kg, i.p.) for 6 h. Liver and blood samples were collected to evaluate liver injury and protein abundance. Treatment with CD significantly reduced APAP-induced hepatotoxicity. Furthermore, CD effectively reduced APAP-induced inflammation by inhibiting high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and NOD-like receptor protein 3 (NLRP3) signaling. In addition, CD induced activation of sequestosome 1 (p62) and NFE2L2 signaling and facilitated autophagy. By applying autophagy inhibitor 3-methyladenine (3-MA; 20 mg/kg, i.p.), further mechanistic exploration revealed that NFE2L2 deficiency promoted autophagic activity induced by CD treatment, which was conducive to the hepatoprotective effect of CD against APAP-induced hepatoxicity in NFE2L2−/− mice. Overall, data suggest that CD has hepatoprotective effect against APAP-induced ALI, which might contribute to the activation of NFE2L2 and autophagy.

Preadipocyte proliferation and differentiation are critical for normal adipose tissue development, including achieving a mature phenotype, characterized by its ability to accumulate triacylglycerol and release fatty acids. In nonruminants, it is well known that all-trans retinoic acid (ATRA), the most-active form of vitamin A, helps regulate proliferation, differentiation, and apoptosis in several types of cells including adipocytes. The purpose of this study was to evaluate the effect of ATRA on proliferation, apoptosis, differentiation, and lipolysis of primary bovine adipocytes isolated from subcutaneous adipose tissue of 5 healthy Holstein cows at 17 (±4 standard deviations) d postpartum. Cells were stimulated with increasing concentrations of ATRA (0.2, 2, and 20 nM) at the preconfluent (2 d) and postconfluent (8 d) preadipocyte stage or at the mature adipocyte stage (2 d). All concentrations of ATRA inhibited preconfluent preadipocyte proliferation with decreased proportion of S-phase cells and reduced protein abundance of cyclins (CCND1, CCND2, CCND3, CCNE1) and cyclin-dependent kinases (CDK2, CDK4, CDK6). Compared with vehicle, ATRA treatment induced apoptosis in preconfluent preadipocytes. Additionally, ATRA (0.2, 2, and 20 nM) supplementation also inhibited differentiation of postconfluent preadipocytes through downregulation of protein abundance of PPARγ and C/EBPα. After induction of differentiation, basal lipolysis in mature adipocytes increased upon treatment with all concentrations of ATRA. However, data on phosphorylated hormone-sensitive lipase or PLIN1 indicated that ATRA had no effect on epinephrine-stimulated lipolysis in mature adipocytes. Overall, these results demonstrate that ATRA might inhibit lipid accumulation by suppressing preadipocyte proliferation and differentiation, subsequently leading to apoptosis in postconfluent preadipocytes and promoting basal lipolysis in mature adipocytes. Overall, these in vitro responses provide some insights into the potential for nutritional management to modulate adipose tissue lipolysis, particularly in overconditioned cows during the dry period, which are more susceptible to suffer metabolic disorders due to excessive fat mobilization postpartum.

Dysregulation in hepatic lipid synthesis by excess dietary carbohydrate intake is often relevant with the occurrence of fatty liver; therefore, the thorough understanding of the regulation of lipid deposition and metabolism seems crucial to search for potential regulatory targets. In the present study, we examined TAG accumulation, lipid metabolism-related gene expression, the enzyme activities of lipogenesis-related enzymes, the protein levels of transcription factors or genes involving lipogenesis in the livers of yellow catfish fed five dietary carbohydrate sources, such as glucose, maize starch, sucrose, potato starch and dextrin, respectively. Generally speaking, compared with other carbohydrate sources, dietary glucose promoted TAG accumulation, up-regulated lipogenic enzyme activities and gene expressions, and down-regulated mRNA expression of genes involved in lipolysis and small ubiquitin-related modifier (SUMO) modification pathways. Further studies found that sterol regulatory element binding protein 1 (SREBP1), a key transcriptional factor relevant to lipogenic regulation, was modified by SUMO1. Mutational analyses found two important sites for SUMOylation modification (K254R and K264R) in SREBP1. Mutant SREBP lacking lysine 264 up-regulated the transactivation capacity on an SREBP-responsive promoter. Glucose reduced the SUMOylation level of SREBP1 and promoted the protein expression of SREBP1 and its target gene stearoyl-CoA desaturase 1 (SCD1), indicating that SUMOylation of SREBP1 mediated glucose-induced hepatic lipid metabolism. Our study elucidated the molecular mechanism of dietary glucose increasing hepatic lipid deposition and found that the SREBP-dependent transactivation was regulated by SUMO1 modification, which served as a new target for the transcriptional programmes governing lipid metabolism.

In clinical practice, doctors usually use computed tomography angiography (CTA) to examine lower extremity atherosclerotic occlusive (ASO). Conveniently and accurately locating occlusive superficial femoral artery (SFA) which is difficult to extract from CTA can facilitate diagnosis and surgery. This paper proposed a method locating the occlusive SFA from CTA conveniently. The proposed method first takes control points at a certain interval to bicubic interpolate, and then feeds image patches generated based on the interpolation results to deep neutral network (DNN) to obtain vessel center points. The final location error is less than 9 pixels, which meets the requirements of clinical assessment accuracy. It can be used to assist the diagnosis and surgery of ASO.

New 8-chloro-2-phenyl-2,7-naphthyridin-1(2

Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-catalyzed insertion of carbenes into the O-H bond of water can be used to incorporate water into the stereogenic center, but the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we report the first highly enantioselective O-H bond insertion reactions between water and α-alkyl- and α-alkenyl-α-diazoesters as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly suppressed competing side reactions, such as β-H migration, carbene dimerization, and olefin isomerization, and thus ensured good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the phosphoric acids and phosphoramides promoted highly enantioselective [1,2]- and [1,3]-proton transfer reactions of the enol intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the original driving force to involve the proton shuttle catalysts in this process.

Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and has high rates of morbidity and mortality worldwide. Agastache rugosa (AR) possesses unique anti-oxidant, anti‑inflammatory and anti-atherosclerosis characteristics. Methods To investigate the effects and the underlying mechanism of AR on NAFLD, we fed mice a high-fat diet (HFD) to establish NAFLD model of mice in vivo experiment and induced lipidosis in AML12 hepatocytes through a challenge with free fatty acids (FFA) in vitro. The contents of total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in liver homogenates were measured. Pathological changes in liver tissue were evaluated by HE staining. Oil red O staining was used to determine degree of lipid accumulation in liver tissue, and Western blot was used to detect abundance of inflammation-, lipid metabolism- and endoplasmic reticulum stress-related proteins. Results Supply of AR alleviated accumulation of lipid in hepatocytes induced by HFD in vivo and challenged with free fatty acids (FFA) in vitro. Compared with the HFD group, supplementing AR decreased p-NF-κB/NF-κB and p-IκB/IκB protein and inhibited abundance of PERK, IRE1 and ATF6 (P P P

Adipose tissue concentration of reactive oxygen species (ROS) increases in dairy cows with ketosis, suggesting that the tissue experiences oxidative stress. Autophagy, an adaptive response to cellular stress, has been shown to promote survival and plays a critical role in antioxidant responses. Dysregulation of adenosine 5'-monophosphate-activated protein kinase (AMPK) is closely related to antioxidant responses and autophagy of adipocytes in animal models of metabolic disorders, but its role in bovine adipose tissue during periods of stress is unknown. We hypothesized that AMPK may play important roles in the regulation of oxidative stress in adipose tissue of ketotic cows. Specific objectives were to evaluate autophagy status and AMPK activity in adipose tissue of ketotic cows, and their link with oxidative stress in isolated bovine adipocytes. Selection of 15 healthy and 15 clinically ketotic Holstein cows at 17 (±4) d postpartum was performed after a thorough veterinary evaluation for clinical symptoms and also based on serum β-hydroxybutyrate concentrations before collection of subcutaneous adipose tissue samples. Primary cultures of bovine adipocytes isolated from the harvested adipose tissue were stimulated with varying concentrations of H2O2 (0, 50, 100, 200, or 400 μM) for 2 h. In another experiment, adipocytes were cultured with the AMPK activator A769662 or adenovirus-containing small interfering RNA (ad-AMPKα-siRNA) for 3 or 48 h, respectively, followed by H2O2 exposure (200 μM) for 2 h. Compared with healthy cows, clinical ketosis led to increased abundance of AMPK and nuclear factor erythroid-derived 2-like 2 (NFE2L2), but lower abundance of Kelch-like ECH-associated protein 1 (KEAP1) in adipose tissue. Abundance of the key proautophagy proteins Beclin1, sequestosome 1 (SQSTM1), autophagy-related gene 7 (ATG7), ATG5, and ratio of microtubule-associated protein light chain 3 (LC3) II to LC3I were greater in adipose tissue of ketotic cows. In bovine adipocytes, treatment with H2O2 induced accumulation of ROS and malondialdehyde (MDA), whereas H2O2 stimulation inhibited activities of the antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). Addition of AMPK activator A769662 increased antioxidant response via activating NFE2L2 and its downstream targets heme oxygenase 1 (HMOX1), superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione-S-transferase (GST) to improve H2O2-induced oxidative stress in adipocytes. Simultaneously, activation of AMPK increased abundance of Beclin1, SQSTM1, ATG7, ATG5, and ratio of LC3II to LC3I. In contrast, inhibition of AMPK downregulated abundance of NFE2L2, HMOX1, SOD1, CAT, Beclin1, SQSTM1, ATG7, ATG5, and ratio of LC3II to LC3I, and further aggravated H2O2-induced oxidative stress. Overall, these data indicate that activation of AMPK, as an adaptive mechanism for acute metabolic regulation of adipose tissue homeostasis, can induce antioxidant responses and autophagy, and further reduce oxidative stress in bovine adipocytes.

New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q.D.), compound 4r exhibits significant tumor growth inhibition (93%) in a U-87MG human gliobastoma xenograft model. The promising selectivity against VEGFR-2 and excellent tumor growth inhibition of compound 4r suggest that it could be used as a new lead molecule for further discovery of selective type II c-Met inhibitors.