Applying machine learning for multi-individual Raman spectroscopic data to identify different stages of proliferating human hepatocytes.

Cell therapy using proliferating human hepatocytes (ProliHHs) is an effective treatment approach for advanced liver diseases. However, rapid and accurate identification of high-quality ProliHHs from different donors is challenging due to individual heterogeneity. Here, we developed a machine learning framework to integrate single-cell Raman spectroscopy from multiple donors and identify different stages of ProliHHs. A repository of more than 14,000 Raman spectra, consisting of primary human hepatocytes (PHHs) and different passages of ProliHHs from six donors, was generated. Using a sliding window algorithm, potential biomarkers distinguishing the different cell stages were identified through differential analysis. Leveraging machine learning models, accurate classification of cell stages was achieved in both within-donor and cross-donor prediction tasks. Furthermore, the study assessed the relationship between donor and cell numbers and its impact on prediction accuracy, facilitating improved quality control design. A similar workflow can also be extended to encompass other cell types.

Application of femtosecond mode-locked SnTe thin films and generation of bound-state solitons.

In the realm of ultrafast laser technology, the exploration of two-dimensional materials as saturable absorbers (SA) has garnered significant research interest. Our research investigates the characteristics of SnTe thin films, a topological crystalline insulator material, as a potential saturable absorber for ultrafast lasers. Using the molecular beam epitaxy (MBE) technique, we analyze the films' morphology and composition through atomic force microscopy (AFM) and successfully deposit SnTe epilayers on Au(111)/mica substrates. Through the utilization of SnTe-SA, an erbium-doped fiber laser is fabricated, demonstrating a pulse output with a width of 276 fs and a center wavelength of 1560 nm, highlighting the potential of SnTe films in manufacturing ultrafast optical devices. Additionally, tightly bound solitons with a soliton interval of 1.01 ps are observed, contributing to the exploration of soliton nonlinear dynamics.

AhR-STAT3-HO-1/COX-2 signalling pathway may restrict ferroptosis and improve hMSC accumulation and efficacy in mouse liver.

BACKGROUND AND PURPOSE: The low efficacy of mesenchymal stem cells (MSCs) has restricted their application in the treatment of liver disease. Emerging evidence suggested that ferroptosis may provoke hepatocyte dysfunction and exacerbate damage to the liver microenvironment. Here, we have investigated the contribution of liver ferroptosis to the elimination and effectiveness of human MSC (hMSC). Furthermore, potential links between liver ferroptosis and aryl hydrocarbon receptors (AhR) were explored. EXPERIMENTAL APPROACH: Two mouse models, iron supplement-induced hepatic ferroptosis and hepatic ischaemia/reperfusion (I/R) injury, were used to identify effects of ferroptosis on hMSC pharmacokinetics (PK)/pharmacodynamics (PD). KEY RESULTS: AhR inhibition attenuated hepatic ferroptosis and improved survival of hMSCs. hMSC viability was decreased by iron supplementation or serum from I/R mice. The AhR antagonist CH223191 reversed iron overload and oxidative stress induced by ferroptosis and increased hMSC concentration and efficacy in mouse models. Effects of CH223191 were greater than those of deferoxamine, a conventional ferroptosis inhibitor. Transcriptomic results suggested that the AhR-signal transducer and activator of transcription 3 (STAT3)-haem oxygenase 1/COX-2 signalling pathway is critical to this process. These results were confirmed in a mouse model of hepatic I/R injury. In mice pre-treated with CH223191, hMSC exhibited more potent protective effects, linked to decreased hepatic ferroptosis. CONCLUSION AND IMPLICATIONS: Our findings showed that ferroptosis was a critical factor in determining the fate of hMSCs. Inhibition of AhR decreased hepatic ferroptosis, thereby increasing survival and therapeutic effects of hMSCs in mouse models of liver disease.

Human-Induced Hepatocytes-Derived Extracellular Vesicles Ameliorated Liver Fibrosis in Mice Via Suppression of TGF-ß1/Smad Signaling and Activation of Nrf2/HO-1 Signaling.

Liver fibrosis is a wound-healing response caused by persistent liver injury and often occurs in chronic liver diseases. Effective treatments for liver fibrosis are still pending. Recent studies have revealed that extracellular vesicles (EVs) derived from primary hepatocytes (Hep-EVs) have therapeutic potential for multiple liver diseases. However, Hep-EVs are difficult to manufacture in bulk because of the limited sources of primary hepatocytes. Human-induced hepatocytes (hiHep) are hepatocyte-like cells that can expand in vitro, and their cell culture supernatant is thus an almost unlimited resource for EVs. This study aimed to investigate the potential therapeutic effects of EVs derived from hiHeps. hiHep-EVs inhibited the expression of inflammatory genes and the secretion of inflammation-related cytokines, and suppressed the activation of hepatic stellate cells by inhibiting the transforming growth factor (TGF)-ß1/Smad signaling pathway. The anti-inflammatory and antifibrotic effects of hiHep-EVs were similar to those of mesenchymal stem cell-EVs. Furthermore, the administration of hiHep-EVs ameliorated oxidative stress, inflammation, and fibrosis in a CCl4-induced liver fibrosis mouse model. The expression of α smooth muscle actin, collagen I, and collagen III was reduced, which may be attributed to the regulation of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 by hiHep-EVs, and the protein expression of Nrf2, HO-1, and NQO1 was increased. Taken together, our results suggested that hiHep-EVs alleviated liver fibrosis by activating the Nrf2/HO-1 signaling pathway and inhibiting the TGF-ß1/Smad signaling pathway. This study revealed the hepatoprotective effect of hiHep-EVs, and provided a new approach to treating liver fibrosis.

[Spatio-temporal dynamics of gross primary productivity in China from 1982 to 2017 based on different datasets]. / 不同数据集的1982­2017年中国总初级生产力的时空动态.

Understanding the spatio-temporal variations of gross primary productivity (GPP) of terrestrial ecosystem and its relationship with climatic factors can provide important basis for vegetation restoration and protection. Based on meteorological data and three public GPP datasets (EC-LUE GPP, GLASS GPP, and NIRv GPP), we syste-matically analyzed the spatial-temporal variations of GPP and its response to climate change in China during 1982-2017. All the results based on the three GPP datasets showed that the annual and seasonal GPP in China increased annually from 1982 to 2017, with that in 1998 and 2002 significantly being higher than the average level during the study period, and that in 1989 and 1992 significantly being lower than the average annual GPP. From 1982 to 2017, GPP showed a significant upward trend in most regions of China, with the regions with significant increases accounting for 75.7%, 73.0%, and 69.6% of the whole study area, respectively. There was a significant positive correlation between annual GPP and precipitation and temperature, but spatial heterogeneity was strong. Among them, the regions with positive correlation between GPP and temperature were mainly distributed in Northwest and Central China, while the regions with positive correlation between GPP and precipitation were mainly distributed in North China. There was obvious spatial-temporal heterogeneity in regions that GPP being affected by temperature and precipitation in different seasons. Temperature was the limiting factor of GPP in spring, autumn and winter, while summer GPP was mainly affected by precipitation.

Responses of Forest Net Primary Productivity to Climatic Factors in China during 1982-2015.

Forest ecosystems play an important role in the global carbon cycle. Clarifying the large-scale dynamics of net primary productivity (NPP) and its correlation with climatic factors is essential for national forest ecology and management. Hence, this study aimed to explore the effects of major climatic factors on the Carnegie−Ames−Stanford Approach (CASA) model-estimated NPP of the entire forest and all its corresponding vegetation types in China from 1982 to 2015. The spatiotemporal patterns of interannual variability of forest NPP were illustrated using linear regression and geographic information system (GIS) spatial analysis. The correlations between forest NPP and climatic factors were evaluated using partial correlation analysis and sliding correlation analysis. We found that over thirty years, the average annual NPP of the forests was 887 × 1012 g C/a, and the average annual NPP per unit area was 650.73 g C/m2/a. The interannual NPP of the entire forest and all its corresponding vegetation types significantly increased (p < 0.01). The increase in the NPP of evergreen broad-leaved forests was markedly substantial among forest types. From the spatial perspective, the NPP of the entire forest vegetation gradually increased from northwest to southeast. Over the years, the proportions of the entire forest and all its corresponding vegetation types with a considerable increase in NPP were higher than those with a significant decrease, indicating, generally, improvements in forest NPP. We also found climatic factors variably affected the NPP of forests over time considering that the rise in temperature and solar radiation improved the interannual forest NPP, and the decline in precipitation diminished the forest NPP. Such varying strength of the relationship between the interannual forest NPP and climatic factors also varied across many forest types. Understanding the spatiotemporal pattern of forest NPP and its varying responses to climatic change will improve our knowledge to manage forest ecosystems and maintain their sustainability under a changing environment.

Varying Responses of Vegetation Greenness to the Diurnal Warming across the Global.

The distribution of global warming has been varying both diurnally and seasonally. Little is known about the spatiotemporal variations in the relationships between vegetation greenness and day- and night-time warming during the last decades. We investigated the global inter- and intra-annual responses of vegetation greenness to the diurnal asymmetric warming during the period of 1982-2015, using the normalized different vegetation index (NDVI, a robust proxy for vegetation greenness) obtained from the NOAA/AVHRR NDVI GIMMS3g dataset and the monthly average daily maximum (Tmax) and minimum temperature (Tmin) obtained from the gridded Climate Research Unit, University of East Anglia. Several findings were obtained: (1) The strength of the relationship between vegetation greenness and the diurnal temperature varied on inter-annual and seasonal timescales, indicating generally weakening warming effects on the vegetation activity across the global. (2) The decline in vegetation response to Tmax occurred mainly in the mid-latitudes of the world and in the high latitudes of the northern hemisphere, whereas the decline in the vegetation response to Tmin primarily concentrated in low latitudes. The percentage of areas with a significantly negative trend in the partial correlation coefficient between vegetation greenness and diurnal temperature was greater than that of the areas showing the significant positive trend. (3) The trends in the correlation between vegetation greenness and diurnal warming showed a complex spatial pattern: the majority of the study areas had undergone a significant declining strength in the vegetation greenness response to Tmax in all seasons and to Tmin in seasons except autumn. These findings are expected to have important implications for studying the diurnal asymmetry warming and its effect on the terrestrial ecosystem.

High-efficiency and low-energy ship recognition strategy based on spiking neural network in SAR images.

Ship recognition using synthetic aperture radar (SAR) images has important applications in the military and civilian fields. Aiming at the problems of the many model parameters and high-energy losses in the traditional deep learning methods for the target recognition in the SAR images, this study has proposed a high-efficiency and low-energy ship recognition strategy based on the spiking neural network (SNN) in the SAR images. First, the visual attention mechanism is used to extract the visual saliency map from the SAR image, and then the Poisson encoder is used to encode it into a spike train, which can suppress the background noise while retaining the visual saliency feature of the SAR image. Besides, an SNN model integrating the time-series information is constructed by combining the leaked and integrated firing spiking neurons with the convolutional neural network (CNN), which can use the firing frequency of the spiking neurons to realize the ship recognition in SAR images. Finally, to solve the problem that SNN model is difficult to train, the arctangent function is used as the surrogate gradient function of the spike emission function during the backpropagation. Hence, applying this backpropagation method to the training process can optimize the SNN model. The experimental results show the following: (1) the proposed strategy can more accurately recognize the ship in the SAR image, and the F1 score can reach 98.55%, which has a better recognition performance than the other traditional deep learning methods; (2) the proposed strategy has the least amount of model parameters (only 3.11MB), which is far less than the model parameters of the other traditional deep learning methods; (3) the proposed strategy has fewer operations (only 17.97M) and can reach 1/30 time of operands of the other traditional deep learning methods, which shows the high efficiency of the proposed strategy using the spike emission signals; (4) the proposed strategy has the energy loss of 1.38 × 10-6J, which can achieve the low energy advantage of nearly three orders of the magnitude compared to the other traditional deep learning methods, indicating that the proposed strategy has a significant energy efficiency.

MSCs cell fates in murine acute liver injury and chronic liver fibrosis induced by carbon tetrachloride.

Mesenchymal stem cells (MSCs) therapy has shown potential benefits in multiple diseases. However, their clinic performance is not as satisfactory as expected. This study aimed to provide an alternative explanation by comparing MSCs' fates in different liver diseases. The distribution and therapeutic effects of hMSCs were investigated in acute liver injury (ALI) and chronic liver fibrosis (CLF) mice models, respectively. The two models were induced by single or repeated injection of carbon tetrachloride (CCl4) separately. The increase of hMSCs exposure in the liver (AUCliver 0-72 h) were more significant in ALI than in CLF (177.1% vs. 96.2%). In the ALI model, the hMSCs exposures in the lung (AUClung 0-72 h) increased by nearly 50% while decreased by 60.7% in CLF. The efficacy satellite study indicated that hMSCs could significantly ameliorate liver injury in ALI, but its effects in CLF were limited. In the ALI, suppressed Natural Killer (NK) cell activities were observed, while NK cell activities were increased in CLF. The depletion of NK cells could increase hMSCs exposure in mice. For mice MSC (mMSCs), their cell fates in ALI were very similar to hMSCs in ALI: mMSCs' exposure in the liver and lung increased in ALI. In conclusion, our study revealed the distinct cell pharmacokinetic patterns of MSCs in ALI and CLF mice, which might be at least partially attributed to the different NK cell activities in the two liver diseases. This finding provided a novel insight into the varied MSCs' therapeutic efficacy in the clinic. Significance Statement Currently, there is little knowledge about the PK behavior of cell products like MSCs. This study was the first time investigating the influence of liver diseases on cell fates and efficacies of MSCs and the underneath rationale. The exposure was distinct between two representative liver disease models, which directly linked with the therapeutic performance that MSCs achieved. The difference could be attributed to the NK cells-mediated MSCs clearance.

Predicting the potential distribution of Campsis grandiflora in China under climate change.

Because the research on the geographical distribution of species significantly influences people's understanding of species protection and utilization, it is important to study the influence of climate change on plants' geographical distribution patterns. Based on 166 distribution records and 11 climate and terrain variables, we used MaxEnt (Maximum Entropy) model and ArcGIS software to predict the potential distribution of Campsis grandiflora under climate change and then determined the dominant climate variables that significantly affected its geographical distribution. In our study, the area under the curve (AUC) value of the training data was 0.939, proving the accuracy of our prediction. Under current climate conditions, the area of potentially suitable habitat is 238.29 × 104 km2, mainly distributed in northern, central, southern, and eastern China. The dominant variables that affect the geographical distribution of C. grandiflora are temperature, precipitation and altitude. In the future climate change scenario, the total area of suitable habitat and highly suitable habitat will increase, whereas the area of moderately suitable habitat and poorly suitable habitat will decrease. In addition, the centroid of the potentially suitable area of C. grandiflora will migrate to higher latitude and higher altitudes areas. The results could give strategic guidance for development, protection, and utilization of C. grandiflora in China.

Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway.

Farnesoid X receptor (FXR) plays an indispensable role in liver homeostasis and has been a promising drug target for hepatic diseases. However, the concerns of undesired biological actions limit the clinical applications of FXR agonists. To reveal the intrinsic mechanism of FXR agonist-induce hepatotoxicity, two typical FXR agonists with different structures (obeticholic acid (OCA) and Px-102) were investigated in the present study. By detecting MMP, ROS, and ATP and analyzing the fate of cells, we found that both OCA and Px-102 reduced the mitochondrial function of hepatocytes and promoted cell apoptosis. Gene ablation or inhibition of FXR or SHP ameliorated the cytotoxicities of OCA and Px-102, which indicated the adverse actions of FXR/SHP activation including down-regulation of phosphorylation of PI3K/AKT and functional hepatic genes. The dose-related injurious effects of OCA (10 mg/kg and 30 mg/kg) and Px-102 (5 mg/kg and 15 mg/kg) on the liver were confirmed on a high-fat diet mouse model. The decrease of hepatocyte-specific genes and augmenter of liver regeneration in the liver caused by OCA or Px-102 suggested an imbalance of liver regeneration and a disruption of hepatic functions. Exploration of intestinally biased FXR agonists or combination of FXR agonist with apoptosis inhibitor may be more beneficial strategies for liver diseases.

FEK self-assembled peptide hydrogels facilitate primary hepatocytes culture and pharmacokinetics screening.

A FEFEFKFK (FEK, F, phenylalaninyl; E, glutamyl; K, lysinyl)-based self-assembling peptide hydrogel (FEK-SAPH) was developed to replace sandwich culture (SC) for improved culture of primary hepatocytes in vitro. Under neutral conditions, FEK self-assembles to form ß-sheet nanofibers, which in turn form FEK-SAPH. For the culture of rat primary hepatocytes (RPH), the use of FEK-SAPH simplified operation steps and promoted excellent cell-cell interactions while maintaining the SC-related RPH polarity trend. Compared with SC, FEK-SAPH cultured RPH for 14 days, the bile duct network was formed, the secretion of albumin and urea was improved, and the metabolic clearance rate based on cytochrome P450 (CYPs) was comparable. In FEK-SAPH culture, the expression level of the biliary efflux transporter bile salt export pump increased by 230.7%, while the biliary excretion index value of deuterium-labeled sodium taurocholate (d8-TCA) differed slightly from the SC value (72% and 77%, respectively, p = .0195). The inhibitory effect of cholestasis drugs on FEK-SAPH was significantly higher than that of SC. In FEK-SAPH, hepatoprotective drugs were more effective in antagonizing hepatotoxicity induced by lithocholic acid (LCA). FEK-SAPH cultured RPH with hepatoprotective drugs can better recover from LCA-induced damage. In summary, FEK-SAPH can be used as a substitute for SC for pharmacokinetic screening to evaluate the drug absorption, disposition, metabolism, excretion, and toxicity (ADMET) in hepatocytes.

[Variation in fractional vegetation cover and its attribution analysis of different regions of Beijing-Tianjin Sand Source Region, China]. / äº¬æ´¥é£Žæ²™æºåŒºä¸åŒåˆ†åŒºæ¤è¢«è¦†ç›–åº¦å˜åŒ–åŠå½’å› åˆ†æž.

Based on the MODIS NDVI data from 2000 to 2018, we estimated the fractional vegetation cover (FVC) using the dimidiate pixel model and analyzed the spatiotemporal characteristics of FVC in the Beijing-Tianjin sand source region (BTSSR). The geographical detector model was used to estimate the impacts of natural and human factors on FVC spatial distribution at the regional scale. The results showed that the FVC of the BBTSR showed an increasing trend from 2000 to 2018, with an annual growth rate of 0.013·(10 a)-1 and a vegetation increase rate of 8.2%. The area with high FVC was concentrated in the Yanshan Mountain water source protection area, followed by the pastoral transitional zone desertified land control area and the Otindag sandy land area. The area with poor FVC was concentrated in the northern arid grassland area. The explanatory power of driving factors to FVC varied across different regions. Among the natural factors, annual precipitation was the main driving factor for the spatial distribution of FVC in the northern arid grassland area, the Otindag sandy land area and the Yanshan Mountain water source protection area. Slope was the main driving factor for the spatial distribution of FVC in the pastoral transitional zone desertified land control area. Among different human activities, the number of large livestock at the year-end was the main driving factor controlling the spatial distribution of FVC in the northern arid grassland area and the pastoral transitional zone desertified land control area, while population density was the main driving factor controlling the spatial distribution of FVC in the Otindag sandy land area and the Yanshan Mountain water source protection area. There were regional differences in the influen-ce of other factors on FVC spatial distribution. The results of the interaction detector showed that the two-factor interactions were mainly the double-synergy and nonlinear synergy. The interaction of human activities with annual precipitation and slope could more fully explain the spatial variations of FVC. The range of suitable vegetation growth identified by the risk detector was the area with annual precipitation of 316.4-486.0 mm, average relative humidity of 48.4%-57.6%, and average annual temperature of 2.5-7.9 ℃, while other driving factors were different in different zones.

Define Mesenchymal Stem Cell from Its Fate: Biodisposition of Human Mesenchymal Stem Cells in Normal and Concanavalin A-Induced Liver Injury Mice.

The pharmaceutical industry and clinical trials have been revolutionized mesenchymal stem cell-based therapeutics. However, the pharmacokinetics of transplanted cells has been little characterized in their target tissues under healthy or disease condition. A quantitative polymerase chain reaction analytical method with matrix effect was developed to track the biodistribution of human mesenchymal stem cells in normal mice and those with Concanavalin A (Con A)-induced liver injury. Mesenchymal stem/stromal cell (MSC) disposition in blood and different organs were compared, and relevant pharmacokinetic parameters were calculated. Human MSCs (hMSCs) and mouse MSCs (mMSCs) displayed a very similar pharmacokinetic profile in all tested doses: about 95% of the detected hMSCs accumulated in the lung and 3% in the liver, and almost negligible cells were detected in other tissues. A significant double peak of hMSC concentration emerged in the lung within 1-2 hours after intravenous injection, as with mMSCs. Prazosin, a vasodilator, could eliminate the second peak in the lung and increase its Cmax and area under the concentration-time curve (AUC) by 10% in the first 2 hours. The injury caused by Con A was significantly reduced by hMSCs, and the Cmax and AUC0-8 (AUC from time 0 to 8 hours) of cells in the injured liver decreased by 54 and 50%, respectively. The Cmax and AUC would be improved with the alleviation of congestion through the administration of heparin. The study provides a novel insight into the pharmacokinetics of exogenous MSCs in normal and Con A-induced liver injury mice, which provides a framework for optimizing cell transplantation. SIGNIFICANCE STATEMENT: Mesenchymal stem/stromal cells (MSCs) are known for their potential as regenerative therapies in treating several diseases, but an insufficient understanding of the pharmacokinetics of MSCs restricts their future application. The current study was the first to elucidate the pharmacokinetics and possible factors, including dosage, species, and derived sources, in a systematic way. The study further revealed that Concanavalin A-induced liver injury significantly prevented cells from entering the injury site, which could be reversed by the diminished congestion achieved by heparin.

Anti-Fibrosis Effects of Magnesium Lithospermate B in Experimental Pulmonary Fibrosis: By Inhibiting TGF-ßRI/Smad Signaling.

Pulmonary fibrosis is a severe and irreversible interstitial pulmonary disease with high mortality and few treatments. Magnesium lithospermate B (MLB) is a hydrosoluble component of Salvia miltiorrhiza and has been reported to have antifibrotic effects in other forms of tissue fibrosis. In this research, we studied the effects of MLB on pulmonary fibrosis and the underlying mechanisms. Our results indicated that MLB treatment (50 mg/kg) for seven days could attenuate bleomycin (BLM)-induced pulmonary fibrosis by reducing the alveolar structure disruption and collagen deposition in the C57 mouse model. MLB was also found to inhibit transforming growth factor-beta (TGF-ß)-stimulated myofibroblastic transdifferentiation of human lung fibroblast cell line (MRC-5) cells and collagen production by human type II alveolar epithelial cell line (A549) cells, mainly by decreasing the expression of TGF-ß receptor I (TGF-ßRI) and regulating the TGF-ß/Smad pathway. Further studies confirmed that the molecular mechanisms of MLB in BLM-induced pulmonary fibrosis mice were similar to those observed in vitro. In summary, our results demonstrated that MLB could alleviate experimental pulmonary fibrosis both in vivo and in vitro, suggesting that MLB has great potential for pulmonary fibrosis treatment.

Functional Proliferating Human Hepatocytes: In Vitro Hepatocyte Model for Drug Metabolism, Excretion, and Toxicity.

To develop a functional alternative hepatocyte model for primary human hepatocytes (PHHs) with proliferative property, essential drug metabolic, and transporter functions, proliferating human hepatocytes (ProliHHs) expanded from PHHs were fully characterized in vitro. Herein, ProliHHs generated from multiple PHHs donors could be expanded more than 200-fold within four passages and maintained their metabolic or transporter capacities partially. Furthermore, ProliHHs were able to regain the mature hepatic property after three-dimensional (3D) culture. Particularly, the downregulated mRNA expression and function of three major cytochrome P450 (P450) enzymes (CYP1A2, CYP2B6, and CYP3A4) in the proliferating process (ProliHHs-P) could be recovered by 3D culture. The metabolic variabilities across different PHHs donors could be inherited to their matured ProliHHs (ProliHHs-M). The intrinsic clearances of seven major P450 enzymes in ProliHHs-M correlated well (r = 0.87) with those in PHHs. Also, bile canaliculi structures could be observed in sandwich-cultured ProliHHs (SC-ProliHHs), and the biliary excretion index of four probe compounds [cholyl-lys-fluorescein, 5-(and-6)-carboxy-2', 7'-dichlorofluorescein diacetate (CDF), deuterium-labeled sodium taurocholate acid, and rosuvastatin] in SC-ProliHHs (>10%) were close to sandwich-cultured PHHs. More importantly, both ProliHHs-P and ProliHHs-M could be used to evaluate hepatotoxicity. Therefore, these findings demonstrated that the 3D and sandwich culture system could be used to recover the metabolic and transporter functions in ProliHHs for clearance prediction and cholestasis risk assessment, respectively. Together, ProliHHs could be a promising substitute for PHHs in drug metabolism, transport, and hepatotoxicity screening. SIGNIFICANCE STATEMENT: This report describes the study of drug metabolic capacities, efflux transporter functions, and toxicity assessments of proliferating human hepatocytes (ProliHHs). The metabolic variability in different primary human hepatocyte donors could be inherited by their matured ProliHHs derivatives. Also, ProliHHs could form canalicular networks in sandwich culture and display biliary excretion capacities. More importantly, both the proliferative and maturation statuses of ProliHHs could be used to evaluate hepatotoxicity. Together, ProliHHs were feasible to support drug candidate screening in hepatic metabolism, disposition, and toxicity.

Fabrication of Folic Acid-Decorated Hollow ZIF-8/Au/CuS Nanocomposites for Enhanced and Selective Anticancer Therapy.

Hollow nanomaterials have been used as an attractive platform for the integration of multiple bioactive components for effective anticancer therapy. Herein, we report a novel and facile strategy for the fabrication of hollow and monodispersed zeolitic imidazolate framework-8 (ZIF-8) by the self-template method with folic acid (FA) as a bioetcher. Gold nanocluster and folic acid were critical for the formation of the hollow ZIF-8 (thickness of 38 nm) during solvothermal synthesis. By integrating CuS nanoparticles (size of 4.9 nm), the resultant quadruple ZIF-8/Au/CuS/FA nanocomposites (denoted as FACZ) exhibited effective anticancer activities on FA receptor-positive MCF-7 and HepG-2 tumor cells but a weak killing effect on HCMEC/D3 cells. Folic acid molecules were conjugated to the external surface of FACZ, which simultaneously offered an excellent tumor-targeting ability and fluorescence imaging property. Although the photothermal therapy caused by CuS was not so obvious due to partial reduction, the nanosized FACZ after cellular uptake was able to release Cu(I) to enable chemodynamic therapy. This catalytically decomposed H2O2 to produce highly reactive oxygen species via the Fenton-like reaction as determined by the extracellular and intracellular hydroxyl radical. Our work offers a simple route for the fabrication of hollow ZIF-8 nanocomposite with active and selective anticancer activity. This is envisaged to have great potentials in biomedical applications.

[Quantitative analysis of the effects of human activities on vegetation in the Beijing-Tianjin sandstorm source region under the climate change].

It is of great practical significance for regional ecological management to understand the quantitative impacts of human activities on vegetation under climate change. Based on GIMMS NDVI3g data, meteorological data (temperature, precipitation) and standardized precipitation evapotranspiration index (SPEI), we used correlation analysis and trend analysis to examine the spatio-temporal variation of vegetation and its driving factors in different periods from 1982 to 2014 in the Beijing-Tianjin sandstorm source region. Regression analysis and residual analysis were used to quantify the impacts of human activities on vegetation changes in different sub-regions. The results showed that from 1982 to 2014, the degradation status in 77.1% of degraded vegetation was significantly improved and 64.1% of vegetation had an increasing trend in the study area, with mean annual NDVI decreasing from southeast to northwest. Vegetation coverage increased in 74.5% of the areas after the implementation of the Beijing-Tianjin sandstorm source control project, with mountains in northern Shanxi showing the most obvious increases. Among all the climate factors, rainfall had the strongest correlation with vegetation change. Human activities, such as ecological engineering, played an active role in most areas, especially in mountains of northern Shanxi, where the contribution of human activities reached 94.9%.

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2.

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 µmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 µmol/L. TER (5 µmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.

Responses of vegetation activity to the daytime and nighttime warming in Northwest China.

Though temperature over the past three decades has shown an asynchronous warming trend between daytime and nighttime, the response of vegetation activity to such non-uniform warming is still not very clear. In this study, the least squares linear trend analysis and geographic information system spatial analysis were conducted to analyze the spatiotemporal patterns of the daytime and nighttime warming based on the daily temperature data from 1982 to 2015 in Northwest China. The normalized difference vegetation index (NDVI) from Global Inventory Monitoring and Modeling System and vegetation type data were used to investigate the responses of vegetation activity to the daytime and nighttime warming using the partial correlation analysis. Our results suggested that (1) there was a very significant increasing trend in both daytime and nighttime temperatures in Northwest China from 1982 to 2015; night temperatures increased about 1.2 times faster than daytime temperatures, showing diurnal asymmetric warming; (2) the responses of vegetation activity to daytime and nighttime warming in Northwest China showed a distinct spatial pattern; the change in night temperatures had a more significant (positive in most regions) effect on vegetation; (3) various types of vegetation responded differently to asymmetric daytime and nighttime warming. Grassland NDVI, broad-leaved, and coniferous forest NDVI significantly responded to daytime warming. Shrub NDVI and desert NDVI significantly responded to night warming. These findings can deepen the understanding of the effects of the daytime and nighttime warming on vegetation activities in arid regions in the context of the current asymmetric warming.