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Yan Lin,1,2,* Gaofeng Zhu,3,* Xiaoyong Li,4,* Huaxiao Yu,5 Yuhang Luo,5 Jiaqiong Lin,6 Renyuan Li,7 Zena Huang2 1Department of Nephrology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Yunkang School of Medicine and Health, Nanfang College, Guangzhou, People’s Republic of China; 3Department of General Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 4Department of General Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5The Third Clinical School, Guangzhou Medical University, Guangzhou, People’s Republic of China; 6Affiliated Dongguan Maternal and Child Healthcare Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 7Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zena Huang, Yunkang School of Medicine and Health, Nanfang College, Guangzhou, People’s Republic of China, Tel +86-13570466614, Email huangzn@nfu.edu.cn Renyuan Li, Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Tel +86-18926146852, Email lirenyuan@gzhmu.edu.cnBackground: Icariin presents protective effect in several kidney diseases. However, the role of icariin in contrast-induced acute kidney injury (CIAKI) is still unclear. This study aimed to investigate the effect of icariin in CIAKI, as well as exploring the underlying mechanism from the aspect of interaction between protein-coding genes and non-coding RNAs.Methods: The effect of icariin was evaluated in both in vivo and in vitro CIAKI models. Rat kidneys were collected for genome-wide sequencing. The differentially expressed genes (DEGs) were screened and visualized by R software. The function annotation of DEGs was analyzed by Metascape. By Cytoscape software, the competing endogenous RNA (ceRNA) network was constructed, and hub genes were selected. Expressions of hub genes were validated by PCR. Association of hub genes in the ceRNA network and renal function was also examined.Results: Icariin protected against CIAKI in both in vivo and in vitro models. Based on DEGs in icariin pretreated CIAKI rats, lncRNA- and circRNA-associated ceRNA networks were constructed, respectively. Function annotation showed the ceRNA networks were enriched in ERK1 and ERK2 cascade, MAPK signaling and NF-κB signaling. Further, two circRNAs, six lncRNAs, four miRNAs and nine mRNAs were selected as hub genes of the ceRNA network. Among them, eight mRNAs (Acot1, Cbwd1, Ly6i, Map3k14, Mettl2b, Nyap1, Set and Utp20) were negatively correlated with renal function, while one mRNA (Tmem44) was positively correlated with renal function.Conclusion: Icariin presented a protective effect against CIAKI. The ceRNA network, involving Acot1, Cbwd1, Ly6i, Map3k14, Mettl2, Nyap1, Set, Tmem44 and Utp20, might partially contribute to the underlying mechanism of icariin protection by regulation of ERK1 and ERK2 cascade, MAPK signaling and NF-κB signaling.Keywords: icariin, contrast medium, acute kidney injury, competing endogenous RNA, non-coding RNA

Purpose STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. Methods Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant. Results WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient. Conclusion Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.

Snow phenology, recurrent seasonal patterns in snow cover and snowfall, has been significantly affected by global warming. Through the interaction with the climate, the dynamic variability of snow phenology affects the regional climate environment, vegetation ecosystem, soil properties, agricultural water resources, snow disasters and animal migration. First, this study compares the advantages, disadvantages and applicability of different sources of observation data and the principal research methods involved in studying snow phenology. Then, this work discusses the spatiotemporal variability and changing trends of snow phenology in the Northern Hemisphere, and summarizes the relationship between climate, vegetation and snow phenology. Finally, this review highlights the key areas related to snow phenology that require further study. Overall, during the past 50 years in the Northern Hemisphere, the snow cover end date (SCED) has shown a significantly advanced trend, the snow cover onset date (SCOD) has also been occurring slowly earlier, and the snow cover days (SCD) has shortened, but these two trends are not significant. The snow phenology variation is closely related to climate factors, atmospheric circulation, vegetation status and some spatial factors. Snow cover impacts climate change through interactions with atmospheric circulation systems. The rise in temperature will delay the SCOD, and the SCED is closely related to the temperature of the snowmelt season. The interaction between seasonal snow cover and climate will either stimulate or impede vegetation growth. With the change in snow cover, especially the decrease in snow cover in the melting stage can impact the climate change, the rise in temperature will change the growth conditions and extend the vegetation growth season. The relationship between snow cover and vegetation is inconsistent in different elevations and latitudes. Snow phenology variation is very complex and is the result of the combined action of many factors. Additionally, snow phenology will also have a great impact on the cryosphere. Therefore, we must understand snow phenology variation and prepare for future changes.

In order to find novel antiplatelet drugs for the treatment of ischemic stroke, a series of 3-butylphthalide derivatives containing isopentenylphenol moiety were designed, synthesized and characterized with spectroscopic analyses. The in vitro antiplatelet activity results indicated that compound 3 better inhibited the arachidonic acid (AA) induced platelet aggregation than aspirin (ASP) and 3-butylphthalide (NBP). Additionally, compared with precursor NBP, compound 3 possessed outstanding antithrombotic activity in the animal experiment model, which could effectively alleviate the formation of tail thrombus and carotid artery thrombus in mice. More importantly, intraperitoneal administration of compound 3 can well protected the rats against ischemia/reperfusion-induced brain injury. Further pharmacokinetic (PK) assay indicated that compound 3 had good absorption characteristics and metabolic stability in vivo. Overall, the present research provides a new candidate compound for the treatment of ischemic stroke caused by platelet aggregation.

TNFα-induced protein 1 (TNFAIP1) serve a role in neurovascular disease. However, the potential role and molecular mechanism of TNFAIP1 in cerebral ischemia-reperfusion (I/R) remains elusive. In the present study, reverse transcription-quantitative PCR and western blotting were used to assess TNFAIP1 mRNA and protein expression levels in PC12 cells. Furthermore, using Cell Counting Kit-8, flow cytometry and western blotting, cell viability and apoptosis were evaluated. Oxidative stress was evaluated using DCFH-DA staining and ELISA was used for assessment of inflammatory factors. Expression of components in the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and ferroptosis were assessed using western blotting analysis and an iron assay kit. TNFAIP1 expression was significantly upregulated in oxygen glucose deprivation and reperfusion (OGD/R)-injured PC12 cells. However, knocking down TNFAIP1 expression restored PC12 cell viability and decreased apoptosis following OGD/R-challenge. Furthermore, TNFAIP1 silencing significantly suppressed OGD/R-induced oxidative stress and inflammatory damage in PC12 cells. TNFAIP1 knockdown inhibited ferroptosis via activation of the Nrf2 signaling pathway in OGD/R-injured PC12 cells. Erastin treatment reversed the beneficial effects of TNFAIP1 knockdown on PC12 cell viability, apoptosis alleviation, oxidative stress and inflammation following OGD/R treatment. These results suggested that TNFAIP1 knockdown could alleviate OGD/R-induced neuronal cell damage by suppressing Nrf2-mediated ferroptosis, which might lay the foundation for the investigation of targeted-therapy for cerebral I/R injury in clinic.

The terrestrial carbon cycle is an important component of global biogeochemical cycling and is closely related to human well-being and sustainable development. However, large uncertainties exist in carbon cycle simulations and observations. Model-data fusion is a powerful technique that combines models and observational data to minimize the uncertainties in terrestrial carbon cycle estimation. In this paper, we comprehensively overview the sources and characteristics of the uncertainties in terrestrial carbon cycle models and observations. We present the mathematical principles of two model-data fusion methods, i.e., data assimilation and parameter estimation, both of which essentially achieve the optimal fusion of a model with observational data while considering the respective errors in the model and in the observations. Based upon reviewing the progress in carbon cycle models and observation techniques in recent years, we have highlighted the major challenges in terrestrial carbon cycle model-data fusion research, such as the “equifinality” of models, the identifiability of model parameters, the estimation of representativeness errors in surface fluxes and remote sensing observations, the potential role of the posterior probability distribution of parameters obtained from sensitivity analysis in determining the error covariance matrixes of the models, and opportunities that emerge by assimilating new remote sensing observations, such as solar-induced chlorophyll fluorescence. It is also noted that the synthesis of multisource observations into a coherent carbon data assimilation system is by no means an easy task, yet a breakthrough in this bottleneck is a prerequisite for the development of a new generation of global carbon data assimilation systems. This article also highlights the importance of carbon cycle data assimilation systems to generate reliable and physically consistent terrestrial carbon cycle reanalysis data products with high spatial resolution and long-term time series. These products are critical to the accurate estimation of carbon cycles at the global and regional scales and will help future carbon management strategies meet the goals of carbon neutrality.

Grasslands are the basis for sustainable development in the northern farming-pastoral transition zone of China, with functions of human production, living, and ecology. Large-scale human activities inevitably lead to significant changes in grasslands, resulting in significant impacts on ecosystem services. To this end, we quantitatively estimated the ecosystem services value in each positive succession process (the improvement in the coverage or area of grasslands) and negative succession process (the degradation in the coverage or area of grasslands). The results indicated that (1) grasslands showed an improving trend from 2000 to 2015. The grassland improvement from low to high coverage dominated the positive succession process. Grassland degradation from high to low coverage dominated the negative succession process. (2) The total ecosystem services value increased by 25,294.87 × 104 yuan from 2000 to 2015. The grassland improvement from low to high coverage was the most important process that led to the increase in ecosystem service value. The degradation between grasslands and non-grasslands was the key process that led to the decrement in ecosystem services value. (3) The impact of grassland dynamics on the regional ecosystem service value showed significant spatial heterogeneity at the town scale. The results will provide some implications for the sustainable development of grassland ecosystem services to improve human well-being.

The ratio of plant transpiration to total terrestrial evapotranspiration (T/ET) captures the role of vegetation in surface-atmosphere interactions. However, several studies have documented a large variability in T/ET. In this paper, we present a new T/ET dataset (also including transpiration, evapotranspiration data) for China from 1981 to 2015 with spatial and temporal resolutions of 0.05° and 8 days, respectively. The T/ET dataset is based on a model-data fusion method that integrates the Priestley-Taylor Jet Propulsion Laboratory (PT-JPL) model with multivariate observational datasets (transpiration and evapotranspiration). The dataset is driven by satellite-based leaf area index (LAI) data from GLASS and GLOBMAP, and climate data from the Chinese Ecosystem Research Network (CERN). Observational annual T/ET were used to validate the model, with R2 and RMSE values were 0.73 and 0.07 (12.41%), respectively. The dataset provides significant insight into T/ET and its changes over the Chinese terrestrial ecosystem and will be beneficial for understanding the hydrological cycle and energy budgets between the land and the atmosphere., Measurement(s) ratio of transpiration to total terrestrial evapotranspiration • evapotranspiration • transpiration Technology Type(s) model-data fusion • computational modeling technique • digital curation Factor Type(s) year of data collection Sample Characteristic - Environment terrestrial biome Sample Characteristic - Location China Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12917642

CuxMnxFe3-2xO4/MWCNT nanocomposites were prepared by co-precipitation method. The structure, morphology, and surface properties of the samples were characterized by X-ray diffraction (XRD), Transmission electron microscopy (TEM), Energy dispersive spectrometer (EDS), Fourier transform infrared spectrometer (FTIR), N2 physical adsorption instrument, and X-ray photoelectron spectrometer (XPS). The successful loading of metal oxides on MWCNTs increased the catalytic activity of nanocomposites. In addition, CuxMnxFe3-2xO4/MWCNTs were used as catalyst for the degradation of PVA wastewater by catalytic wet air oxidation. Under the degradation conditions, pH was 2.5, catalyst dosage was1.5 g/L, reaction temperature was 275 °C, oxygen pressure was 1.0MP, the PVA degradation rate was 99.94%, the viscosity average molecular weight was decreased by 99.36%, and the degradation products were small molecules such as aldehydes, phenols, and acids, which basically confirmed the degradation of PVA wastewater. The degradation principle and kinetics were analyzed. The catalyst was washed and recovered and can maintain good catalytic capacity after four times of repeated use.

In this study, a series of naringenin

Precipitation change is critical for the Three-River Headwaters (TRH) region, which serves downstream communities in East Asia. The spring (March–May) precipitation over the TRH region shows an increasing trend from 1979 to 2018, as revealed by a Chinese gridded precipitation product (CN05.1). However, the physical processes responsible for this precipitation change are still unclear. This study investigated the characteristics of spring precipitation and the water budget over the TRH region using the ERA5 global reanalysis and the Weather Research and Forecast (WRF) Model. The WRF version employed in this study includes online calculations of the atmospheric water budget and an evapotranspiration (ET) tagging procedure to trace evapotranspired water in the atmosphere. Both ERA5 and WRF reproduce the spring precipitation increase. Moreover, WRFD02 (with a 3-km domain) reduces the wet bias by around 60% and 77% compared to WRFD01 (9 km) and ERA5 (30 km). Both ERA5 and WRF demonstrate that the increase of spring precipitation is dominated by moisture convergence, especially the atmospheric water fluxes from the southern boundary. The enhanced moisture inflow is sustained by enhanced mass flux while the enhanced moisture outflow is sustained by increased moisture. The ET-tagging results further demonstrate the weakened precipitation recycling process because of the significant increase of precipitation produced by external moisture. Compared to ERA5, the reduced wet bias with WRF is attributed to a better spatial resolution of orographic barrier effects, which reduce the southerly water fluxes. The results highlight the potential of regional climate downscaling to better represent the atmospheric water budget in complex terrain.

The commonly applied pedotransfer functions (PTFs), which predict soil hydraulic properties (SHPs) from easily measured soil properties such as texture information, often account only for capillary...

Hydraulic conductivity curves (HCCs) are important parameters in land surface modeling. The general way for predicting HCC from soil water retention curve (SWRC) requires an additional input of the...

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC

Due to the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy presented the best pharmacological option for AD treatment. Herein, a series of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives was rationally designed and synthesized. Of these derivatives, 5c was a good multifunctional agent (eeAChE IC50 =7.9 μM, MAO-B IC50 = 9.9 μM, BACE1 IC50 = 8.3 μM) in vitro and displayed a mixed-type AChE inhibition, which could bind to the CAS and PAS of AChE. Compound 5c also exhibited good antioxidant activity (ORAC = 2.5 eq) and neuroprotective effects. Furthermore, compound 5c was a selective metal ions chelator. And it could cross blood-brain barrier in vitro and complied with drug-like properties rule of 5. Therefore, compound 5c was a promising multifunctional agent for the treatment of AD.

Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC