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Abstract: Purpose: The purpose of our study was to compare three-dimensional (3D) negative-contrast CT cholangiopancreatography (3D-nCTCP) with 3D MR cholangiopancreatography (3D-MRCP) for the diagnosis of obstructive biliary diseases. Materials and methods: 3D-nCTCP and 3D-MRCP were performed on seventy clinically documented obstructive biliary diseases patients. The accuracy of each technique in determining the location and cause of biliary obstruction was evaluated compared with the final clinical diagnoses. Results: Both methods achieved 100% of accuracy in the diagnosis of the presence and location of biliary obstruction, and had a similar sensitivity, specificity, accuracy in differentiating benign from malignant biliary obstruction or calculous from noncalculous biliary obstruction (p >0.05). At 3D-nCTCP, six patients with stones were misinterpreted as cholangitis (N =2), papillitis (N =3), or bile duct adenocarcinoma (N =1); two metastases were mistaken as acute pancreatitis or pancreatic head carcinomas, and one intrahepatic cholangiocarcinoma was misled as bile duct adenoma. At 3D-MRCP, one small stone, one ampullary adenoma, and one intrahepatic cholangiocarcinoma were mistaken as cholangitis, ampullary stone, and intrahepatic bile duct stone, respectively, and three gallbladder carcinomas and another intrahepatic cholangiocarcinoma were misdiagnosed as hilar cholangiocarcinoma (N =3) or common hepatic duct stone (N =1); four metastases were mistaken as pancreatic head carcinomas (N =3) or distal cholangiocarcinoma (N =1). The overall accuracy in making specific diagnosis of the cause of biliary obstruction was 87.1% for 3D-nCTCP and 84.3% for 3D-MRCP, respectively, (p >0.05). Conclusion: 3D-nCTCP has the similar effects as 3D-MRCP for the diagnosis of biliary obstruction and, the location and the cause of biliary obstruction. In view of selected cases contraindications for MRI, 3D-nCTCP is a potential substitute. [Copyright &y& Elsevier]

Abstract: Textured surface boron-doped zinc oxide (ZnO:B) thin films were directly grown via low pressure metal organic chemical vapor deposition (LP-MOCVD) on polyethylene terephthalate (PET) flexible substrates at low temperatures and high-efficiency flexible polymer silicon (Si) based thin film solar cells were obtained. High purity diethylzinc and water vapors were used as source materials, and diborane was used as an n-type dopant gas. P-i-n silicon layers were fabricated at ~398K by plasma enhanced chemical vapor deposition. These textured surface ZnO:B thin films on PET substrates (PET/ZnO:B) exhibit rough pyramid-like morphology with high transparencies (T ~80%) and excellent electrical properties (Rs ~10Ω at d ~1500nm). Finally, the PET/ZnO:B thin films were applied in flexible p-i-n type silicon thin film solar cells (device structure: PET/ZnO:B/p-i-n a-Si:H/Al) with a high conversion efficiency of 6.32% (short-circuit current density J SC =10.62mA/cm2, open-circuit voltage V OC =0.93V and fill factor=64%). [Copyright &y& Elsevier]

This paper presents a multi-proxy reconstruction of the climate change in Caotanhu wetland using pollen, phytolith and charcoal records, and the data of loss of ignition (LOl), grain size analysis, and susceptibility. Results reveal that between 4550 and 2500 cal. a BP, a dry climatic condition was not favorable for the accumulation of peat. Since 2500 cal. a BP, the climate became humid and the wetland developed with abundant freshwater aquatic plants, which contributed to peat accumulation. Nevertheless, alternate periods of rain and dry climate occurred during that period. Between 2500 and 1810 cal. a BP (550 BC-140 AD), the climate was more humid than at present. A lot of emerged plants, such as Phragmites, Typha and Sparganium, and freshwater green algae grew in the wetland which was surrounded by desert-steppe vegetation composed mainly of Chenopodiaceae, Artemisia, Compositae and Thalictrum. However, from 1810 to 1160 cal. a BP (140-790 AD), the water level started to decrease and hydrophyte species reduced greatly, but some Phragmites still grew in the wetland and around it was desert vegetation with high proportion of Chenopodiaceae and Artemisia. Then from 1160 to 650 a BP (790-1300 AD), it entered a period of desert-steppe with abundant mesic and xerophytic plants. And a lot of aquatic plants prevailed in the wetland. Here, what is noticeable is that percentages of arboreal pollen, consisting mainly of Betula and Picea, increased greatly and reached a maximal value of 27.2%, in which, Betula percentages rose to 23.2%. Hence, it is reasonable to conclude that Betula grew in the highland of the wetland, or Picea timberline shifted downward resulting in the increase of percentages of Betula and Picea pollen, which were transported into the wetland by flood or wind. But since 650 cal. a BP, desert vegetation prevailed around the wetland again with dominant Chenopodiaceae and Artemisia, and the climate was similar to modern one. Despite some aquatic plants still growing in the wetland at that time, their amounts diminished greatly. [ABSTRACT FROM AUTHOR]

A modern pollen dataset with an even distribution of sites is essential for pollen-based past vegetation and climate estimations. As there were geographical gaps in previous datasets covering the central and eastern Tibetan Plateau, lake surface sediment samples (n=117) were collected from the alpine meadow region on the Tibetan Plateau between elevations of 3720 and 5170 m a.s.l. Pollen identification and counting were based on standard approaches, and modern climate data were interpolated from a robust modern meteorological dataset. A series of numerical analyses revealed that precipitation is the main climatic determinant of pollen spatial distribution: Cyperaceae, Ranunculaceae, Rosaceae, and Salix indicate wet climatic conditions, while Poaceae, Artemisia , and Chenopodiaceae represent drought. Model performance of both weighted-averaging partial least squares (WA-PLS) and the random forest (RF) algorithm suggest that this modern pollen dataset has good predictive power in estimating the past precipitation from pollen spectra from the eastern Tibetan Plateau. In addition, a comprehensive modern pollen dataset can be established by combining our modern pollen dataset with previous datasets, which will be essential for the reconstruction of vegetation and climatic signals for fossil pollen spectra on the Tibetan Plateau. Pollen datasets including both pollen counts and percentages for each sample, together with their site location and climatic data, are available at the National Tibetan Plateau Data Center (TPDC; Cao et al., 2021; 10.11888/Paleoenv.tpdc.271191). [ABSTRACT FROM AUTHOR]

miRNAs belong to small non-coding RNAs that are related to a number of complicated biological processes. Considerable studies have suggested that miRNAs are closely associated with many human diseases. In this study, we proposed a computational model based on Similarity Constrained Matrix Factorization for miRNA-Disease Association Prediction (SCMFMDA). In order to effectively combine different disease and miRNA similarity data, we applied similarity network fusion algorithm to obtain integrated disease similarity (composed of disease functional similarity, disease semantic similarity and disease Gaussian interaction profile kernel similarity) and integrated miRNA similarity (composed of miRNA functional similarity, miRNA sequence similarity and miRNA Gaussian interaction profile kernel similarity). In addition, the L2 regularization terms and similarity constraint terms were added to traditional Nonnegative Matrix Factorization algorithm to predict disease-related miRNAs. SCMFMDA achieved AUCs of 0.9675 and 0.9447 based on global Leave-one-out cross validation and five-fold cross validation, respectively. Furthermore, the case studies on two common human diseases were also implemented to demonstrate the prediction accuracy of SCMFMDA. The out of top 50 predicted miRNAs confirmed by experimental reports that indicated SCMFMDA was effective for prediction of relationship between miRNAs and diseases. Author summary: Considerable studies have suggested that miRNAs are closely associated with many human diseases, so predicting potential associations between miRNAs and diseases can contribute to the diagnose and treatment of diseases. Several models of discovering unknown miRNA-diseases associations make the prediction more productive and effective. We proposed SCMFMDA to obtain more accuracy prediction result by applying similarity network fusion to fuse multi-source disease and miRNA information and then utilizing similarity constrained matrix factorization to make prediction based on biological information. The global Leave-one-out cross validation and five-fold cross validation were applied to evaluate our model. Consequently, SCMFMDA could achieve AUCs of 0.9675 and 0.9447 that were obviously higher than previous computational models. Furthermore, we implemented case studies on significant human diseases including colon neoplasms and lung neoplasms, 47 and 46 of top-50 were confirmed by experimental reports. All results proved that SCMFMDA could be regard as an effective way to discover unverified connections of miRNA-disease. [ABSTRACT FROM AUTHOR]

The northern slopes of central Tianshan Mountains in Xinjiang, northwestern China can provide an ideal database to research palaeoclimate as disturbance by human impact is relatively low and the vegetation zones reflect climatic gradients. In order to establish the correlation between modern climatic factors and surface pollen assemblages and to reconstruct palaeoclimate on the northern slope of central Tianshan Mountains, three Holocene sections in Daxigou, Huashuwozi and Sichanghu located at different elevations and vegetation zones were chosen for study. A total of 80 surface pollen samples in 86 vegetation quadrats were collected for pollen-vegetation relationship analysis. The Warmth Index (WI) and Moisture Index (MI) were calculated based on averaged modern climate data during 1951 - 2000 at eight weather stations in the study area. Pollen percentages of Picea, Artemisia, Chenopodiaceae, Ephedra, and Tamarix, as well as A/C (Artemisia/Chenopodiaceae) and AP/NAP (arboreal/nonarboreal pollen) ratio were selected as pollen variables and WI and MI were chosen as climatic variables. The relationship between pollen percentages (Picea, Artemisia, Chenopodiaceae and Tamarix), A/C, AP/NAP ratio, WI and MI values were estimated (95% confidence interval) using stepwise multiple linear regression analysis. WI and MI values for the three sections were calculated using these regression equations, and palaeoclimate for the study area could be reconstructed. The results showed periods of both cool-humid and warm-dry conditions on the northern slopes of Tianshan Mountain during the late Holocene. [ABSTRACT FROM AUTHOR]

Xinjiang Autonomous Region is located in the arid area of westerly of China and there are many arguments about the changes of past temperature and moisture. Most of the lakes on the plain in northern Xinjiang are sealed lakes and terminal lakes. They can evidently reflect the changes in palaeoclimate. The palaeoenvironmental changes of some plain lakes in northern Xinjiang during the late Holocene will be analysed mainly based on the data of pollen, sedimentary facies, loss on ignition (LOl), susceptibility and grain size from the Sichang Lake, Dongdaohaizi Lake and Aibi Lake. Results reveal an assembled pattern of temperature and moisture dominated by cold-wet and warm-dry. In addition, the impact factor will be discussed. [ABSTRACT FROM AUTHOR]

The extracellular matrix protein 1 (ECM1) is a secreted protein that has been implicated with cell proliferation, angiogenesis and differentiation. In the present study, we used immunohistochemical staining to examine the expression of ECM1 in a panel of human tumors and found that it was closely correlated with some types of tumors including: invasive breast ductal carcinoma (83%), esophageal squamous carcinoma (73%), gastric cancer (88%) and colorectal cancer (78%). Significantly, ECM1expression was correlated with the metastatic properties of the tumors. Primary breast cancers that had formed metastases were 76% positive while those that had not metastasized were only 33% positive. ECM1 expression was also correlated with PCNA a marker for proliferation, but not with CD34, a marker for endothelial cells. These results indicate that ECM1 tends to be preferentially expressed by metastatic epithelial tumors. [Copyright &y& Elsevier]

Background: MicroRNAs (miRNAs) have been confirmed to have close relationship with various human complex diseases. The identification of disease-related miRNAs provides great insights into the underlying pathogenesis of diseases. However, it is still a big challenge to identify which miRNAs are related to diseases. As experimental methods are in general expensive and time-consuming, it is important to develop efficient computational models to discover potential miRNA-disease associations.Methods: This study presents a novel prediction method called HFHLMDA, which is based on high-dimensionality features and hypergraph learning, to reveal the association between diseases and miRNAs. Firstly, the miRNA functional similarity and the disease semantic similarity are integrated to form an informative high-dimensionality feature vector. Then, a hypergraph is constructed by the K-Nearest-Neighbor (KNN) method, in which each miRNA-disease pair and its k most relevant neighbors are linked as one hyperedge to represent the complex relationships among miRNA-disease pairs. Finally, the hypergraph learning model is designed to learn the projection matrix which is used to calculate uncertain miRNA-disease association score.Result: Compared with four state-of-the-art computational models, HFHLMDA achieved best results of 92.09% and 91.87% in leave-one-out cross validation and fivefold cross validation, respectively. Moreover, in case studies on Esophageal neoplasms, Hepatocellular Carcinoma, Breast Neoplasms, 90%, 98%, and 96% of the top 50 predictions have been manually confirmed by previous experimental studies.Conclusion: MiRNAs have complex connections with many human diseases. In this study, we proposed a novel computational model to predict the underlying miRNA-disease associations. All results show that the proposed method is effective for miRNA-disease association predication. [ABSTRACT FROM AUTHOR]

Background: Gene and chemical therapy has become one of the rising stars in the field of molecular medicine during the last two decades. However, there are still numerous challenges in the development of efficient, targeted, and safe delivery systems that can avoid siRNA degradation and reduce the toxicity and adverse effects of chemotherapy medicine. Results: In this paper, a highly efficient AS1411 aptamer modified, dsDNA and MMP-2 cleavable peptide-fabricated gold nanocage vehicle, which could load doxorubicin hydrochloride (DOX) and siRNAs to achieve a combination of tumor responsive genetic therapy, chemotherapy, and photothermal treatment is presented. Our results show that this combined treatment achieved targeted gene silencing and tumor inhibition. After nearly one month of treatment with DOX-loaded Au-siRNA-PAA-AS1411 nanoparticles with one dose every three days in mice, a synergistic effect promoting the eradication of long-lived tumors was observed along with an increased survival rate of mice. The combined genetic, chemotherapeutic, and photothermal treatment group exhibited more than 90% tumor inhibition ratio (tumor signal) and a ~ 67% survival rate compared with a 30% tumor inhibition ratio and a 0% survival rate in the passive genetic treatment group. Conclusions: The development of nanocarriers with double-stranded DNA and MMP-2 cleavable peptides provides a new strategy for the combined delivery of gene and chemotherapy medicine. Au-siRNA-PAA-AS1411 exerts high anticancer activities on lung cancer, indicating immense potentials for clinical application. [ABSTRACT FROM AUTHOR]

Three novel inorganic-organic hybrid materials, [PbI 3 (BTA-1)] n (1) (BTA-1 = N -((1 H -benzotriazole-1-yl)methyl)- N , N -dimethyl ethylammonium)，[Cu 2 I 3 (BTA-2)] n (2) (BTA-2 = 1-(1 H -benzotriazole-1-yl)- N , N , N -trimethylammonium carbamate) and [ZnI 3 (BTA-3)] n (3) (BTA-3 = 3-(1 H -benzotriazole-1-yl)- N , N , N -trimethylpropane-1-ammonium), have been was prepared by a solvent volatilization method. All three complexes have been characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD) and thermogravimetric (TG) analysis. Based on different metal iodides, they stack in different structural modes with different cluster cores, such as [PbI 6 ]2- in complex 1 , [Cu 4 I 6 ]2- in complex 2 and [ZnI 3 N]2- in complex 3. The fluorescence analysis show that complex 1 and 2 produced green light when the excitation wavelength was 318 nm and 328 nm, respectively. While complex 3 exhibited near white light when the excitation wavelength was 424 nm (CIE: 0.332, 0.395). It shows that complex 3 can be used as a white light emitting material for direct blue light excitation. By solvent volatilization method, three late-model inorganic-organic hybrid materials, [PbI 3 (BTA-1)] n (1)，[Cu 2 I 3 (BTA-2)] n (2) and [ZnI 3 (BTA-3)] n (3) (BTA = 1 H -benzotriazole), have been prepared. The fluorescence properties showed that complex 1 and 2 produced green light respectively. While complex 3 exhibited near white light (CIE: 0.332,0.395). It shows that complex 3 can be used as a white light emitting material for direct blue light excitation. [Display omitted] • Three luminescent inorganic-organic hybrid materials, 1 – 3 , have been was prepared by a solvent volatilization method. • Based on different metal iodides, they stack in different structural modes with different cluster cores, such as [PbI 6 ]2- in 1 , [Cu 4 I 6 ]2- in 2 and [ZnI 3 N]2- in 3. • This regulation realize complexes' emission from green light to near-white light. • Complex 3 exhibited near white light when excited at 424 nm. It shows 3 can be used as a white light emitting material for direct blue light excitation. [ABSTRACT FROM AUTHOR]

• Pollen-based mean annual precipitation reconstruction on northeastern TP. • High precipitation in mid-Holocene contributed by the ASM. • Late-Holocene wetting trend may relate to varied rainfall seasonality. • Westerlies contributed to the increased non-monsoonal rainfall in late Holocene. Both the Asian Summer Monsoon (ASM) and Westerlies exhibit strong impacts on climate changes of the Tibetan Plateau (TP), but little is known about their contributions to regional precipitation during the Holocene. Here we reported a pollen record from Lake Alake, based on which the quantitative mean annual precipitation (P ANN) was reconstructed. Herbaceous taxa of Cyperaceae, Poaceae, Chenopodiaceae, and Artemisia were dominant in Alake pollen assemblage whose variations were mainly affected by humidity changes. The precipitation was high in 7200–5400 cal. yr BP, followed by decreasing trends in 5000–3000 cal. yr BP, and obviously increased after 3000 cal. yr BP. The variations of P ANN in the Alake record suggest that high precipitation in middle Holocene was primarily contributed by the ASM driven by orbital forcing of insolation. However, the rising trend of P ANN during the late Holocene probably indicated the increased of non-monsoonal precipitation and highlighted the contribution from the Westerlies. Our results suggest that the variation of precipitation transported by Westerlies might have reduced the seasonal variability of precipitation and contributed to the long-term wetting trend on the northeastern TP during the late Holocene. [ABSTRACT FROM AUTHOR]

• Investigate the impacts of climate and land use change on four Camellia oilseed species in China. • Climate is expected to override the effects of land use. • Some species would benefit from future changes while others were negatively affected. • The four species shift not only to northwards but also in other directions. • The persistent suitable areas occupied different regions with little overlap except Camellia oleifera. Predicting changes in suitable areas under climate and land use changes, and identifying persistent suitable areas for economically valuable plant species, are critical for future conservation and cultivation. Camellia chekiangoleosa , Camellia drupifera , Camellia oleifera and Camellia reticulata serve as important woody oilseed species in China, providing both economic and ecological benefits. Here, we predict the distributions of the four species under climate and land use changes (SSP126, SSP245 and SSP585 in 2070) combining two dispersal constraint scenarios (full dispersal and 20 km/decade) by using ensemble species distribution models. The results showed that the current potential suitable areas of the four species coincided with their current known distribution regions; most of these areas are of high suitability. Among the environmental variables, climatic factors have stronger effects on the distribution of the four species than land use factors. In response to climate and land use changes, the range sizes of C. chekiangoleosa and C. drupifera were projected to increase, while for C. oleifera and C. reticulata the range would contract. In addition, the centroid of the suitable range would shift in different directions and distances for different species. As a result of distinctive range shifts, the studied species have their own specific areas of persistent suitability in southern China. Notably, except for the widespread C. oleifera , there is almost no overlap in the persistent suitable areas among the other three species. This study gives us a better understanding of the impact of climate and land use changes on the major Camellia oilseed species in China, thus guiding the selection of sites for oil tea plantations and the conservation of germplasm resources. [ABSTRACT FROM AUTHOR]

[Display omitted] • CZnONPs and GZnONPs mitigated the dissemination risks of ARGs in cattle manure. • The GZnONPs group exhibited a significant reduction in manure zinc content. • Different QS-related KEGG Orthology caused changes in expression patterns of ARGs. • Zinc selection pressure during anaerobic fermentation affected the ARG profiles. • Dominant ARG subtypes were shifted because of the changing abundance of ARG hosts. This study used metagenomic sequencing to examine the effects of carbon-based zinc oxide nanoparticles (CZnONPs) and graphene-based zinc oxide nanoparticles (GZnONPs) on quorum sensing (QS), antibiotic resistance genes (ARGs) and microbial community changes during cattle manure production. The manure zinc content was significantly reduced in GZnONPs group. In the QS pathway, the autoinducer gene increases significantly in Control group, while the transporter and repressor genes experience a substantial increase in CZnONPs group. These results contributed to the significantly decreased the abundance of ARGs in GZnONPs group. The co-occurrence network analysis revealed a correlation between core ARGs and QS-related KEGG Orthology or ARGs' hosts, indicating that the selective pressure of zinc influences microbial QS, forming a unique ARG pattern in in vivo anaerobic fermentation. These findings suggest that implementing nutritional regulation in farming practices can serve as a preventive measure to mitigate the potential transmission of ARGs resulting from livestock waste. [ABSTRACT FROM AUTHOR]

• Clinical trials of drug research and development approved by NMPA. • A total of 9,401 clinical trials were analyzed in this article. • Analyzed the phase, indication, dosage form, applicant of the clinical trials. • Analyzed the status and provided proposal for drug R&D in China. The research and development (R&D) of new drugs indicates scientific progress and economic development. However, little is known regarding ongoing or recent clinical trials in China. We analyzed data from clinical trials published before December 31, 2019, and found that the annual registration numbers are increasing annually in the country. Based on clinical indications, most tested drugs target cancers, nervous system, infections, and the cardiovascular system. Furthermore, clinical trials are mostly concentrated in Beijing, Shanghai, and Jiangsu, and conducted by large pharmaceutical companies, with multiple trials for several generic drugs. Going forward, it will be necessary to promote R&D in China of clinically relevant innovative drugs, drug delivery systems, and novel traditional Chinese medicine (TCM) and biological products, as well as to have a balanced distribution of clinical trials to sustainably meet public health needs. [ABSTRACT FROM AUTHOR]

Acetylshikonin, a naphthoquinone derivative, is mainly extracted from some species of the family Boraginaceae, such as Lithospermum erythrorhizon Sieb. et Zucc., Arnebia euchroma (Royle) Johnst., and Arnebia guttata Bunge. As a bioactive compound, acetylshikonin has attracted much attention because of its broad pharmacological properties. This review provides a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of acetylshikonin focussing on its mechanisms on the basis of currently available literature. The information of acetylshikonin from 1977 to 2020 was collected using major databases including Elsevier, Scholar, PubMed, Springer, Web of Science, and CNKI. Acetylshikonin, pharmacology, toxicity, pharmacokinetics, and naphthoquinone derivative were used as key words. According to emerging evidence, acetylshikonin exerts a wide spectrum of pharmacological effects such as anticancer, anti-inflammatory, lipid-regulatory, antidiabetic, antibacterial, antifungal, antioxidative, neuroprotective, and antiviral properties. However, only a few studies have reported the adverse effects of acetylshikonin, with respect to reproductive toxicity and genotoxicity. Pharmacokinetic studies demonstrate that acetylshikonin is associated with a wide distribution and poor absorption. Although experimental data supports the beneficial effects of this compound, acetylshikonin cannot be considered as a therapy drug without further investigations, especially, on the toxicity and pharmacokinetics. [ABSTRACT FROM AUTHOR]

The tunability of their structure and function is why metal organic frameworks (MOFs) are widely used in drug carrier research. The modification of organic ligands can achieve the regulation of the functions and properties of MOFs. In our research, the amino-functionalized metal organic framework of Zn with 2-aminoterephthalate, IRMOF-3, was studied as an antitumor drug curcumin carrier. The nanoparticles can efficiently encapsulate the anticancer drug curcumin. IRMOFs and drug-loaded IRMOFs were characterized using different techniques. Furthermore, a simulated release test was carried out on the nanomedicine system in vitro. In addition, the drug loading and release activity has been compared with that of the isostructural amino-free MOF (IRMOF-1). The drug load capacity of IRMOF-3 (55.36%) is found to be significantly higher than that of IRMOF-1 (49.30%). And the cumulative release rate of curcumin from IRMOF-3 was slower than that from IRMOF-1. That is to say, IRMOF-3 has a more pronounced slow release behavior than IRMOF-1. The superior performance of IRMOF-3 has been attributed to the affinity between the side chain amino group and curcumin. Amino groups increase the affinity of the MOFs with curcumin, which can increase the drug loading capacity and slow the drug release rate. Also, the low cytotoxicity and good biocompatibility of the two materials were certified using an MTT assay. Thus, the addition of groups will have a certain effect on the drug loading performance of MOFs. We propose to synthesize different group-functionalized metal organic frameworks to obtain excellent drug carrier materials. [ABSTRACT FROM AUTHOR]

Lentinan is widely used as a therapeutic agent for treatment of malignant tumors in clinical practice. The chemical structure of lentinan is highly associated with its biological activity. In this study, the correlation between the structure of lentinan and its immune activity was investigated to assess the function of key parameters that can influence quality control of lentinan. The results showed that the batch-to-batch consistency of two lentinan samples was satisfactory, indicating the stability of production process of lentinan. However, although the chemical composition and triple-helical conformation (THC) of the tested samples were relatively similar, their M w, polydispersity index (PDI), and R g z remarkably varied due to different production processes. In vitro immunomodulatory assay reflects that lentinan could stimulate the macrophages phagocytic capacity. Meanwhile, lentinan samples could improve the spleen and thymus indices, promote the proliferation of lymphocytes and adjust for the percentages of CD4+ and CD8+ T cells in vivo. Furthermore, the immunomodulatory effect of lentinan sample B (M w: 650,700 g/mol) was superior than that of the sample A (M w: 4,818,700 g/mol). It was noted that the M w should be detected as a necessary index for quality control of lentinan to ensure stability and effectiveness of the production process. • M w, PDI and Rgz of lentinan (LNT) from different manufactures remarkably varied due to different production processes. • Batch-to-batch consistency of two LNT was satisfactory. • LNT from two manufactures showed great immunomodulatory effects. • The immunomodulatory effects of LNT B manufacturer with M w 650700 g/mol was superior than that of LNT A with M w 4818700 g/mol. • M w is a key factor highly associated to its activity, which should be detected for quality control of LNT. [ABSTRACT FROM AUTHOR]

Human activities in the historical period were determined by the natural environment and social characteristics. The Zuojiang Huashan Rock Art Cultural Landscape in Guangxi is the most important World Heritage for prehistorical culture in southwestern China. However, knowledge about the natural environment and associated historic human–climate interactions during the period of cliff painting creation remains scarce, which has been an obstacle to understanding the process of regional civilization. Here, we report a pollen record from the core distributing region of Huashan cliff paintings to interpret the natural environment and climate changes, and further to discuss how and why ancient people create these giant cliff paintings based on the relationships of human–climate interactions. Pollen results imply an existence of a mixed broad-leaf and conifer forest in the woodland landscape at Huashan region before 1860 cal. yr BP, after which pine forests were more prevalent. During the cliff painting period from 2370 to 2115 cal. yr BP, broad-leaf and conifer trees dominated the tree layer and provided the key source materials for painting. It can be reasonably assumed that people used stake or ladder to climb the cliffs and created the cliff paintings during a humid climate condition from 2560 to 2000 cal. yr BP. Furthermore, the humid climate during 2700 and 2400 cal. yr BP had been interrupted by short-term drought episodes. These turbulent climate episodes probably played the role of disasters and impacted on the human activities, leading to the social–political tensions and the out-break of war. During the Qin and Han Dynasties, social–political changes relieved the pressure from natural climate changes and led to a more stable society, in which the creating of cliff paintings was gradually fading. Our results manifest the necessity to analyze the natural environment and social–political background in combination in this study on ancient human activities. [ABSTRACT FROM AUTHOR]

TRIM13, a member of the TRIM family, is a RING domain containing E3 ubiquitin ligase which plays critical roles in diverse cellular processes including cell death, cancer and antiviral immunity. However, its expression and molecular mechanism on renal cell carcinoma (RCC) have not been characterized. This study explored the clinical significance and biological function of TRIM13 in human RCC. Western blot analyses and Immunohistochemical were performed in RCC tissues. The clinical relevance of TRIM13 in RCC was evaluated by immunohistochemical staining using tissue microarray. The role of TRIM13 in migration was studied in renal cell carcinoma cell lines of 786-O through knocking down TRIM13 with siRNA and over-expression of TRIM13. The regulation of TRIM13 on migration and invasion were determined by wound-healing and transwell assays. Western blot analyses showed that TRIM13 expression was dramatically decreased in RCC tissues compared with adjacent non-tumorous tissues. Up-regulation of TRIM13 in 786-O cells resulted in decreased NF-kB, MMP-9 and p-AKT levels and the capability for migration and invasion. In contrast, the ectopic expression of TRIM13 decreased the migration and invasion ability of 786-O cells. These findings indicate that TRIM13 decreases RCC metastasis and invasion may serve as a candidate RCC prognostic marker and a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Aims: Polyphyllin I, a steroidal saponin in Rhizoma paridis, which possess broad application prospects in cancer prevention and treatment. The purpose of this study was to determine the potential cytotoxicity and mechanism of Polyphyllin I in HepG2 cells. Main methods: In this study, we used MTT to evaluate cell survival. Cell apoptosis rate, cell cycle distribution, mitochondrial membrane potential and ros levels were measured by flow cytometry, and the expression of apoptosis-related proteins was determined by Western blot analysis. Key findings: Polyphyllin I significantly reduced cell viability and induced HepG2 cell apoptosis in a dose and time-dependent manner. Compared with the control group, it could induce reactive oxygen species (ROS) generation and depolarization of matrix metalloproteinases in liver cells. Polyphyllin I dose-dependent increased the release of mitochondrial cytochrome c, and levels of Fas, p53, p21, and Bax/Bcl-2 ratios, as well as the activation of cleaved caspase-3, -8, -9, and subsequent cleavage of the poly (ADP-ribose) polymerase (PARP). The G2/M phase cell cycle arrest was induced by increasing the expression of p21 and cyclin E1, and significantly reducing the expression of cyclin A2 and CDK2. Significance: Our results suggested that Polyphylin I inhibited cell proliferation and growth by triggering G2/M cell cycle arrest, and induced apoptosis through intracellular and extracellular apoptosis pathways to cause cell death by generating reactive oxygen species. [ABSTRACT FROM AUTHOR]

As a source of genetic variation, almond germplasm resources are of great significance in breeding. To better reveal the mutation characteristics and evolution patterns of the almond chloroplast (cp) genome, the complete cp genomes from six almond species were analyzed. The lengths of the chloroplast genome of the six almond species ranged from 157,783 bp to 158,073 bp. For repeat sequence analysis, 53 pairs of repeats (30 bp or longer) were identified. A total of 117 SSR loci were observed, including 96 polymorphic SSR loci. Nine highly variable regions with a nucleotide variability (Pi) higher than 0.08, including rps16, rps16-psbK, atpF-atpH, rpoB, ycf3-rps4, rps4-ndhJ, accD-psaI and rps7-orf42 (two highly variable regions) were located. Based on the chloroplast genome evolution analysis, three species (P. tenella, P. pedunculata and P. triloba) and wild cherry (P. tomentosa) were grouped into clade I. Clade II consisted of two species (P. mongolica and P. tangutica) and wild peach (P. davidiana). Clade III included the common almond (P. dulcis), cultivated peach (P. persica) and GanSu peach (P. kansuensis). This result expands the researchers' vision of almond plant diversity and promotes an understanding of the evolutionary relationship among almond species. In brief, this study provides abundant resources for the study of the almond chloroplast genome, and has an important reference value for study of the evolution and species identification of almond. [ABSTRACT FROM AUTHOR]

Dysregulation of CDK8 (Cyclin-Dependent Kinase 8) and its regulatory partner CycC (Cyclin C), two subunits of the conserved Mediator (MED) complex, have been linked to diverse human diseases such as cancer. Thus, it is essential to understand the regulatory network modulating the CDK8-CycC complex in both normal development and tumorigenesis. To identify upstream regulators or downstream effectors of CDK8, we performed a dominant modifier genetic screen in Drosophila based on the defects in vein patterning caused by specific depletion or overexpression of CDK8 or CycC in developing wing imaginal discs. We identified 26 genomic loci whose haploinsufficiency can modify these CDK8- or CycC-specific phenotypes. Further analysis of two overlapping deficiency lines and mutant alleles led us to identify genetic interactions between the CDK8-CycC pair and the components of the Decapentaplegic (Dpp, the Drosophila homolog of TGFβ) signaling pathway. We observed that CDK8-CycC positively regulates transcription activated by Mad (Mothers against dpp), the primary transcription factor downstream of the Dpp/TGFβ signaling pathway. CDK8 can directly interact with Mad in vitro through the linker region between the DNA-binding MH1 (Mad homology 1) domain and the carboxy terminal MH2 (Mad homology 2) transactivation domain. Besides CDK8 and CycC, further analyses of other subunits of the MED complex have revealed six additional subunits that are required for Mad-dependent transcription in the wing discs: Med12, Med13, Med15, Med23, Med24, and Med31. Furthermore, our analyses confirmed the positive roles of CDK9 and Yorkie in regulating Mad-dependent gene expression in vivo. These results suggest that CDK8 and CycC, together with a few other subunits of the MED complex, may coordinate with other transcription cofactors in regulating Mad-dependent transcription during wing development in Drosophila. Author summary: CDK8 and its dedicated partner CycC are conserved subunits of the Mediator complex that bridges transcription factors with RNA Polymerase II in eukaryotes. Here we explore the function and regulation of the CDK8-CycC pair in Drosophila by performing a dominant modifier genetic screen based on wing vein patterning defects caused by specific alteration of CDK8-CycC activities. We have observed that multiple components of the Dpp/TGFβ signaling pathway genetically interact with CDK8-CycC. CDK8 and CycC positively regulate gene expression activated by Mad, the key transcription factor downstream of Dpp/TGFβ signaling, and CDK8 can directly interact with the linker region of the Mad protein. We also identify additional, but not all, subunits of the Mediator complex that play positive roles in regulating Mad-dependent gene expression. Given the fundamental role of Dpp/TGFβ signaling in regulating development and its misregulation in a variety of diseases, understanding how Mad/Smad interacts with the Mediator complex may have broad implications in understanding the pathogenesis of these diseases. [ABSTRACT FROM AUTHOR]

Despite their essential function in terminating translation, readthrough of stop codons occurs more frequently than previously supposed. However, little is known about the regulation of stop codon readthrough by anatomical site and over the life cycle of animals. Here, we developed a set of reporters to measure readthrough in Drosophila melanogaster. A focused RNAi screen in whole animals identified upf1 as a mediator of readthrough, suggesting that the stop codons in the reporters were recognized as premature termination codons (PTCs). We found readthrough rates of PTCs varied significantly throughout the life cycle of flies, being highest in older adult flies. Furthermore, readthrough rates varied dramatically by tissue and, intriguingly, were highest in fly brains, specifically neurons and not glia. This was not due to differences in reporter abundance or nonsense-mediated mRNA decay (NMD) surveillance between these tissues. Readthrough rates also varied within neurons, with cholinergic neurons having highest readthrough compared with lowest readthrough rates in dopaminergic neurons. Overall, our data reveal temporal and spatial variation of PTC-mediated readthrough in animals, and suggest that readthrough may be a potential rescue mechanism for PTC-harboring transcripts when the NMD surveillance pathway is inhibited. [ABSTRACT FROM AUTHOR]

Nanocarriers for chemo‐photothermal therapy suffer from insufficient retention at the tumor site and poor penetration into tumor parenchyma. A smart drug‐dye‐based micelle is designed by making the best of the structural features of small‐molecule drugs. P‐DOX is synthesized by conjugating doxorubicin (DOX) with poly(4‐formylphenyl methacrylate‐co‐2‐(diethylamino) ethyl methacrylate)‐b‐polyoligoethyleneglycol methacrylate (P(FPMA‐co‐DEA)‐b‐POEGMA) via imine linkage. Through the π–π stacking interaction, IR780, a near‐infrared fluorescence dye as well as a photothermal agent, is integrated into the micelles (IR780‐PDMs) with the P‐DOX. The IR780‐PDMs show remarkably long blood circulation (t1/2β = 22.6 h). As a result, a progressive tumor accumulation and retention are presented, which is significant to the sequential drug release. Moreover, when entering into a moderate acidic tumor microenvironment, IR780‐PDMs can dissociate into small‐size conjugates and IR780, which obviously increases the penetration depth of drugs, and then improves the lethality to deep‐seated tumor cells. Owing to the high delivery efficiency and superior chemo‐photothermal therapeutic efficacy of IR780‐PDMs, 97.6% tumor growth in the A549 tumor‐bearing mice is suppressed with a low dose of intravenous injection (DOX, 1.5 mg kg−1; IR780, 0.8 mg kg−1). This work presents a brand‐new strategy for long‐acting intensive cancer therapy. [ABSTRACT FROM AUTHOR]

• Chronic Cr(VI) treatment caused liver toxicity and fibrosis. • Cr(VI) treatment activated hepatic stellate cells (HSCs). • Cr(VI) treatment activated Hedgehog (Hh) signaling pathway-related molecules. • In Shh+/− mice, HSC activation, Hh signaling and liver fibrosis were ameliorated. With the spread of hexavalent chromium [Cr(VI)] contamination, risk of exposure in non-occupational populations is increasing. The liver is the main target organ for Cr(VI) accumulation; however, the effect of long-term Cr(VI) exposure on liver toxicity is largely unknown. In this study, we investigated the effect of chronic Cr(VI) exposure on liver fibrosis and its possible mechanism. Mice were injected with Cr(VI) for two months, and our results showed Cr(VI) treatment caused liver toxicity characterized by liver structure disorganization, liver dysfunction, and antioxidant enzyme system inhibition. The development of liver fibrosis was also found via the emergence of collagen fibril deposition, increased expression of extracellular matrix-related genes, activation of hepatic stellate cells (HSCs) and increase the expression levels of Hedgehog (Hh) signaling pathway-related molecules. To demonstrate the role of Hh signaling in the regulation of Cr(VI)-induced liver fibrosis, genetically modified mice with heterozygous deficiency of Shh (Shh+/−) were used. In the Shh+/− mice, Hh signaling, HSCs activation and liver fibrosis development were all ameliorated. In conclusion, we demonstrated that Cr(VI)-induced liver fibrosis development resulted from Hh pathway-mediated HSCs activation. Our findings strongly suggest that inhibition of Hh pathway may help in the development of new strategies for Cr(VI)-associated liver fibrosis. [ABSTRACT FROM AUTHOR]

In this paper, we first report the PTB7-Th:PC 70 BM:PC 60 BM TPSCs whose active layer is capable of forming the self-assembled nano-ridged (SANR) structures, and the SANR-active layer coupled with the textured-ZnO is able to form the double ridge superimposed system with broad spectrum light trapping characteristic, offering a promising way for the efficiency enhancement of the devices. • Self-assembled nano-ridged (SANR) structures was observed in TPSCs. • SANR can significantly enhances the light absorption of the active layer. • SANR coupled with textured-ZnO is able to form double ridge superimposed system (DRSS). • DRSS shows the characteristics of broad spectrum light trapping. • TPSCs with DRSS gives a optimal PCE of 10.68%. Ternary blend polymer solar cells (TPSCs) comprising one donor and two fullerene acceptors is efficient method for improving the power conversion efficiency (PCE). In this paper, the PTB7-Th-based TPSCs which is incorporating PC 70 BM and PC 60 BM as mixed acceptors are fabricated and investigated. Impressively, the remarkable self-assembled nano-ridged (SANR) structures are discovered in the active layer with the weight ratio of 50% PC 60 BM in fullerenes. Thanks to the enlarged interface area, enhanced light absorption and balanced carrier transport, the PTB7-Th:PC 70 BM:PC 60 BM TPSCs with the SANR active layer gives an optimal PCE of 9.68%. In addition, it is worth emphasizing that by combining the textured-ZnO with the SANR active layer, a double ridge superimposed system (DRSS) with broad spectrum light trapping characteristic is constructed, which can further enhance the light absorption of the devices. Finally, benefiting from the further increase in short circuit current density (J sc), the PTB7-Th:PC 70 BM:PC 60 BM TPSCs with the DRSS gives an optimal PCE of 10.68%. This work provides a feasible ternary strategy to increase the devices performances and is proved be a simple and efficient strategy for fabricating PTB7-Th:PC 70 BM:PC 60 BM TPSCs with SANR active layer. [ABSTRACT FROM AUTHOR]

Background: The aberrant expression of microRNAs is closely connected to the occurrence and development of a great deal of human diseases. To study human diseases, numerous effective computational models that are valuable and meaningful have been presented by researchers. Results: Here, we present a computational framework based on graph Laplacian regularized L2, 1-nonnegative matrix factorization (GRL2, 1-NMF) for inferring possible human disease-connected miRNAs. First, manually validated disease-connected microRNAs were integrated, and microRNA functional similarity information along with two kinds of disease semantic similarities were calculated. Next, we measured Gaussian interaction profile (GIP) kernel similarities for both diseases and microRNAs. Then, we adopted a preprocessing step, namely, weighted K nearest known neighbours (WKNKN), to decrease the sparsity of the miRNA-disease association matrix network. Finally, the GRL2,1-NMF framework was used to predict links between microRNAs and diseases. Conclusions: The new method (GRL2, 1-NMF) achieved AUC values of 0.9280 and 0.9276 in global leave-one-out cross validation (global LOOCV) and five-fold cross validation (5-CV), respectively, showing that GRL2, 1-NMF can powerfully discover potential disease-related miRNAs, even if there is no known associated disease. [ABSTRACT FROM AUTHOR]

Highlights: MnO2@Ce6 nanoprobes-loaded-iPS cells (iPS-MnO2@Ce6) were developed for enhanced photodynamic and immunotherapy against cancer. Under the guidance of multi-mode real-time imaging, iPS-MnO2@Ce6 achieved an enhanced photodynamic therapeutic effect and stimulated a strong anti-tumor immune response in the tumor-bearing mouse. How to trigger strong anti-tumor immune responses has become a focus for tumor therapy. Here, we report the human-induced pluripotent stem cells (iPSs) to deliver MnO2@Ce6 nanoprobes into tumors for simultaneous photodynamic therapy (PDT) and enhanced immunotherapy. Ce6 photosensitizer was attached on manganese dioxide (MnO2) nanoparticles, and resultant MnO2@Ce6 nanoprobes were delivered into mitomycin-treated iPSs to form iPS-MnO2@Ce6 nanoprobes. The iPS-MnO2@Ce6 actively targeted in vivo tumors, the acidic microenvironment triggered interaction between MnO2 and H2O2, released large quantities of oxygen, alleviated hypoxia in tumor. Upon PDT, singlet oxygen formed, broken iPSs released tumor-shared antigens, which evoked an intensive innate and adaptive immune response against the tumor, improving dendritic cells matured, effector T cells, and natural killer cells were activated. Meanwhile, regulatory T cells were reduced, and then the immune response induced by iPS-MnO2@Ce6 was markedly stronger than the immune reaction induced by MnO2@Ce6 (P < 0.05). The iPS-MnO2@Ce6 markedly inhibited tumor growth and metastasis and reduced mortality in mice models with tumor. Human iPSs loaded with MnO2-based nanoprobes are a promising strategy for simultaneous PDT and enhanced immunotherapy against tumor and own clinical translational prospect. [ABSTRACT FROM AUTHOR]

Pollen records from Siberia are mostly absent in global or Northern Hemisphere synthesis works. Here we present a taxonomically harmonized and temporally standardized pollen dataset that was synthesized using 173 palynological records from Siberia and adjacent areas (northeastern Asia, 42–75 ∘ N, 50–180 ∘ E). Pollen data were taxonomically harmonized, i.e. the original 437 taxa were assigned to 106 combined pollen taxa. Age–depth models for all records were revised by applying a constant Bayesian age–depth modelling routine. The pollen dataset is available as count data and percentage data in a table format (taxa vs. samples), with age information for each sample. The dataset has relatively few sites covering the last glacial period between 40 and 11.5 ka (calibrated thousands of years before 1950 CE) particularly from the central and western part of the study area. In the Holocene period, the dataset has many sites from most of the area, with the exception of the central part of Siberia. Of the 173 pollen records, 81 % of pollen counts were downloaded from open databases (GPD, EPD, PANGAEA) and 10 % were contributions by the original data gatherers, while a few were digitized from publications. Most of the pollen records originate from peatlands (48 %) and lake sediments (33 %). Most of the records (83 %) have ≥3 dates, allowing the establishment of reliable chronologies. The dataset can be used for various purposes, including pollen data mapping (example maps for Larix at selected time slices are shown) as well as quantitative climate and vegetation reconstructions. The datasets for pollen counts and pollen percentages are available at 10.1594/PANGAEA.898616 (Cao et al., 2019a), also including the site information, data source, original publication, dating data, and the plant functional type for each pollen taxa. [ABSTRACT FROM AUTHOR]

The properties of woody debris (WD) vary across different forests under various soil conditions. Owing to the relatively shallow and low amounts of soils on karst terrains, it is necessary to determine the WD carbon inventory of karst forests. In this study, we recorded WD with a basal diameter for standing snags and the large-end diameter for fallen logs of ≥ 1 cm. The carbon density of WD in a secondary karst mixed evergreen and deciduous broad-leaved forest that had been clear-cut 55 years ago in southwestern China were inventoried in a 2 ha plot. Woody debris carbon density calculated using specific gravity and carbon concentration was 4.07 Mg C ha−1. Woody debris with diameters ≥ 10 cm (coarse WD) constituted 53.8% of total carbon storage whereas WD < 10 cm in diameters (fine WD) accounted for more pieces of WD (89.9%). Lithocarpus confinis contributed the most WD carbon (26.5%). Intermediate decayed WD was relatively more abundant, but WD with final decay contributed the least to the total pieces of WD (6.7%). The contribution of WD to carbon storage of karst forest was low compared to other forests worldwide. Significant positive correlations were found between WD carbon and biodiversity (R2 = 0.035, p < 0.01) and elevation (R2 = 0.047, p < 0.01) and negative correlations was found in outcrop coverage (R2 = 0.034, p < 0.01). Further studies are needed to elucidate the ecological functions of WD to better understand their roles in maintaining biodiversity, enhancing productivity, and controlling vegetation degradation in karst forest ecosystems. [ABSTRACT FROM AUTHOR]

The 4.2 ka event was a period of global drought and climate cooling linked to the widespread disruption of Neolithic culture. However, the detailed climatic changes during this period are not completely understood. In this paper, we report a high-resolution pollen record for the Dayanghu wetland in the Zhejiang region of southeastern China, which we use to infer mean annual precipitation (MAP) fluctuations during the period spanning 4600–4000 calendar years before present (cal. yr BP). There was a long-term trend of decreasing MAP during this interval, consistent with weakening of the East Asian Summer Monsoon since the mid-Holocene. This trend was punctuated by episodes of relatively high MAP at 4350–4320, ca. 4260, and 4220–4200 cal. yr BP, and extreme droughts at 4200 and 4150 cal. yr BP. We propose that solar activity promoted El Niño events and contributed to dramatic MAP fluctuations in the Dayanghu wetland. La Niña events and negative-phase intervals of the Pacific Decadal Oscillation may have been responsible for the extreme drought at 4200–4150 cal. yr BP. In summary, we propose a close relationship between MAP and solar forcing, with short-term enhanced solar activity increasing the intensity of the East Asian Summer Monsoon and contributing to increasing decadal variability in the inner tropical Pacific, which ultimately leads to increased precipitation variability in southeast China. The results improve our understanding of the detailed climatic features of the 4.2 ka event. • High-resolution pollen record for ca. 4.2 ka for the Zhejiang region, China. • Pollen-based mean annual precipitation was quantitatively reconstructed. • Long-term droughts tended to occur during 4600–4000 cal. yr BP. • La Niña-dominated ENSO contributed to a catastrophic drought at 4200–4150 cal. yr BP. [ABSTRACT FROM AUTHOR]

The direction and intensity of Asian Summer Monsoon (ASM) circulation in the Tibetan Plateau (TP) region strongly influence pollen dispersal patterns; however, this spatial effect has been rarely quantified. In this paper, we explore the relative importance of this directional spatial effect. Specifically, we construct a wind connectivity diagram for modern pollen sample sites according to the prevailing monsoon direction, and extract latent spatial variables representing the directional process of the ASM, using the method of asymmetric eigenvector maps. We fit redundancy analysis models using both spatial variables and local climate factors, and conduct variation partitioning to quantify the effect of directional spatial effect by the ASM. Taking into account the joint effect with local climate, the directional spatial process induced by the ASM significantly explains the variation of pollen assemblages on the TP. The effect is detected in pollen groups with contrasting functional types and dispersal modes; for example, the composition of arboreal pollen and non-arboreal pollen are both significantly affected by the ASM, yet best explained by models assuming different monsoon directions. Anemophilous pollen shows a higher percentage of variation explained by the ASM than non-anemophilous pollen. Our results indicate that directional processes induced by the monsoon is an important influence on pollen assemblages in the TP and support the idea that deposition patterns of pollen, especially arboreal pollen is a useful proxy for studying monsoon evolution. A similar approach can also be applied to paleomonsoon simulations using fossil pollen records. The role of directional dispersal in affecting fossil pollen composition and abundance by prevailing winds deserves further investigation when undertaking Quaternary paleoenvironmental reconstructions using pollen. • Asian Summer Monsoon (ASM) affects pollen assemblages on the Tibetan Plateau via directional spatial process significantly. • Arboreal pollen and non-arboreal pollen are both significantly affected by ASM. • Anemophilous pollen shows a higher percentage of variation explained by the ASM than non-anemophilous pollen. • Arboreal pollen fossil is a suitable potential proxy of studying evolution of monsoon direction and intensity. • Role of directional pollen dispersal by winds deserves more research in pollen-based paleoenvironments reconstruction. [ABSTRACT FROM AUTHOR]

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new class of endogenous lipids with anti-inflammatory and anti-diabetic effects, having the potential to treat type 2 diabetes (T2D). In view of the important regulatory and therapeutic actions of FAHFAs on age-related diseases such as T2D, we hypothesized that they may also play crucial roles in the growth, development, and aging process. Here, we investigated the FAHFA footprint in the visceral adipose tissue (VAT) of mice across lifespan to attain potential clues for understanding the roles of FAHFAs in growth, development, and aging using chemical isotope labeling assisted liquid chromatography-mass spectrometry. VAT samples were harvested from 80 C57BL/6J male mice of nine different ages (1, 2, 3, 6, 9, 12, 15, 18, and 24 months). The results showed that a total of 51 FAHFA families, including 301 regioisomers, were detected in the VAT of mice of all ages, and the number of FAHFAs (both family and regioisomer) in VAT increased with age, from 35 families (186 ± 0 regioisomers) at 1-month-old mice to 46 families (278 ± 6 regioisomers) in 18-month-old mice. Furthermore, the content of 12 FAHFA families per 100 mg of VAT of mice was highly correlated with age, and was usually low in the middle-age (3–15 months). However, because the VAT mass was 4–5 fold higher in middle-aged mice compared to younger or older mice, the total amount of most of the FAHFA regioisomers in VAT was increased in middle-aged mice. To the best of our knowledge, this is the first study to show that the number of regioisomers from 51 FAHFA families and abundance of 15 FAHFA families are strongly dependent on age, which would be helpful for understanding the mechanisms underlying the effects of FAHFAs on growth, development, and aging. Unlabelled Image • CIL-LC-MS was used to explore the FAHFA footprint in VAT of mice across lifespan. • 51 FAHFA families (301 regioisomers) were detected in VAT of mice of all ages. • The number of FAHFAs in VAT increased with age. • The levels of 12 FAHFA families in VAT were highly correlated with age. [ABSTRACT FROM AUTHOR]

Granules which could efficiently mineralize azo dyes were cultivated through immobilization of aerobic degradation strains in a core composed of anaerobic decolorization cultures. The core was obtained in a up-flow anaerobic sludge blanket (UASB) reactor incubated with anaerobic decolorization bacteria. Aerobic degradation strains were then grown on the surface of the anaerobic core in a sequencing batch reactor (SBR). Three of the granules' surface layers demonstrated the occurrence of immobilization. The granulation process was monitored with 16S rDNA high throughput sequencing. Anaerobic decolorization cultures belonging to the genera of unclassified , Levilinea, and Petrimonas and the aerobic degradation genera of Thauera , unclassified , Thermomonas, and Ottowia were successfully fixed in the granules. The obtained granules were capable of decolorizing azo dyes under anaerobic situation, and the generated aromatic amines were then completely mineralized in aerated environment. Comparative studies on the relationship between removed contaminates and typical components concentrations in low to high strength azo dye wastewater showed that the granules have great potentials in treating wastewater with different complexity. The removal efficiency of COD and TOC was not restricted by loading concentrations. Image 1 • Granular sludge containing decolorization and degradation cultures was obtained. • Azo dyes were completely mineralized with the cultivated granules. • Facultative bacteria belonging to an unclassified genus were crucial for cultivation. • The efficiency of COD and TOC removal was not restricted by loading concentration. [ABSTRACT FROM AUTHOR]

Rhizoma Paridis, a traditional Chinese medicine, has shown promise in cancer prevention and therapy. Polyphyllin II is one of the most significant saponins in Rhizoma Paridis and it has toxic effects on kinds of cancer cells. However, our results in this study proved that the polyphyllin II has hepatotoxicity in vitro through caspases activation and cell‐cycle arrest. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide results indicated polyphyllin II inhibited proliferation, induced apoptosis in HepaRG cells and HL‐7702 cells and showed a concentration and time‐dependent. Then, we selected the innovative cell model‐HepaRG cells to explore the mechanism of hepatotoxicity. Our data showed the reactive oxygen species (ROS) increased and the mitochondrial membrane potential decreased in HepaRG cells after administration of polyphyllin II. Besides, with the increase of concentration, the release of lactate dehydrogenase increased and the S phase of the cell cycle was arrested. Nevertheless, when pretreatment with antioxidant N‐acetylcysteine, apoptotic cells decreased significantly, inhibited the production of ROS and improved the decrease of membrane potential in HepaRG cells. Moreover, polyphyllin II treatment increased levels of Fas, Bax, cytochrome c, activated caspase‐3, ‐8, ‐9, cleaved poly(ADP‐ribose) polymerase and decreased Bcl‐2 expression levels. Finally, we identified two signal pathways of apoptosis induced by polyphyllin II including the death receptor pathway and the mitochondria pathway. This study confirmed the hepatotoxicity of the polyphyllin II in vitro, which has never been discovered and gave a wake‐up call for the clinical application of Rhizoma Paridis. This study confirmed the hepatotoxicity of the polyphyllin II in vitro, which has never been discovered and gave a wake‐up call for the clinical application of Rhizoma Paridis. Moreover, we identified two signaling pathways of apoptosis induced by polyphyllin II including death receptor pathway and the mitochondria pathway. [ABSTRACT FROM AUTHOR]

Bai Le Mian capsule (BLMC), which is composed of fifteen kinds of traditional Chinese Medicine, is a popular traditional Chinese medicine for the treatment of insomnia with anxiety. This study was to investigate the anxiolytic effect of BLMC in mice. BLMC (81, 162, and 325 mg/kg, i.g.) was given once or consecutively for 2 weeks, and anxiety behaviors were tested by the elevated plus maze, open field, and light/dark box, in normal mice and anxious model mice by meta-chlorophenyl-piperazine, a compound with known anxiogenic actions. In normal mice, single administration of BLMC at 325 mg/kg prolonged the time spent in central area by 2.1-fold in open-field test. Repeated administration once a day for 2 weeks, BLMC at 325 mg/kg increased the time spent in central area, open arms and light box by 2.8-, 2.0-, and 1.7-fold, respectively. Similarly, in anxious model mice, single treatment of BLMC at 325 mg/kg increased more time in the open arms by 2.1-fold. Consecutive administration for 2 weeks, BLMC at 325 mg/kg increased the time spent in open arms and light box by 2.3- and 2.1-fold. Immunohistochemical study showed that mCPP increased c-Fos expression in the central nucleus of the amygdala and bed nucleus of stria terminalis by 57% and 60%, and the mCPP-induced c-Fos expression could be reversed by single administration of BLMC. These results indicate that BLMC is an effective treatment for anxiety in mice. [ABSTRACT FROM AUTHOR]

Rosuvastatin is a synthetic statin of 3-hydroxy-methyl-3-glutamyl coenzyme A reductase inhibitor. It has pleiotropic characteristics including hepatic selectivity, minimal metabolism, inhibition of inflammation, and induction of osteoblast differentiation. In this study, dental pulp stem cells (DPSCs) were treated with lipopolysaccharide alone or with rosuvastatin. Then, we examined the accelerative effects of rosuvastatin on odontoblast differentiation and mineralized nodule formation by real-time polymerase chain reaction (RT-PCR), western blot, alizarin red S staining, and alkaline phosphatase staining. The extent of anti-inflammation was determined by RT-PCR and analysis of the expression of tumor necrosis factor α, interleukin 1β (IL-1β), and IL-6. Furthermore, the activation of nuclear factor kappa B (NF-κB) was determined by western blot. This study demonstrates that rosuvastatin may speed up odontoblast differentiation and rescue inflammatory reaction by suppressing the NF-κB signaling pathway. It is believed that our findings provide novel perceptions on odontogenic differentiation of DPSCs. [ABSTRACT FROM AUTHOR]

Drug delivery carriers with a high drug loading capacity and biocompatibility, especially for controlled drug release, are urgently needed due to the side effects and frequent dose in the traditional therapeutic method. Guided by nanomaterials, we have successfully synthesized zirconium-based metal−organic frameworks, Zr-TCPP (TCPP: tetrakis (4-carboxyphenyl) porphyrin), namely, PCN-222, which is synthesized by solvothermal method. And it has been designed as a drug delivery system (DDS) with a high drug loading of 38.77 wt%. In our work, PCN-222 has achieved pH-sensitive drug release and showed comprehensive SEM, TEM, PXRD, DSC, FTIR, and N2 adsorption-desorption. The low cytotoxicity and good biocompatibility of PCN-222 were certificated by the in vitro results from an MTT assay, DAPI staining, and Annexin V/PI double-staining even cultivated L02 cells and HepG2 cells for 48h. Furthermore, Oridonin, a commonly used cancer chemotherapy drug, is adsorbed into PCN-222 via the solvent diffusion technique. Based on an analysis of the Oridonin release profile, results suggest that it can last for more than 7 days in vitro. And cumulative release rate of Ori at the 7 d was about 86.29% and 63.23% in PBS (pH 5.5 and pH 7.2, respectively) at 37°C. HepG2 cells were chosen to research the cytotoxicity of PCN-222@Ori and free Oridonin. The results demonstrated that the PCN-222@Ori nanocarrier shows higher cytotoxicity in HepG2 cells compared to Oridonin. [ABSTRACT FROM AUTHOR]

Highlights • Leastcost and coordination hypotheses support species strategy and ecosystem function. • An alternative framework of classifying dynamic roles based in plant traits. • Trait variation was linked to climate within a narrow tropical climatic range. • Optimality concepts and forest dynamics may represent PFTs more faithfully in DGVMs. Abstract The conventional representation of Plant Functional Types (PFTs) in Dynamic Global Vegetation Models (DGVMs) is increasingly recognized as simplistic and lacking in predictive power. Key ecophysiological traits, including photosynthetic parameters, are typically assigned single values for each PFT while the substantial trait variation within PFTs is neglected. This includes continuous variation in response to environmental factors, and differences linked to spatial and temporal niche differentiation within communities. A much stronger empirical basis is required for the treatment of continuous plant functional trait variation in DGVMs. We analyse 431 sets of measurements of leaf and plant traits, including photosynthetic measurements, on evergreen angiosperm trees in tropical moist forests of Australia and China. Confining attention to tropical moist forests, our analysis identifies trait differences that are linked to vegetation dynamic roles. Coordination theory predicts that Rubisco- and electron-transport limited rates of photosynthesis are co-limiting under field conditions. The least-cost hypothesis predicts that air-to-leaf CO 2 drawdown minimizes the combined costs per unit carbon assimilation of maintaining carboxylation and transpiration capacities. Aspects of these predictions are supported for within-community trait variation linked to canopy position, just as they are for variation along spatial environmental gradients. Trait differences among plant species occupying different structural and temporal niches may provide a basis for the ecophysiological representation of vegetation dynamics in next-generation DGVMs. [ABSTRACT FROM AUTHOR]

Highlights • Behavioral analysis demonstrated that the CPSP animals displayed a significant decrease in mechanical allodynia threshold. • A significant increase in P2 × 4 receptors expression in microglia in thalamic peri-lesion tissues post-hemorrhage. • The mechanical allodynia in rats with CPSP were reversed by blocking P2 × 4 receptors. • A significant alleviation of mechanical allodynia was achieved following the administration of adrenergic antidepressants and antiepileptics. • A significant decrease in P2 × 4 receptor expression after treatment with adrenergic antidepressants and antiepileptics. Abstract Stroke is the leading cause of disability and death in the world. Central post-stroke pain (CPSP), a central neuropathic pain syndrome occurring after cerebral stroke, is a serious problem. But on account of the lack of reliable animal models, the mechanisms underlying CPSP remains poorly understood. To better understand of the pathophysiological basis of CPSP, we developed and characterized a new rat model of CPSP. This model is based on a hemorrhagic stroke lesion with intra-thalamic autologous blood (ITAB) injection in the ventral posterolateral nucleus of the thalamus. Behavioral analysis demonstrated that the animals displayed a significant decrease in mechanical allodynia threshold. We found a significant increase in P2 × 4 receptor expression in microglia in thalamic peri-lesion tissues post-hemorrhage. The mechanical allodynia in rats with CPSP were reversed by blocking P2 × 4 receptors. A significant alleviation of mechanical allodynia was achieved following the administration of adrenergic antidepressants and antiepileptics. Meanwhile, we found a significant decrease in P2 × 4 receptor expression after treatment with these drugs. Taken together, our results suggest that targeting P2 × 4 receptor may be effective in the treatment of CPSP. [ABSTRACT FROM AUTHOR]

We fabricated inverted polymer solar cells (PSCs) with the structure of ITO/ZnO NPs/Active layer/MoO3/Ag, in which ZnO NPs act as electron transport layer (ETL), poly{4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b0]-dithiophene-2,6-diyl-alt-3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophene-4,6-diy (PTB7) as donor and [6,6]-phenyl-C71-butyric-acidmethyl-ester (PC71BM) as accepter. It is found that the temperature employed during the annealing process of ZnO NPs has significant impact on the efficiency of the resulted PSCs. The optimized PSC with ZnO NPs annealed at 150 °C based on PTB7:PC71BM (1:1.5 w/w) exhibited a power-conversion efficiency of 7.37% with open-circuit voltage (Voc) of 0.722 V, short-circuit current density (Jsc) of 15.38 mA cm−2, and fill factor (FF) of 66.4%. The effects of the annealing temperature on photovoltaic performances were further illustrated with transmission spectrum, atomic force microscopy, X-ray diffraction and PL spectra, meanwhile electrical performance were illustrated with conductivity. Our result indicated that the improved efficiency is due to the optimized ETL/active layer interface, the enhanced transparency and electron transport of the ETLs. As its facile preparation process, this kind of ETL is compatible with roll-to-roll manufacturing of larger area flexible PSCs. [ABSTRACT FROM AUTHOR]

Realgar and indigo naturalis are clinically combined to treat varieties of leukemia. Exploring the drug-drug interactions might be beneficial to find active substances and develop new targeted drugs. This study aimed at exploring the change of arsenic concentration in mice and across MDCK-MDR1 cells and the cytotoxicity on K562 cells when realgar and indigo naturalis were combined. In the presence or absence of indigo naturalis, pharmacokinetics and cell-based permeability assays were used to evaluate the change of arsenic concentration, and K562 cell line was applied to evaluate the change of cytotoxicity. The drug concentration-time profiles exhibited that the combination medication group generated higher AUC, thalf, and longer MRT for arsenic, compared with the single administration of realgar. The apparent permeability coefficients (Papp) of bidirectional transport in MDCK-MDR1 cell permeability experiments showed that arsenic permeability obviously went up when indigo naturalis was incubated together. The combination medication significantly decreased the cell viability of K562 cells when both the concentration of realgar and the concentration of indigo naturalis were nontoxic. The pharmacokinetic research, the MDCK-MDR1 based permeability study, and the K562 cytotoxicity study were united together to verify the combination medication of realgar and indigo naturalis enhanced the absorption and the permeability across cells for arsenic and effectively inhibited the proliferation of K562 cell line. The molecular binding of As4S4 and indirubin was analyzed by computational study. It is predicted that the formation of the complex [As4S4…Indirubin] involves noncovalent interaction that changes the concentration of arsenic. [ABSTRACT FROM AUTHOR]

We investigate the influence of argon plasma assistance on the depletion of SiH 4 in the preparation of μc-Si:H films via plasma-enhanced chemical vapor deposition (PECVD). From optical emission spectrometry (OES) data of the μc-Si:H deposition, we infer that the excited Ar + and metastable Ar * states enhance the dissociation of SiH 4 and H 2 molecules to generate ultra-depletion of SiH 4 . The ultra-depletion of SiH 4 increases the μc-Si:H thin-film deposition rate from 4.5 Å/s to 23.4 Å/s at 6-sccm flow of SiH 4 . This ultra-depletion condition facilitates the gradual substitution of H 2 by Ar, which leads to reduced crystallinity at low argon fractions (f ar ), preferential crystallographic orientation along the (111) direction, and fluctuation of the hydrogen content and microstructure factor (R). Thus, the properties of the μc-Si:H thin films can be controlled via control of the atomic hydrogen generation and physical sputtering effects. The highest photosensitivity (2.2 × 10 3 ) is observed at f ar = 56%. Furthermore, we fabricate an a-Si:H/μc-Si:H tandem solar cell with a total thickness of 1450 nm. The cell exhibits an initial efficiency of 11.44%, and the efficiency reduces to 10.24% after 1000 h of light soaking. The cell also exhibits a significantly higher V oc × FF stability over that of J sc . [ABSTRACT FROM AUTHOR]

The interaction between light and wavelength-sized photonic nanostructure is highly promising for light management applied to thin-film photovoltaics (PVs). In this work, we put forward a practical wave-optical dielectric hemispheroidal nanostructure strategy under cost-effective anodic oxidation approach and substrate transfer method. By adjusting the oxidation voltage, periodic hemispheroidal nanostructure with diametral scale over 650 nm was obtained. Due to their wavelength-scale dimension, enhanced diffraction behavior and guided resonance were identified through finite-difference-time-domain (FDTD) simulation resulting in significant forward-scattering capabilities. The coherent optical performance was investigated experimentally and theoretically. To leverage the benefits of hemispheroidal nanostructure, amorphous silicon absorb layer and solar cell were fabricated. Compared with the planer structure, the developed hemispheroidal nanostructure could significantly improve the absorption of a-Si:H layer via light management with a 10.97% enhancement in the overall external quantum efficiency. Effective improvements in Voc and FF performances were also obtained in comparison to an etched AZO structure with high surface roughness. As the first demonstration, it was found that the hemispheroidal nanostructure by coating on the surface of a-Si:H thin film solar cells led to 7.79% and 7.38% enhancements respectively in overall energy conversion efficiency in comparison to the planar and the etched AZO structure. [ABSTRACT FROM AUTHOR]

Recent global warming is pronounced in high-latitude regions (e.g. northern Asia), and will cause the vegetation to change. Future vegetation trends (e.g. the “arctic greening”) will feed back into atmospheric circulation and the global climate system. Understanding the nature and causes of past vegetation changes is important for predicting the composition and distribution of future vegetation communities. Fossil pollen records from 468 sites in northern and eastern Asia were biomised at selected times between 40 cal ka bp and today. Biomes were also simulated using a climate-driven biome model and results from the two approaches compared in order to help understand the mechanisms behind the observed vegetation changes. The consistent biome results inferred by both approaches reveal that long-term and broad-scale vegetation patterns reflect global- to hemispheric-scale climate changes. Forest biomes increase around the beginning of the late deglaciation, become more widespread during the early and middle Holocene, and decrease in the late Holocene in fringe areas of the Asian Summer Monsoon. At the southern and southwestern margins of the taiga, forest increases in the early Holocene and shows notable species succession, which may have been caused by winter warming at ca. 7 cal ka bp. At the northeastern taiga margin (central Yakutia and northeastern Siberia), shrub expansion during the last deglaciation appears to prevent the permafrost from thawing and hinders the northward expansion of evergreen needle-leaved species until ca. 7 cal ka bp. The vegetation-climate disequilibrium during the early Holocene in the taiga-tundra transition zone suggests that projected climate warming will not cause a northward expansion of evergreen needle-leaved species. [ABSTRACT FROM AUTHOR]

To realize high-performance perovskite solar cells (PSCs) ensuring low-cost flexible application with low energy consumption, efficient electron transport layers (ETL) that can be processed at low temperatures are desired. In this contribution, low temperature (about 70 °C) UV/ozone irradiation was applied to synthesis crystallized TiO 2 films as ETL. The UV exposure induces photo-catalytic removal of the organic ligands and spontaneous coalescence of the TiO 2 framework, resulting in excellent TiO 2 films with considerable crystallinity. UV irradiation induces both complete removal of organic media and more efficient charge collection. Accordingly, planar heterojunction (PH) PSCs with such ETL exhibited outstanding photovoltaic performance up to 17.03%, which is even higher than the value (12.98%) of counterpart device with high temperature thermal sintered TiO 2 ETL (without TiCl 4 treatment). These low temperature solution-processed TiO 2 films by facile UV irradiation are suitable for the low-cost, large yield solution process on a flexible substrate for photoelectric devices. [ABSTRACT FROM AUTHOR]

Quantitative proxy-based and high-resolution palaeoclimatic datasets are scarce for the lower reaches of the Yangtze River (LYR) basin. This region is in a transitional vegetation zone which is climatologically sensitive; and as a birthplace for prehistorical civilization in China, it is important to understand how palaeoclimatic dynamics played a role in affecting cultural development in the region. We present a pollen-based and regionally-averaged Holocene climatic twin-dataset for mean total annual precipitation (PANN) and mean annual temperature (TANN) covering the last 10,000 years for the LYR region. This is based on the technique of weighted averaging-partial least squares regression to establish robust calibration models for obtaining reliable climatic inferences. The pollen-based reconstructions generally show an early Holocene climatic optimum with both abundant monsoonal rainfall and warm thermal conditions, and a declining pattern of both PANN and TANN values in the middle to late Holocene. The main driving forces behind the Holocene climatic changes in the LYR area are likely summer solar insolation associated with tropical or subtropical macro-scale climatic circulations such as the Intertropical Convergence Zone (ITCZ), Western Pacific Subtropical High (WPSH), and El Niño/Southern Oscillation (ENSO). Regional multi-proxy comparisons indicate that the Holocene variations in precipitation and temperature for the LYR region display an in-phase relationship with other related proxy records from southern monsoonal China and the Indian monsoon-influenced regions, but are inconsistent with the Holocene moisture or temperature records from northern monsoonal China and the westerly-dominated region in northwestern China. Overall, our comprehensive palaeoclimatic dataset and models may be significant tools for understanding the Holocene Asian monsoonal evolution and for anticipating its future dynamics in eastern Asia. [ABSTRACT FROM AUTHOR]

Background/Aims: Cardiac remodeling is associated with oxidative stress. Sesamin, a wellknown antioxidant from sesamin seeds, have been used extensively as traditional health foods. However, there is little known about the effect of sesamin on cardiac remodeling. Therefore, the present study aimed to determine whether sesamin could protect against cardiac remodeling and to clarify potential molecular mechanisms. Methods: The mice were subjected to either transverse aortic constriction (TAC) or sham surgery (control group). Beginning one week after surgery, the mice were oral gavage treated with sesamin (100mg·kg-1·day-1) or vehicle for 3 weeks. Cardiac hypertrophy was assessed by echocardiographic parameters, histological analyses and hypertrophic markers. Results: Sesamin alleviated cardiac hypertrophy, inhibited fibrosis and attenuated the inflammatory response. The increased production of reactive oxygen species, the activation of ERK1/2-dependent nuclear factor-κB and the increased level of Smad2 phosphorylation were observed in cardiac remolding model that were treated with sesamin. Furthermore, TAC induced alteration of Sirt3 and SOD2 was normalized by sesamin treatment. Finally, a selective Sirt3 inhibitor 3-TYP blocks all the protective role of sesamin, suggesting that a Sirt3-dependent effect of sesamin on cardiac remodeling. Conclusion: Sesamin improves cardiac function and prevents the development of cardiac hypertrophy via Sirt3/ROS pathway. Our results suggest the protective effect of sesamin on cardiac remolding. [ABSTRACT FROM AUTHOR]

Pollen-based quantitative reconstructions of past climate variables is a standard palaeoclimatic approach. Despite knowing that the spatial extent of the calibration-set affects the reconstruction result, guidance is lacking as to how to determine a suitable spatial extent of the pollen-climate calibration-set. In this study, past mean annual precipitation (P ann ) during the Holocene (since 11.5 cal ka BP) is reconstructed repeatedly for pollen records from Qinghai Lake (36.7°N, 100.5°E; north-east Tibetan Plateau), Gonghai Lake (38.9°N, 112.2°E; north China) and Sihailongwan Lake (42.3°N, 126.6°E; north-east China) using calibration-sets of varying spatial extents extracted from the modern pollen dataset of China and Mongolia (2559 sampling sites and 168 pollen taxa in total). Results indicate that the spatial extent of the calibration-set has a strong impact on model performance, analogue quality and reconstruction diagnostics (absolute value, range, trend, optimum). Generally, these effects are stronger with the modern analogue technique (MAT) than with weighted averaging partial least squares (WA-PLS). With respect to fossil spectra from northern China, the spatial extent of calibration-sets should be restricted to radii between ca. 1000 and 1500 km because small-scale calibration-sets (<800 km radius) will likely fail to include enough spatial variation in the modern pollen assemblages to reflect the temporal range shifts during the Holocene, while too broad a scale calibration-set (>1500 km radius) will include taxa with very different pollen-climate relationships. [ABSTRACT FROM AUTHOR]