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The ultrahigh‐pressure (UHP) eclogites from the Kaghan Valley in Pakistan, which formed by the deep subduction of the Indian plate beneath the Asian plate in the Eocene, contain complex metamorphic vein systems (including both isolated veins and vein networks), with mineral assemblages of epidote + quartz + kyanite + phengite ± omphacite ± garnet. The investigations on the Kaghan UHP eclogite‐vein systems provide important insights into the mechanism and timing of metamorphic dehydration, fluid flow, and fluid–rock interaction in the deeply subducted Indian continental slab as well as the chemical characteristics of slab‐derived, aqueous fluids. Abundant lawsonite pseudomorphs, characterized by prismatic aggregates of epidote, kyanite, and quartz porphyroblasts, are first recognized in the Kaghan eclogites. This observation, in combination with the occurrence of coesite pseudomorphs in epidote porphyroblasts as well as the coexistence of epidote and coesite in the eclogite zircon, indicates the previous existence of UHP lawsonite in these eclogites. Petrological studies and phase equilibrium modelling reveal clockwise P–T trajectories for the Kaghan eclogites that are featured by prograde vectors in lawsonite‐stability regions with peak conditions of 3.0–3.4 GPa/650–690°C, followed by isothermal decompression and lawsonite breakdown under UHP conditions during the initial exhumation stage. The results of metamorphic evolution, together with in situ epidote and bulk Sr isotopic analyses, indicate that the fluids responsible for vein systems are most likely derived from the breakdown of UHP lawsonite in the eclogites. SIMS U–Pb dating of metamorphic zircons from the eclogites, integrated with the Raman analysis of inclusions in zircons, indicates that the UHP dehydration of eclogites occurred at 46.4 ± 1.2 and 46.8 ± 0.9 Ma. Analyses of hydrothermal zircons from the veins yielded slightly younger ages of 44.7 ± 1.0 and 44.9 ± 1.4 Ma, which represent the timing of fluid flow and/or vein crystallization during exhumation of the UHP rocks. Mass‐balance calculation results, in combination with the vein compositions, show that the fluid flow and fluid‐eclogite interaction led to the transfer of Si, Al, Ca, K, and incompatible trace elements from the eclogites into the fluids, from which the vein systems crystallized. This study indicates cold deep subduction of Indian continental crust along low geothermal gradients (6–7°C/km). The UHP fluid liberation and channelized fluid flow occurred during the initial exhumation of the cold Indian slab and are expected to induce the transfer of H2O and incompatible trace elements from the Indian slab to the Asian lithosphere, which potentially contributes to the formation of post‐collisional magmas. Moreover, we suggest that metamorphic vein systems in UHP lawsonite eclogites offer important constraints on the occurrence and timing of fast slab exhumation in continental subduction‐collision zones. [ABSTRACT FROM AUTHOR]

Grassland and other herbaceous communities cover significant portions of Earth's terrestrial surface and provide many critical services, such as carbon sequestration, wildlife habitat, and food production. Forecasts of global change impacts on these services will require predictive tools, such as process‐based dynamic vegetation models. Yet, model representation of herbaceous communities and ecosystems lags substantially behind that of tree communities and forests. The limited representation of herbaceous communities within models arises from two important knowledge gaps: first, our empirical understanding of the principles governing herbaceous vegetation dynamics is either incomplete or does not provide mechanistic information necessary to drive herbaceous community processes with models; second, current model structure and parameterization of grass and other herbaceous plant functional types limits the ability of models to predict outcomes of competition and growth for herbaceous vegetation. In this review, we provide direction for addressing these gaps by: (1) presenting a brief history of how vegetation dynamics have been developed and incorporated into earth system models, (2) reporting on a model simulation activity to evaluate current model capability to represent herbaceous vegetation dynamics and ecosystem function, and (3) detailing several ecological properties and phenomena that should be a focus for both empiricists and modelers to improve representation of herbaceous vegetation in models. Together, empiricists and modelers can improve representation of herbaceous ecosystem processes within models. In so doing, we will greatly enhance our ability to forecast future states of the earth system, which is of high importance given the rapid rate of environmental change on our planet. [ABSTRACT FROM AUTHOR]

The parameterization of key photosynthesis parameters is one of the key uncertain sources in modeling ecosystem gross primary productivity (GPP). Solar‐induced chlorophyll fluorescence (SIF) offers a good proxy for GPP since it marks the actual process of photosynthesis; while machine learning (ML) provides a robust approach to model the GPP‐SIF relationship. Here, we trained the boosted regressing tree (BRT) and the Random Forest ML models with Greenhouse Gases Observing Satellite SIF data and in situ GPP observations from 49 eddy covariance towers. These trained ML GPP‐SIF models were fed into the Energy Exascale Earth System Model (E3SM) Land Model (ELM) to generate ELM‐simulated global SIF estimates, which were then benchmarked against satellite SIF observations with a surrogate modeling approach. Our results indicated good modeling performance of the ML‐based GPP‐SIF relationship. The ELM model when fed with the ML GPP‐SIF models also can well predict the spatial‐temporal variations in SIF. We also found high model accuracy for the surrogate modeling. Model parameter sensitivity analysis suggested that the fraction of leaf nitrogen in RuBisCO (flnr) is the most sensitive parameter to the SIF; other sensitive parameters include the Ball‐Berry stomatal conductance slope (mbbopt) and the vcmax entropy (vcmaxse). The posterior uncertainty in simulated GPP was greatly reduced after benchmarking, and the model produced improved spatial patterns of mean GPP relative to FLUXCOM GPP. Our integrated approach provides a new avenue for improving land models and using remote‐sensing SIF, which can be further improved in the future with more ground‐ and satellite‐based observations. Plain Language Summary: Model estimation of photosynthesis product, that is, gross primary productivity (GPP), is a challenging but vital task. One of the keys is to find better values for key parameters. This parameter searching process requires good proxies for GPP that can be widely available across space and time, good statistical methods to relate proxies to GPP and to make best estimations that reduce the gaps between modeled results and observations. Here, we designed a new method that use solar‐induced chlorophyll fluorescence (SIF, a good proxy for photosynthesis) as a key input, and employ machine learning (a robust way to relate SIF and GPP) and surrogate modeling (a good method for finding the best parameters), to improve the photosynthesis parameterization in the Energy Exascale Earth System Model (E3SM) Land Model (ELM), a state‐of‐the‐art terrestrial biosphere model. Our results demonstrate that this new integrated approach has great potential for improving the parameterization of key photosynthesis parameters in land models. Key Points: We built a unique method to improve gross primary productivity (GPP) modeling in land modelsThis method integrates solar‐induced chlorophyll fluorescence observations, machine learning, and surrogate modelingThe method reduced posterior uncertainties in simulated GPP and improved the modeling of its spatial patterns [ABSTRACT FROM AUTHOR]

Gradient and scale are two key concepts in ecology and evolution that are closely related but inherently distinct. While scale commonly refers to the dimensional space of a specific ecological/evolutionary (eco–evo) issue, gradient measures the range of a given variable. Gradient and scale can jointly and interactively influence eco–evo patterns. Extensive previous research investigated how changing scales may affect the observation and interpretation of eco–evo patterns; however, relatively little attention has been paid to the role of changing gradients. Here, synthesizing recent research progress, we suggest that the role of scale in the emergence of ecological patterns should be evaluated in conjunction with considering the underlying environmental gradients. This is important because, in most studies, the range of the gradient is often part of its full potential range. The difference between sampled (partial) versus potential (full) environmental gradients may profoundly impact observed eco–evo patterns and alter scale–gradient relationships. Based on observations from both field and experimental studies, we illustrate the underlying features of gradients and how they may affect observed patterns, along with the linkages of these features to scales. Since sampled gradients often do not cover their full potential ranges, we discuss how the breadth and the starting and ending positions of key gradients may affect research design and data interpretation. We then outline potential approaches and related perspectives to better integrate gradient with scale in future studies. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article Cold deep subduction of Indian continental crust and release of ultrahigh‐pressure fluid during initial exhumation: Insights from coesite‐bearing eclogite‐vein systems in Kaghan Valley, Pakistan by Shun Guo et al., https://doi.org/10.1111/jmg.12760.By Shun Guo; Anping Chen; Xirun Cai; Yi Chen; Pan Tang and Qiuli LiReported by Author; Author; Author; Author; Author; Author [Extracted from the article]

Satellite‐derived sun‐induced chlorophyll fluorescence (SIF) has been increasingly used for estimating gross primary production (GPP). However, the relationship between SIF and GPP has not been well defined, impeding the translation of satellite observed SIF to GPP. Previous studies have generally assumed a linear relationship between SIF and GPP at daily and longer time scales, but support for this assumption is lacking. Here, we used the GPP/SIF ratio to investigate seasonal variations in the relationship between SIF and GPP over the Northern Hemisphere (NH). Based on multiple SIF products and MODIS and FLUXCOM GPP data, we found strong seasonal hump‐shaped patterns for the GPP/SIF ratio over northern latitudes, with higher values in the summer than in the spring or autumn. This hump‐shaped GPP/SIF seasonal variation was confirmed by examining different SIF products and was evident for most vegetation types except evergreen broadleaf forests. The seasonal amplitude of the GPP/SIF ratio decreased from the boreal/arctic region to drylands and the tropics. For most of the NH, the lowest GPP/SIF values occurred in October or September, while the maximum GPP/SIF values were evident in June and July. The most pronounced seasonal amplitude of GPP/SIF occurred in intermediate temperature and precipitation ranges. GPP/SIF was positively related to temperature in the early and late parts of the growing season, but not during the peak growing months. These shifting relationships between temperature and GPP/SIF across different months appeared to play a key role in the seasonal dynamics of GPP/SIF. Several mechanisms may explain the patterns we observed, and future research encompassing a broad range of climate and vegetation settings is needed to improve our understanding of the spatial and temporal relationships between SIF and GPP. Nonetheless, the strong seasonal variation in GPP/SIF we identified highlights the importance of incorporating this behavior into SIF‐based GPP estimations. [ABSTRACT FROM AUTHOR]

Vegetation productivity first increases and then decreases with temperature; and temperature corresponding to the maximum productivity is called optimal temperature (Topt). In this study, we used satellite derived near‐infrared reflectance of vegetation (NIRv) data to map Topt of vegetation productivity at the spatial resolution of 0.1° on the Tibetan Plateau (TP), one of most sensitive regions in the climate system. The average Topt of non‐forest vegetation on the TP is about 14.7°C, significantly lower than the Topt value used in current ecosystem models. A remarkable geographical heterogeneity in Topt is observed over the TP. Higher Topt values generally appear in the north‐eastern TP, while the south‐western TP has relatively lower Topt (<10°C), in line with the difference of climate conditions and topography across different regions. Spatially, Topt tends to decrease by 0.41°C per 100 m increase in elevation, faster than the elevational elapse rate of growing season temperature, implying a potential CO2 regulation of Topt in addition to temperature acclimation. Topt increases by 0.66°C for each 1°C of rising mean annual temperature as a result of vegetation acclimation to climate change. However, at least at the decadal scale, there is no significant change in Topt between 2000s and 2010s, suggesting that the Topt climate acclimation may not keep up with the warming rate. Finally, future (2091–2100) warming could be close to and even surpass Topt on the TP under different RCP scenarios without considering potential climate acclimation. Our analyses imply that the temperature tipping point when the impact of future warming shifts from positive to negative on the TP is greatly overestimated by current vegetation models. Future research needs to include varying thermal and CO2 acclimation effects on Topt across different time scales in vegetation models. [ABSTRACT FROM AUTHOR]

Effective use of solar‐induced chlorophyll fluorescence (SIF) to estimate and monitor gross primary production (GPP) in terrestrial ecosystems requires a comprehensive understanding and quantification of the relationship between SIF and GPP. To date, this understanding is incomplete and somewhat controversial in the literature. Here we derived the GPP/SIF ratio from multiple data sources as a diagnostic metric to explore its global‐scale patterns of spatial variation and potential climatic dependence. We found that the growing season GPP/SIF ratio varied substantially across global land surfaces, with the highest ratios consistently found in boreal regions. Spatial variation in GPP/SIF was strongly modulated by climate variables. The most striking pattern was a consistent decrease in GPP/SIF from cold‐and‐wet climates to hot‐and‐dry climates. We propose that the reduction in GPP/SIF with decreasing moisture availability may be related to stomatal responses to aridity. Furthermore, we show that GPP/SIF can be empirically modeled from climate variables using a machine learning (random forest) framework, which can improve the modeling of ecosystem production and quantify its uncertainty in global terrestrial biosphere models. Our results point to the need for targeted field and experimental studies to better understand the patterns observed and to improve the modeling of the relationship between SIF and GPP over broad scales. [ABSTRACT FROM AUTHOR]

There is a large literature examining the effects of agglomeration on income distribution but less is known about its effects in developing countries. In this study, we apply panel data from a microfirm‐level survey and from city‐level data to investigate whether there is a causal relationship between agglomeration and establishment wage dispersion in China. Given the potential endogeneity of city size, we employ an instrumental variable regression approach. We find strong evidence that agglomeration has significant effects on wage inequality in the short and long run. The link between agglomeration and wage inequality is heterogeneous across regions. The spatially varying results appear to be due to different stages of development. Our results are consistent with the sorting models in that it appears that the most productive and least productive firms are relatively thriving in coastal cities, but not inland. [ABSTRACT FROM AUTHOR]

Reactive gaseous nitrogen (Ngr) emissions significantly affect Earth's climate system. Disagreement exists, however, over Ngr contributions to short‐ versus long‐term climate forcing, from local to global scales and among different gaseous forms, including NH3, NOx, and N2O. Here, we provide a comprehensive inventory of Ngr from China's croplands based on a new bottom‐up, mass flow‐based approach integrated with fine‐resolution agricultural activity data and nitrogen emission factors. We demonstrate that China's croplands emit about 8.87 Tg N to the atmosphere in 2014. Across different prefectures, Ngr emission per capita conforms to a "Kuznets curve," that is, first increases then decreases, along the gradient of increasing urbanization. Ngr emission per gross domestic productivity (GDP) decreases exponentially with increasing urbanization or per capita GDP. Furthermore, climate change impact analyses suggest that the global‐scale warming effect of China's cropland N2O emissions dominate over local cooling effects ascribed to its NH3 and NOx emissions. Plain Language Summary: Reactive gaseous nitrogen, sourced to the world's highest fertilizer application rates in China, imparts local cooling effects on short time scales. The effects are ultimately counterbalanced by nitrous oxide emissions over the long term, leading to substantial warming effects on the global climate system. We base our conclusion on the first‐ever high‐resolution assessment of reactive nitrogen emissions to the atmosphere from China's croplands. Owing to limited high‐resolution reactive gaseous nitrogen emissions data, hitherto, large uncertainties have existed in the detailing the role of China's cropland reactive gaseous nitrogen emissions on climate forcing. This paucity of information poses a challenge for informing China's agricultural sustainability policies with regard to maintaining/increasing agricultural yields while reduces reactive gaseous nitrogen emissions and their warming potential. Our analyses provide essential information for further sustainable N management and the interactions between agriculture and climate change. We provide policy‐relevant information for mitigation targets, including the 2°C limit goal set by the 2015 Paris Agreement of the United Nations Framework Convention on Climate Change, enabling progress related to multiple United Nations Sustainable Development Goals. Key Points: We provide new high‐resolution estimates of reactive gaseous nitrogen (Ngr) emissions from China's croplands and their seasonal dynamicsAcross different prefectures, Ngr emission per capita follows an environmental Kuznets curve against urbanization rateThe overall warming effect of N2O emissions dominate over local cooling effects ascribed to NH3 and NOx emissions each year [ABSTRACT FROM AUTHOR]

Since 2007, China's growth has fallen from around 10% to about 6%–7% per annum. This paper investigates the experience of this slowdown at the provincial level. We use a vector‐autoregressive modelling approach and annual data from 1978 to decompose each province's growth into various factors. We find that (a) all provinces experienced the slowdown; (b) there is considerable variation in this experience across provinces; (c) national factors dominate the provincial slowdown while province‐specific factors explain most of the interprovincial variation; (d) when the national factor is separated into supply and demand components, the supply component dominates. [ABSTRACT FROM AUTHOR]

The 400-year natural history of a tropical coastal mangrove-fringed lagoon: What can we learn? Coastal lagoon ecosystems are important natural carbon sinks but are threatened by both climate change and direct human disturbances. Enhancing carbon sequestration and reducing soil erosion of the hinterland ecosystem may decrease the carbon sink of lagoon ecosystems, but can provide long-term increases in carbon sequestration and ecosystem services of the coupled hinterland-lagoon ecosystems. [Extracted from the article]

An introduction is presented in which the editor discusses various reports within the issue on topics including volatility of Chinese economic activities, globalization and industrial performance in China, and regional disparities and productivity in China.

China has promised large cuts in CO2 emissions by 2020, which is likely to have differential effects across regions. We know little about the regional effects of pollution reduction. We make a contribution to filling this gap using a small theoretical model with two regions, features of the Chinese economy and the right to emit CO2 as a factor of production. We find regionally differentiated effects on income, welfare and output and explore government policies designed to reduce these effects. The effects of fiscal policies depend crucially on whether one or both regions respond and on whether output or welfare is targeted. Boosts to productive capacity do better in terms of output but not welfare. [ABSTRACT FROM AUTHOR]

The sensitivity of vegetation productivity to precipitation (Sppt) is a key metric for understanding the variations in vegetation productivity under changing precipitation and predicting future changes in ecosystem functions. However, a comprehensive assessment of Sppt over all the global land is lacking. Here, we investigated spatial patterns and temporal changes of Sppt across the global land from 2001 to 2018 with multiple streams of satellite observations. We found consistent spatial patterns of Sppt with different satellite products: Sppt was highest in dry regions while low in humid regions. Grassland and shrubland showed the highest Sppt, and evergreen needle‐leaf forest and wetland showed the lowest. Temporally, Sppt showed a generally declining trend over the past two decades (p <.05), yet with clear spatial heterogeneities. The decline in Sppt was especially noticeable in North America and Europe, likely due to the increase in precipitation. In central Russia and Australia, however, Sppt showed an increasing trend. Biome‐wise, most ecosystem types exhibited significant decrease in Sppt, while grassland, evergreen broadleaf forest, and mixed forest showed slight increases or non‐significant changes in Sppt. Our finding of the overall decline in Sppt implies a potential stabilization mechanism for ecosystem productivity under climate change. However, the revealed Sppt increase for some regions and ecosystem types, in particular global grasslands, suggests that grasslands might be increasingly vulnerable to climatic variability with continuing global climate change. [ABSTRACT FROM AUTHOR]

Despite high economic growth over the past 30 years, China's substantial and persistent regional disparities have been the subject of continuing concern to policy makers, as well as the target of a wide variety of policies. An important issue in the policy debate about whether and how best to attack these disparities is whether measures designed to improve regional equality come at a cost to national development, i.e., whether there is a trade-off between the level of national output and the equality of its distribution across the regions. There is little analysis of this issue in the literature. We help fill this gap by setting up a two-region model designed to capture some of the salient features of the Chinese economy. We subject this model to a number of policy shocks and assess the effects on regional disparities in per capita output, on the one hand, and on aggregate output on the other to investigate the trade-off. We also consider income and welfare as alternatives to output. We find, first, that disparities in per capita output, income, and welfare may move in different directions so that it is important to specify which disparity is being targeted. Second, since both disparities and aggregate outcomes are endogenous, how they move together depends on the nature of the shock driving the model. Thus, some policies designed to reduce disparities face a trade-off and others do not. Only a reduction in internal migration restrictions unambiguously reduces all three disparity measures and increases aggregate output, income, and welfare. All other policies considered face a trade-off in at least one dimension. Third, whether there is a trade-off depends also on the time horizon-some policies face a trade-off in the short run and not in the long run and vice versa. [ABSTRACT FROM AUTHOR]

Background and Purpose: Hyperleptinemia is commonly found in obese patients, associated with non-alcoholic steatohepatitis and hepatic fibrosis. Hepatic stellate cells (HSCs) are the most relevant effectors during hepatic fibrogenesis. We recently reported that leptin stimulated HSC activation, which was eliminated by curcumin, a phytochemical from turmeric. This study was designed to explore the underlying mechanisms, focusing on their effects on intracellular glucose in HSCs. We hypothesized that leptin stimulated HSC activation by elevating the level of intracellular glucose, which was eliminated by curcumin by inhibiting the membrane translocation of glucose transporter-4 (GLUT4) and inducing the conversion of glucose to glucose-6-phosphate (G-6-P).Experimental Approach: Levels of intracellular glucose were measured in rat HSCs and immortalized human hepatocytes. Contents of GLUT4 in cell fractions were analysed by Western blotting analyses. Activation of signalling pathways was assessed by comparing phosphorylation levels of protein kinases.Key Results: Leptin elevated the level of intracellular glucose in cultured HSCs, which was diminished by curcumin. Curcumin suppressed the leptin-induced membrane translocation of GLUT4 by interrupting the insulin receptor substrates/phosphatidyl inositol 3-kinase/AKT signalling pathway. Furthermore, curcumin stimulated glucokinase activity, increasing conversion of glucose to G-6-P.Conclusions and Implications: Curcumin prevented leptin from elevating levels of intracellular glucose in activated HSCs in vitro by inhibiting the membrane translocation of GLUT4 and stimulating glucose conversion, leading to the inhibition of HSC activation. Our results provide novel insights into mechanisms of curcumin in inhibiting leptin-induced HSC activation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Obesity is often accompanied by hypercholesterolemia characterized by elevated levels of plasma low-density lipoprotein (LDL) and associated with non-alcoholic steatohepatitis, which could progress to hepatic fibrosis. Hepatic stellate cells (HSCs) are the major effectors of hepatic fibrogenesis. This study aims to clarify effects of LDL on activation of HSC, to evaluate roles of curcumin in suppressing these effects and to further elucidate the underlying molecular mechanisms.Experimental Approaches: HSCs were prepared from rats and cell proliferation was measured by cell proliferation assays (MTS assays). Transient transfection assays were performed to evaluate gene promoter activities. Real-time polymerase chain reaction and Western blotting were used to analyse the expression of genes.Key Results: LDL stimulated HSC activation in vitro, which was attenuated by curcumin. Curcumin reduced the abundance of LDL receptor (LDLR) in activated HSCs, decreasing cellular cholesterol. Curcumin-dependent activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) differentially regulated the expression of the transcription factors, sterol regulatory element-binding proteins (SREBPs), in activated HSCs, resulting in the suppression of LDLR gene expression.Conclusions and Implications: Curcumin suppressed LDLR gene expression in activated HSCs in vitro by activating PPARgamma and differentially regulating gene expression of SREBPs, reducing cellular cholesterol and attenuating the stimulatory effects of LDL on HSC activation. These results provide novel insights into the roles and mechanisms of curcumin in the inhibition of LDL-induced HSC activation. This curcumin, a constituent of turmeric, may be useful in preventing hypercholesterolemia-associated hepatic fibrogenesis. [ABSTRACT FROM AUTHOR]

The article presents information on the housing markets in China. China has developed more rapidly as compared to any other country in the history. A study conduced by Siqi Zheng & colleagues investigated spatial heterogeneity pattern in housing prices is related to the public goods provision of a centralized metropolitan government.

Background and Purpose: Senescence in hepatic stellate cells (HSCs) limits liver fibrosis. Glutaminolysis promotes HSC activation. Here, we investigated how emodin affected HSC senescence involving glutaminolysis. Experimental Approach: Senescence, glutaminolysis metabolites, Nur77 nuclear translocation, glutaminase 1 (GLS1) promoter methylation and related signalling pathways were examined in human HSC‐LX2 cells using multiple cellular and molecular approaches. Fibrotic mice with shRNA‐mediated knockdown of Nur77 were treated with emodin‐vitamin A liposome for investigating the mechanisms in vivo. Human fibrotic liver samples were examined to verify the clinical relevance. Key Results: Emodin upregulated several key markers of senescence and inhibited glutaminolysis cascade in HSCs. Emodin promoted Nur77 nuclear translocation, and knockdown of Nur77 abolished emodin blockade of glutaminolysis and induction of HSC senescence. Mechanistically, emodin facilitated Nur77/DNMT3b interaction and increased GLS1 promoter methylation, leading to inhibited GLS1 expression and blockade of glutaminolysis. Moreover, the glutaminolysis intermediate α‐ketoglutarate promoted extracellular signal‐regulated kinase (ERK) phosphorylation, which in turn phosphorylated Nur77 and reduced its interaction with DNMT3b. This led to decreased GLS1 promoter methylation and increased GLS1 expression, forming an ERK/Nur77/glutaminolysis positive feedback loop. However, emodin repressed ERK phosphorylation and interrupted the feedback cascade, stimulating senescence in HSCs. Studies in mice showed that emodin‐vitamin A liposome inhibited glutaminolysis and induced senescence in HSCs, and consequently alleviated liver fibrosis; but knockdown of Nur77 abrogated these beneficial effects. Similar alterations were validated in human fibrotic liver tissues. Conclusions and Implications: Emodin stimulated HSC senescence through interruption of glutaminolysis. HSC‐targeted delivery of emodin represented a therapeutic option for liver fibrosis. [ABSTRACT FROM AUTHOR]

Plant phenology, the annually recurring sequence of plant developmental stages, is important for plant functioning and ecosystem services and their biophysical and biogeochemical feedbacks to the climate system. Plant phenology depends on temperature, and the current rapid climate change has revived interest in understanding and modeling the responses of plant phenology to the warming trend and the consequences thereof for ecosystems. Here, we review recent progresses in plant phenology and its interactions with climate change. Focusing on the start (leaf unfolding) and end (leaf coloring) of plant growing seasons, we show that the recent rapid expansion in ground‐ and remote sensing‐ based phenology data acquisition has been highly beneficial and has supported major advances in plant phenology research. Studies using multiple data sources and methods generally agree on the trends of advanced leaf unfolding and delayed leaf coloring due to climate change, yet these trends appear to have decelerated or even reversed in recent years. Our understanding of the mechanisms underlying the plant phenology responses to climate warming is still limited. The interactions between multiple drivers complicate the modeling and prediction of plant phenology changes. Furthermore, changes in plant phenology have important implications for ecosystem carbon cycles and ecosystem feedbacks to climate, yet the quantification of such impacts remains challenging. We suggest that future studies should primarily focus on using new observation tools to improve the understanding of tropical plant phenology, on improving process‐based phenology modeling, and on the scaling of phenology from species to landscape‐level. [ABSTRACT FROM AUTHOR]

This study develops a convolutional recurrent deep learning model to accurately predict fine‐resolution spatiotemporal changes in grass coverage in arid regions. Applying the model to the Gobi Desert reveals that ecological flow regulation contributes to 61.8% of the total increase in grass cover (130.6 km2) in the study area (40,423 km2) over 2005–2015, nearly triple the contribution of local climate change (+23.0%). The transboundary hydrological impact (+32.4%) and interactions between drivers (−17.2%) are also significant. In an intermediate future climate change scenario, we found no statistically significant trend for the total grass‐covered area due to the counteracting effects among different drivers. The study findings suggest that timely, adaptive and spatially heterogeneous ecological flow management is crucial for addressing grassland degradation in arid regions. This study provides a promising approach to land surface modeling under climate change and human disturbance and expands the existing understanding of the global greening process. Plain Language Summary: The Earth's recent greening (i.e., vegetation increase) has boosted the terrestrial carbon sink, intensified the hydrologic cycle, and contributed to mitigating global warming. CO2 fertilization has been identified as the primary cause at the global scale, while climate change, land use changes, and nitrogen deposition also contribute. However, there are still many gaps in our understanding of how grasslands in arid areas are being affected. Studies in Central Asia identified precipitation as the dominant factor affecting grassland change and grazing as the main influence from humans. Based on satellite data, we employ a novel deep learning (DL) approach to emulate spatiotemporal changes in grass coverage at a 1‐km resolution over an area of 40,423 km2 in the Gobi Desert in northwestern China. Our study identified previously overlooked mechanisms contributing to the increase in grass coverage, including ecological flow management and transboundary hydrological impact. Ecological flow management was found to be responsible for almost three times the increase in grass coverage over 2005–2015 than that of local climate changes. Our findings suggest that timely, adaptive, and spatially targeted ecological flow management is urgently needed to prevent further grassland degradation in arid regions, and DL‐based artificial intelligence can offer valuable management suggestions. Key Points: Deep learning (DL) precisely emulates spatiotemporal changes in grass coverage at a 1‐km resolution over an area of 40,423 km2DL interprets ecological flow regulation (EFR) as the leading cause of grassland greening in the Gobi DesertTimely, adaptive and spatially heterogeneous ecological flow management is desired to prevent grassland degradation in arid regions [ABSTRACT FROM AUTHOR]

Global greening, characterized by an increase in leaf area index (LAI), implies an increase in foliar carbon (C). Whether this increase in foliar C under climate change is due to higher photosynthesis or to higher allocation of C to leaves remains unknown. Here, we explored the trends in foliar C accumulation and allocation during leaf green‐up from 2000 to 2017 using satellite‐derived LAI and solar‐induced chlorophyll fluorescence (SIF) across the Northern Hemisphere. The accumulation of foliar C accelerated in the early green‐up period due to both increased photosynthesis and higher foliar C allocation driven by climate change. In the late stage of green‐up, however, we detected decreasing trends in foliar C accumulation and foliar C allocation. Such stage‐dependent trends in the accumulation and allocation of foliar C are not represented in current terrestrial biosphere models. Our results highlight that a better representation of C allocation should be incorporated into models. [ABSTRACT FROM AUTHOR]

Negative extreme anomalies in vegetation growth (NEGs) usually indicate severely impaired ecosystem services. These NEGs can result from diverse natural and anthropogenic causes, especially climate extremes (CEs). However, the relationship between NEGs and many types of CEs remains largely unknown at regional and global scales. Here, with satellite‐derived vegetation index data and supporting tree‐ring chronologies, we identify periods of NEGs from 1981 to 2015 across the global land surface. We find 70% of these NEGs are attributable to five types of CEs and their combinations, with compound CEs generally more detrimental than individual ones. More importantly, we find that dominant CEs for NEGs vary by biome and region. Specifically, cold and/or wet extremes dominate NEGs in temperate mountains and high latitudes, whereas soil drought and related compound extremes are primarily responsible for NEGs in wet tropical, arid and semi‐arid regions. Key characteristics (e.g., the frequency, intensity and duration of CEs, and the vulnerability of vegetation) that determine the dominance of CEs are also region‐ and biome‐dependent. For example, in the wet tropics, dominant individual CEs have both higher intensity and longer duration than non‐dominant ones. However, in the dry tropics and some temperate regions, a longer CE duration is more important than higher intensity. Our work provides the first global accounting of the attribution of NEGs to diverse climatic extremes. Our analysis has important implications for developing climate‐specific disaster prevention and mitigation plans among different regions of the globe in a changing climate. [ABSTRACT FROM AUTHOR]

Large‐scale reforestation can potentially bring both benefits and risks to the water cycle, which needs to be better quantified under future climates to inform reforestation decisions. We identified 477 water‐insecure basins worldwide accounting for 44.6% (380.2 Mha) of the global reforestation potential. As many of these basins are in the Asia‐Pacific, we used regional coupled land‐climate modeling for the period 2041–2070 to reveal that reforestation increases evapotranspiration and precipitation for most water‐insecure regions over the Asia‐Pacific. This resulted in a statistically significant increase in water yield (p <.05) for the Loess Plateau–North China Plain, Yangtze Plain, Southeast China, and Irrawaddy regions. Precipitation feedback was influenced by the degree of initial moisture limitation affecting soil moisture response and thus evapotranspiration, as well as precipitation advection from other reforested regions and moisture transport away from the local region. Reforestation also reduces the probability of extremely dry months in most of the water‐insecure regions. However, some regions experience nonsignificant declines in net water yield due to heightened evapotranspiration outstripping increases in precipitation, or declines in soil moisture and advected precipitation. [ABSTRACT FROM AUTHOR]

Over the last century the Northern Hemisphere has experienced rapid climate warming, but this warming has not been evenly distributed seasonally, as well as diurnally. The implications of such seasonal and diurnal heterogeneous warming on regional and global vegetation photosynthetic activity, however, are still poorly understood. Here, we investigated for different seasons how photosynthetic activity of vegetation correlates with changes in seasonal daytime and night-time temperature across the Northern Hemisphere (>30°N), using Normalized Difference Vegetation Index ( NDVI) data from 1982 to 2011 obtained from the Advanced Very High Resolution Radiometer ( AVHRR). Our analysis revealed some striking seasonal differences in the response of NDVI to changes in day- vs. night-time temperatures. For instance, while higher daytime temperature ( Tmax) is generally associated with higher NDVI values across the boreal zone, the area exhibiting a statistically significant positive correlation between Tmax and NDVI is much larger in spring (41% of area in boreal zone - total area 12.6 × 106 km2) than in summer and autumn (14% and 9%, respectively). In contrast to the predominantly positive response of boreal ecosystems to changes in Tmax, increases in Tmax tended to negatively influence vegetation growth in temperate dry regions, particularly during summer. Changes in night-time temperature ( Tmin) correlated negatively with autumnal NDVI in most of the Northern Hemisphere, but had a positive effect on spring and summer NDVI in most temperate regions (e.g., Central North America and Central Asia). Such divergent covariance between the photosynthetic activity of Northern Hemispheric vegetation and day- and night-time temperature changes among different seasons and climate zones suggests a changing dominance of ecophysiological processes across time and space. Understanding the seasonally different responses of vegetation photosynthetic activity to diurnal temperature changes, which have not been captured by current land surface models, is important for improving the performance of next generation regional and global coupled vegetation-climate models. [ABSTRACT FROM AUTHOR]

Targeting the elimination of activated hepatic stellate cells (HSCs) and blocking excessive deposition of extracellular matrix are recognized as an effective strategy for the treatment of hepatic fibrosis. As a newly discovered programmed cell death mode, the regulatory mechanism of ferroptosis in the clearance of activated HSCs has not been fully elucidated. In the present study, we reported that the induction of ferroptosis in activated HSCs was required for dihydroartemisinin (DHA) to alleviate hepatic fibrosis. Treatment with DHA could improve the damage of hepatic fibrosis in vivo and inhibit the activation of HSCs in vitro. Interestingly, DHA treatment could trigger ferroptosis to eliminate activated HSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Specific ferroptosis inhibitors ferrostatin‐1 and liproxstatin‐1 could impair DHA‐induced ferroptosis and also damage DHA‐mediated the inhibition of activated HSCs. Importantly, autophagy activation may be closely related to DHA‐induced ferroptosis. ATG5 siRNA could prevent DHA‐mediated autophagy activation and ferroptosis induction, whereas ATG5 plasmid could promote the effect of DHA on autophagy and ferroptosis. Of note, the upregulation of nuclear receptor coactivator 4 (NCOA4) may play a critical role in the molecular mechanism. NCOA4 siRNA could impair DHA‐induced ferroptosis, whereas NCOA4 plasmid could enhance the promoting effect of DHA on ferroptosis. Overall, our study revealed the potential mechanism of DHA against hepatic fibrosis and showed that ferroptosis could be a new way to eliminate activated HSCs. [ABSTRACT FROM AUTHOR]

Objective: The benefit of Se supplementation in rheumatoid arthritis (RA) has been tested in clinical trials, but results remain inconclusive. The objective of this study was to specifically investigate the potential benefit of supranutritional Se by examining human samples from an area with supranutritional Se intake and testing a mouse model of RA. Methods: Peripheral blood mononuclear cells (PBMCs) from RA patients (N = 57) and healthy controls (HC, N = 71) from an area of supranutritional Se intake (Enshi, Hubei, China) were analysed by flow cytometry. Serum cytokine and Se levels were measured by cytometric beads array (CBA) and inductively coupled plasma mass spectrometry (ICP‐MS), respectively. With sufficient or supranutritional selenium intake, mice were induced with collagen‐induced arthritis (CIA) and examined for disease activity and immunopathology. The influence of Se supplementation in the generation of RANKL‐expressing osteoclastogenic CD4+ T cells was investigated by in vitro assays. Results: In Enshi city, HC showed the above‐normal concentrations of serum Se concentrations while RA patients were enriched in the normal range (70–150 ng mL−1) or below. RA patients with higher Se levels demonstrated milder disease and lower levels of C‐reactive protein, IL‐6, RANKL and Th17 cells. In the mouse CIA model, supranutritional Se supplementation delayed disease onset, ameliorated joint pathology and reduced CD4+CD44+RANKL+ T cells. Se supplementation could suppress RANKL expression in cultured mouse Th17 cells. Conclusion: Supranutritional Se suppresses RANKL‐expressing osteoclastogenic CD4+ T cells and could be beneficial to RA, which warrants formal testing in randomised clinical trials. [ABSTRACT FROM AUTHOR]

Aims: This study was designated to illustrate the underlying mechanisms of emodin anti‐liver fibrosis via network pharmacology and experiment. Methods: The TSMCP and Genecards database were applied to screen the relevant targets of emodin or liver fibrosis. The essential target was selected by using Cytoscape to analyze the topological network of potential targets. Furthermore, we constructed a preliminary molecule docking study to explore the binding site by Surflex‐Dock suite SYBYL X 2.0. The DAVID database was selected for gene functional annotations and KEGG enrichment analysis. Moreover, we demonstrated the ameliorating effect of emodin on carbon tetrachloride (CCl4)‐induced liver injury in mice. We also verified the network predictions in vitro via various techniques. Results: The collected results showed that 35 targets were related to emodin, and 6,198 targets were associated with liver fibrosis. The Venn analysis revealed that 17 intersection targets were correlated with emodin anti‐liver fibrosis. The topological network analysis suggested that the p53 was the remarkable crucial target. Besides, the molecule docking results showed that emodin could directly interact with p53 by binding the active site residues ASN345, GLN331, and TYR347. Finally, KEGG pathway enrichment results indicated that essential genes were mainly enriched in mitogen‐activated protein kinase (MAPK) signaling pathways. Moreover, our study confirmed that emodin alleviated CCl4‐induced liver injury in mice, inducing hepatic stellate cells (HSCs) apoptosis via regulating the p53/ERK/p38 axis. Conclusions: This study partially verified the network pharmacological prediction of emodin inducing HSCs cell apoptosis through the p53/ERK/p38 axis. [ABSTRACT FROM AUTHOR]

The 2015−2016 El Niño was one of the strongest on record, but its influence on the carbon balance is less clear. Using Northern Hemisphere atmospheric CO2 observations, we found both detrended atmospheric CO2 growth rate (CGR) and CO2 seasonal‐cycle amplitude (SCA) of 2015−2016 were much higher than that of other El Niño events. The simultaneous high CGR and SCA were unusual, because our analysis of long‐term CO2 observations at Mauna Loa revealed a significantly negative correlation between CGR and SCA. Atmospheric inversions and terrestrial ecosystem models indicate strong northern land carbon uptake during spring but substantially reduced carbon uptake (or high emissions) during early autumn, which amplified SCA but also resulted in a small anomaly in annual carbon uptake of northern ecosystems in 2015−2016. This negative ecosystem carbon uptake anomaly in early autumn was primarily due to soil water deficits and more litter decomposition caused by enhanced spring productivity. Our study demonstrates a decoupling between seasonality and annual carbon cycle balance in northern ecosystems over 2015−2016, which is unprecedented in the past five decades of El Niño events. [ABSTRACT FROM AUTHOR]

Background and Purpose: Portal hypertension is a lethal complication of cirrhosis. Its mechanism and therapeutic targets remain largely unknown. Hepatic stellate cell (HSC) contraction increases intrahepatic vascular resistance contributing to portal hypertension. We investigated how HSC contraction was regulated by Wnt signalling and the therapeutic implications.Experimental Approach: Liver tissues from cirrhotic patients were examined. Cirrhotic mice with genetic or pharmacological treatments were used for in vivo assessments, and their primary cells were isolated. Cellular functions and signalling pathways were analysed in human HSC-LX2 cells using real-time PCR, Western blotting, siRNA, luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation and site-directed mutagenesis.Key Results: Wnt/β-catenin correlated with HSC contraction in human cirrhotic liver. Wnt3a stimulated Smo-independent Gli1 nuclear translocation followed by LARG-mediated RhoA activation leading to HSC contraction. Suppressor of fused (Sufu) negatively mediated Wnt3a-induced Gli1 nuclear translocation. Wnt/β-catenin repressed transcription of Sufu dependent on β-catenin/TCF4 interaction and TCF4 binding to Sufu promoter. Molecular simulation and site-directed mutagenesis identified the β-catenin residues Lys312 and Lys435 critically involved in this interaction. TCF4 binding to the sequence CACACCTTCC at Sufu promoter was required for transrepression of Sufu. In cirrhotic mice, short-term liver-targeting β-catenin deficiency or acute treatment with β-catenin inhibitors reduced portal pressure via restriction of HSC contraction rather than inhibiting HSC activation. Long-term deficiency or treatments also ameliorated liver injury, fibrosis and inflammation.Conclusion and Implications: Interaction between Wnt/β-catenin and Smo-independent Gli1 pathways promoted HSC contraction via TCF4-dependent transrepression of Sufu. HSC-specific inhibition of β-catenin may have therapeutic benefits for cirrhotic portal hypertension. [ABSTRACT FROM AUTHOR]

Accurate quantification of vegetation carbon turnover time (τveg) is critical for reducing uncertainties in terrestrial vegetation response to future climate change. However, in the absence of global information of litter production, τveg could only be estimated based on net primary productivity under the steady‐state assumption. Here, we applied a machine‐learning approach to derive a global dataset of litter production by linking 2401 field observations and global environmental drivers. Results suggested that the observation‐based estimate of global natural ecosystem litter production was 44.3 ± 0.4 Pg C year−1. By contrast, land‐surface models (LSMs) overestimated the global litter production by about 27%. With this new global litter production dataset, we estimated global τveg (mean value 10.3 ± 1.4 years) and its spatial distribution. Compared to our observation‐based τveg, modelled τveg tended to underestimate τveg at high latitudes. Our empirically derived gridded datasets of litter production and τveg will help constrain global vegetation models and improve the prediction of global carbon cycle. [ABSTRACT FROM AUTHOR]

Ferroptosis is a metabolic disorder of lipid oxides in cells, which leads to abnormal metabolism under the catalysis of iron, which produces an expansive number of lipids, wrecks the redox in cells, attacks biological macromolecules and triggers cell death. This death process was marked by the increase of cytoplasmic and lipid reactive oxygen species, the decrease of mitochondria and the higher density of mitochondrial membrane. Non‐coding RNA (ncRNA) is a kind of small RNA molecules found in recent years, which can transcribe but do not encode proteins and have specific functions. These ncRNAs play a key role in controlling gene expression by combining with proteins or other molecules to turn genes on or off. Ferroptosis is viewed as a leap forward in the medication of tumors and some intractable maladies. Under the circumstances that there are still many mysteries in the study of ferroptosis, the research on the role of ncRNAs in ferroptosis is even less. By consulting the pertinent literature, this article reviews the research advance about ncRNAs on ferroptosis, which provides a new research direction and ideas for the study of ferroptosis. [ABSTRACT FROM AUTHOR]

Objective: Hepatic sinusoidal angiogenesis owing to dysfunctional liver sinusoidal endothelial cells (LSECs) accompanied by an abnormal angioarchitecture is a symbol related to liver fibrogenesis, which indicates a potential target for therapeutic interventions. However, there are few researches connecting angiogenesis with liver fibrosis, and the deeper mechanism remains to be explored. Materials and Methods: Cell angiogenesis and angiogenic protein were examined in primary LSECs of rats, and multifarious cellular and molecular assays revealed the efficiency of curcumol intervention in fibrotic mice. Results: We found that curcumol inhibited angiogenic properties through regulating their upstream mediator hypoxia‐inducible factor‐1α (HIF‐1α). The transcription activation of HIF‐1α was regulated by hedgehog signalling on the one hand, and the protein stabilization of HIF‐1α was under the control of Prospero‐related homeobox 1 (PROX1) on the other. A deubiquitinase called USP19 could be recruited by PROX1 and involved in ubiquitin‐dependent degradation of HIF‐1α. Furthermore, our researches revealed that hedgehog signalling participated in the activation of PROX1 transcription probably in vitro. Besides, curcumol was found to ameliorate liver fibrosis and sinusoid angiogenesis via hedgehog pathway in carbon tetrachloride (CCl4) induced liver fibrotic mice. The protein expression of key regulatory factors, PROX1 and HIF‐1α, was consistent with the Smo, the marker protein of Hh signalling pathway. Conclusions: In this article, we evidenced that curcumol controlling LSEC‐mediated angiogenesis could be a promising therapeutic approach for liver fibrosis. [ABSTRACT FROM AUTHOR]

A widely used approach for estimating actual evapotranspiration (AET) in hydrological and earth system models is to constrain potential evapotranspiration (PET) with a single empirical stress factor (Ω = AET/PET). Ω represents the water availability and is fundamentally linked to canopy–atmosphere coupling. However, the mean and seasonal variability of Ω in the models have rarely been evaluated against observations, and the model performances for different climates and biomes remain unclear. In this study, we first derived the observed Ω from 28 FLUXNET sites over North America during 2000–2007, which was then used to evaluate Ω in six large‐scale model‐based datasets. Our results confirm the importance of incorporating canopy height in the formulation of aerodynamic conductance in the case of forests. Furthermore, leaf area index (LAI) is central to the prediction of Ω and can be quantitatively linked to the partitioning between transpiration and soil evaporation (R2 = 0.43). The substantial differences between observed and model‐based Ω in forests (range: 0.2~0.9) are highly related to the way these models estimated PET and the way they represented the responses of Ω to the environmental drivers, especially wind speed and LAI. This is the first assessment of Ω in models based on in situ observations. Our findings demonstrate that the observed Ω is useful for evaluating, validating, and optimizing the modeling of AET and thus of water and energy balances. This study provides the first assessment of seasonality of the actual to potential evapotranspiration (AET/PET) ratio in models based on the FLUXNET observations over North America. The AET/PET ratio is closely related to green leaf area and evapotranspiration partitioning, and is strongly linked to canopy height in forests. Models fail to capture the mean and variability of the ratio mainly mainly due to the way they formulate PET and represent the sensitivities of the ratio to wind speed and leaf area index. [ABSTRACT FROM AUTHOR]

Surface temperature variations across the tropics exhibit different levels of spatial coherence, yet this is poorly characterized. Years of high temperature anomalies occurring simultaneously across large geographical regions have the potential to adversely impact food production and societal well‐being. Using cluster analysis of correlations between extensive temperature measurements from the last six decades, we find a major change occurs in the late 1970s. Two spatial clusters merge to a single dominant one, and therefore, warmer years are experienced at the same time across most tropical land regions. Noting this change occurs at the same time as the Pacific Decadal Oscillation shifts a warm phase, we investigate this potential driver by a range of coupled ocean‐atmosphere‐land climate models. These simulations verify that stronger spatial tropical land temperature coherence tends to occur in Pacific Decadal Oscillation warm phases, although model differences exist in projections of how climate change may modulate this dependence. Plain Language Summary: Recent increasing surface temperature variations significantly enhance weather extremes and exacerbate food production and societal well‐being. Adverse impacts of high temperature variations could be further aggravated when fluctuations of annual temperature are spatially coherent. Compared to isolated weather disasters, simultaneous co‐occurrences of events may cause much broader damages and impair mitigation capacity. Yet it is unclear how temperature covaries across different regions, and if covariation strength is changing. Using cluster analysis of correlations between gridded temperature anomalies over the last six decades, we demonstrate increasing spatial coherence in temperature interannual variability. At the late 1970s, two spatial clusters merged into one dominant cluster covering tropical land regions. Stronger spatial temperature coherence tends to occur in Pacific Decadal Oscillation warm phases, although climate change may modulate this dependence. Key Points: Variations of annual temperature for tropical land regions have become much more spatially synchronized in recent decadesStronger spatial coherence of tropical land temperature tends to occur in warm phases of the oceanic Pacific Decadal OscillationClimate models suggest that the linkage between PDO state and coherence of tropical land temperature can adjust under global warming [ABSTRACT FROM AUTHOR]

Ferroptosis is recently reported as a new mode of regulated cell death. Its essential characteristics are disturbed redox homeostasis, overloaded iron, and increased lipid peroxidation. However, the role of ferroptosis in liver fibrosis remains poorly understood. In this study, we attempted to investigate the effect of artemether (ART) on ferroptosis in hepatic fibrosis and to further clarify the possible mechanisms. Our data showed that ART treatment markedly attenuated liver injury and reduced fibrotic scar formation in the mouse model of liver fibrosis. Moreover, experiments in vitro also confirmed that ART treatment significantly decreased expression of hepatic stellate cell (HSC) activation markers. Interestingly, HSCs treated by ART presented morphological features of ferroptosis. Furthermore, ART remarkably triggered ferroptosis by promoting the accumulation of iron and lipid peroxides, whereas inhibition of ferroptosis by specific inhibitor ferrostatin‐1 (Fer‐1) completely abolished ART‐induced antifibrosis effect. More importantly, our discovery determined that tumor suppressor P53 was an upstream molecule in the facilitation of ART‐induced HSC ferroptosis. Conversely, knockdown of P53 by siRNA evidently blocked ART‐induced HSC ferroptosis in turn exacerbated liver fibrosis. Overall, our findings revealed that P53‐dependent induction of ferroptosis is necessary for ART to ameliorate CCl4‐induced hepatic fibrosis and inhibit HSC activation. © 2018 IUBMB Life, 71(1):45–56, 2019 [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Oroxylin A, a natural flavonoid isolated from Scutellaria baicalensis, has been reported to have anti‐hepatic injury effects. However, the effects of oroxylin A on alcoholic liver disease (ALD) remains unclear. The aim of this study was to elucidate the effects of oroxylin A on ALD and the potential mechanisms. Materials and methods: Male ICR mice and human hepatocyte cell line LO2 were used. Yes‐associated protein (YAP) overexpression and knockdown were achieved using plasmid and siRNA technique. Cellular senescence was assessed by analyses of the senescence‐associated β‐galactosidase (SA‐β‐gal), senescence marker p16, p21, Hmga1, cell cycle and telomerase activity. Results: Oroxylin A alleviated ethanol‐induced hepatocyte damage by suppressing activities of supernatant marker enzymes. We found that oroxylin A inhibited ethanol‐induced hepatocyte senescence by decreasing the number of SA‐β‐gal‐positive LO2 cells and reducing the expression of senescence markers p16, p21 and Hmga1 in vitro. Moreover, oroxylin A affected the cell cycle and telomerase activity. Of importance, we revealed that YAP pharmacological inhibitor verteporfin or YAP siRNA eliminated the effect of oroxylin A on ethanol‐induced hepatocyte senescence in vitro, and this was further supported by the evidence in vivo experiments. Conclusion: Therefore, these aggregated data suggested that oroxylin A relieved alcoholic liver injury possibly by inhibiting the senescence of hepatocyte, which was dependent on its activation of YAP in hepatocytes. [ABSTRACT FROM AUTHOR]

Varied pathogenetic elements have been touched upon the liver fibrosis, including inflammatory, stress, apoptosis and unfolded proteins aggregation. Magnesium Isoglycyrrhizinate (MgIG) has been accepted to be a neuroprotective effect, hepatoprotective and anti-inflammatory molecule. In our vitro researches, MgIG was considered to activate hepatic stellate cells (HSCs) apoptosis by promoting endoplasmic reticulum stress (ERS) detrimental response to a certain extent. Consequently, MgIG showed its potential therapeutic capacity in fibrogenesis and counteracted the pathogenetic aspects, which were involved in integrating current treatments correcting liver fibrosis. In addition, we further verificated the behavior and pathogenic mechanisms in the CCl4-induced liver fibrosis in male mice. What surprised us was that with the treatment of MgIG caused the activation of ERS and resisted the activated HSCs in the protective effects on liver damage. We found MgIG significantly promoted the apoptosis of activated HSCs and protected the CCl4-induced liver fibrosis. Main molecules came down to the unfolded protein response signaling pathway. Furthermore, MgIG inhibited the levels of the downstream inflammatory cytokines, which were triggered by CCl4-induced liver fibrosis. Here, we reported that MgIG improved behavioral impairments induced by intraperitoneal injection of CCl4 and decreased the expression of proinflammatory factor, which indicated the preserving effects on liver fibrosis. © 2017 BioFactors, 43(6):836-846, 2017 [ABSTRACT FROM AUTHOR]

Alcoholic liver disease (ALD), characterized by excessive deposition of lipids in hepatocytes, causes heavy health burden personally and socially. Mechanistically, hedgehog signaling was activated during the development of ALD, and exerted compelling role in regulating lipometabolism. The current promising intervention strategy is inhibition of lipid accumulation and apoptosis in hepatocytes. Magnesium isoglycyrrhizinate (MgIG) has been widely used in various liver diseases for its good hepatoprotective activities. However, the role of MgIG in ALD has not been elucidated. Therefore, this study was aimed to explore the role of MgIG and further identify the potential mechanisms. We found for the first time that MgIG reduced lipid accumulation, including triglyceride, and total cholesterol, probably via inducing peroxisome proliferator-activated receptor-alpha and inhibiting sterol regulatory element-binding protein-1c. Further, MgIG alleviated ethanol-induced oxidative stress, evidenced by reduced abundance of reactive oxygen species and increased levels of glutathione, superoxide dismutase, and mitochondrial transmembrane potential. Besides, MgIG protected hepatocytes from ethanol-induced apoptosis. In addition, MgIG dose-dependently suppressed hedgehog signaling. Of note was that disruption of hedgehog signaling could mimic the effects of MgIG, whereas activation of hedgehog signaling abrogated the effects of MgIG. These findings suggested that MgIG prevented ethanol-induced hepatocyte steatosis and apoptosis via a hedgehog signaling inhibition-dependent mechanism. © 2017 IUBMB Life, 69(7):540-552, 2017 [ABSTRACT FROM AUTHOR]

Background and Purpose: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating angiogenesis during liver fibrosis. We aimed to elucidate the mechanisms by which hedgehog signalling regulated HSC angiogenic properties and to validate the therapeutic implications.Experimental Approach: Rats and mice were treated with carbon tetrachloride for in vivo evaluation of hepatic angiogenesis and fibrotic injury. Diversified molecular approaches including real-time PCR, Western blot, luciferase reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay and co-immunoprecipitation were used to investigate the underlying mechanisms in vitro.Key Results: Angiogenesis was concomitant with up-regulation of Smoothened (SMO) and hypoxia inducible factor-1α (HIF-1α) in rat fibrotic liver. The SMO inhibitor cyclopamine and Gli1 inhibitor GANT-58 reduced expression of VEGF and angiopoietin 1 in HSCs and suppressed HSC tubulogenesis capacity. HIF-1α inhibitor PX-478 suppressed HSC angiogenic behaviour, and inhibition of hedgehog decreased HIF-1α expression. Furthermore, heat shock protein 90 (HSP90) was characterized as a direct target gene of canonical hedgehog signalling in HSCs. HSP90 inhibitor 17-AAG reduced HSP90 binding to HIF-1α, down-regulated HIF-1α protein abundance and decreased HIF-1α binding to DNA. 17-AAG also abolished 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) (a SMO agonist)-enhanced HSC angiogenic properties. Finally, the natural compound ligustrazine was found to inhibit canonical hedgehog signalling leading to suppressed angiogenic properties of HSCs in vitro and ameliorated liver fibrosis and sinusoidal angiogenesis in mice.Conclusion and Implications: We have provided evidence that the canonical hedgehog pathway controlled HSC-mediated liver angiogenesis. Selective inhibition of HSC hedgehog signalling could be a promising therapeutic approach for hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that hedgehog signaling plays a pivotal role in pathological angiogenesis and is involved in wound-healing responses in a number of adult tissues, including the liver. We previously demonstrated that hedgehog signaling promoted proliferation and inhibited apoptosis in hepatic stellate cells. This study was aimed to evaluate the effect of tetramethylpyrazine (TMP) on hedgehog signaling and to further examine the molecular mechanisms of TMP-induced antiangiogenesic effects in liver fibrosis. We found that TMP ameliorated the expression of proangiogenic markers vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGF-R2), platelet-derived growth factor BB (PDGF-BB), platelet-derived growth factor-β receptor (PDGF-βR) and hypoxia inducible factor 1α (HIF-1α), concomitant with reduced abundance of endothelial markers platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), CD34 and von willebrand factor in vivo and in vitro. Interestingly, TMP attenuated the abundance of sonic hedgehog, smoothened (Smo) and glioblastoma but increased the expression of hedgehog-interacting protein in liver sinusoidal endothelial cells, which was underlying mechanism for the antiangiogenesic activity of TMP. Downregulation of Smo activity, using selective Smo inhibitor cyclopamine, lead to a synergistic effect with TMP, whereas Smo overexpression plasmid impaired the induction of antiangiogenesic effects of TMP. Overall, these results provide novel implications to reveal the molecular mechanism of TMP-inhibited liver sinusoidal angiogenesis, by which points to the possibility of using TMP-based antiangiogenic drugs for the treatment of liver fibrosis. © 2017 IUBMB Life, 69(2):115-127, 2017 [ABSTRACT FROM AUTHOR]

Background and Purpose: Diabetes is characterized by hyperglycaemia, which facilitates the formation of advanced glycation end-products (AGEs). Type 2 diabetes mellitus is commonly accompanied by non-alcoholic steatohepatitis, which could lead to hepatic fibrosis. Receptor for AGEs (RAGE) mediates effects of AGEs and is associated with increased oxidative stress, cell growth and inflammation. The phytochemical curcumin inhibits the activation of hepatic stellate cells (HSCs), the major effectors during hepatic fibrogenesis. The aim of this study was to explore the underlying mechanisms of curcumin in the elimination of the stimulating effects of AGEs on the activation of HSCs. We hypothesize that curcumin eliminates the effects of AGEs by suppressing gene expression of RAGE.Experimental Approach: Gene promoter activities were evaluated by transient transfection assays. The expression of rage was silenced by short hairpin RNA. Gene expression was analysed by real-time PCR and Western blots. Oxidative stress was evaluated.Key Results: AGEs induced rage expression in cultured HSCs, which played a critical role in the AGEs-induced activation of HSCs. Curcumin at 20 µM eliminated the AGE effects, which required the activation of PPARγ. In addition, curcumin attenuated AGEs-induced oxidative stress in HSCs by elevating the activity of glutamate-cysteine ligase and by stimulating de novo synthesis of glutathione, leading to the suppression of gene expression of RAGE.Conclusion and Implications: Curcumin suppressed gene expression of RAGE by elevating the activity of PPARγ and attenuating oxidative stress, leading to the elimination of the AGE effects on the activation of HSCs.Linked Article: This article is commented on by Stefanska, pp. 2209-2211 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01959.x. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Diabetes is characterized by hyperglycaemia, which facilitates the formation of advanced glycation end-products (AGEs). Type 2 diabetes mellitus is commonly accompanied by non-alcoholic steatohepatitis, which could lead to hepatic fibrosis. Receptor for AGEs (RAGE) mediates effects of AGEs and is associated with increased oxidative stress, cell growth and inflammation. The phytochemical curcumin inhibits the activation of hepatic stellate cells (HSCs), the major effectors during hepatic fibrogenesis. The aim of this study was to explore the underlying mechanisms of curcumin in the elimination of the stimulating effects of AGEs on the activation of HSCs. We hypothesize that curcumin eliminates the effects of AGEs by suppressing gene expression of RAGE. EXPERIMENTAL APPROACH Gene promoter activities were evaluated by transient transfection assays. The expression of rage was silenced by short hairpin RNA. Gene expression was analysed by real-time PCR and Western blots. Oxidative stress was evaluated. KEY RESULTS AGEs induced rage expression in cultured HSCs, which played a critical role in the AGEs-induced activation of HSCs. Curcumin at 20 µM eliminated the AGE effects, which required the activation of PPARγ. In addition, curcumin attenuated AGEs-induced oxidative stress in HSCs by elevating the activity of glutamate-cysteine ligase and by stimulating de novo synthesis of glutathione, leading to the suppression of gene expression of RAGE. CONCLUSION AND IMPLICATIONS Curcumin suppressed gene expression of RAGE by elevating the activity of PPARγ and attenuating oxidative stress, leading to the elimination of the AGE effects on the activation of HSCs. LINKED ARTICLE This article is commented on by Stefanska, pp. 2209-2211 of this issue. To view this commentary visit [ABSTRACT FROM AUTHOR]

Climate warming is likely inducing carbon loss from soils of northern ecosystems, but little evidence comes from large-scale observations. Here we used data from a repeated soil survey and remote sensing vegetation index to explore changes in soil organic carbon (SOC) stock on the Tibetan Plateau during the past two decades. Our results showed that SOC stock in the top 30 cm depth in alpine grasslands on the plateau amounted to 4.4 Pg C (1 Pg=1015 g), with an overall average of 3.9 kg C m−2. SOC changes during 1980s–2004 were estimated at −0.6 g C m−2 yr−1, ranging from −36.5 to 35.8 g C m−2 yr−1 at 95% confidence, indicating that SOC stock in the Tibetan alpine grasslands remained relatively stable over the sampling periods. Our findings are nonconsistent with previous reports of loss of soil C in grassland ecosystems due to the accelerated decomposition with warming. In the case of the alpine grasslands on the Tibetan Plateau studied here, we speculate that increased rates of decomposition as soils warmed during the last two decades may have been compensated by increased soil C inputs due to increased grass productivity. These results suggest that soil C stock in terrestrial ecosystems may respond differently to climate change depending on ecosystem type, regional climate pattern, and intensity of human disturbance. [ABSTRACT FROM AUTHOR]