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Eolagurus luteus (yellow steppe lemming Eolagurus luteus Eversmann, 1840) is a keystone species in the desert steppe of northern Xinjiang, one of the regions most affected by global climate change. Their behavior of eating grassland vegetation and digging holes has resulted in the reduction of grassland vegetation and soil erosion in northern Xinjiang, which has seriously affected the ecological balance of the grassland in northern Xinjiang, and pathogens carried by E. luteus pose a great threat to human health. Climate change exacerbates the uncertainty of the outbreak of E. luteus. Predicting the suitable habitat area of this species under climate change scenarios will help farmers and herders deal with the potential threat of an E. luteus outbreak. In this study, 117 actual occurrence points of E. luteus were used, and 24 climate models, 6 soil factors and 3 topographic factors from the Coupled Model Intercomparison Project (CMIP6) were taken into account. Combining the MaxEnt model and the overlay analysis function of ArcGIS software, the potential geographic distribution of E. luteus in 2030 and 2050 for the green development path (SSP126), the intermediate development path (SSP245), the regional competition path (SSP370), and the high development path (SSP585) was predicted. The change trend of the suitable area and distribution pattern of E. luteus in Xinjiang under future climate conditions was analyzed, and the main environmental factors affecting the distribution of E. luteus are discussed. The results show that the average area under curve (AUC) and true skill statistics (TSS) of the MaxEnt model are 0.993 and 0.8816, respectively, indicating that the model has a good prediction effect. The analysis of environmental factors showed that the main environmental factors affecting the potential geographical distribution of E. luteus are average annual temperature, isotherm, average temperature in the wettest quarter, average temperature in the driest quarter, and precipitation variation coefficient. With the increase of radiation intensity and time, the suitable areas of E. luteus will continue to decrease. Especially in the 2050s under the SSP585 scenario, the middle and high suitable areas will decrease by 2.58 × 104 km2 and 1.52 × 104 km2, respectively. Although the potential habitat area of E. luteus is shrinking, the future threat of E. luteus to grassland ecological security and human health should not be underestimated due to ecological adaptation of the community and the frequent occurrence of extreme weather. Therefore, studying changes in the potential geographic distribution of E. luteus under climate change scenarios and developing appropriate monitoring programs are of great importance for grassland ecological security and human health. This study fills in the gaps in the study of the potential geographical distribution of E. luteus and provides methodological and literature support for the study of the potential geographical distribution of other rodents.

Fig. S1. Structure-based ligand discovery of STAT3 inhibitorsFig. S2. Surface plasmon resonance analysis of interactions between WB436B to STATfamily proteinsFig. S3. The biology evaluation of WB436B inactive analogue WB345Fig. S4. The mutation in STAT3 SH2 domain directly inhibited STAT3 transcriptionalactivitiesFig. S5. WB436B induced pancreatic cancer cells apoptosisFig. S6. STAT3 knockdown reduced PDAC cells growth and colony formationFig. S7. WB436B displayed little cytotoxicity to STAT3 stable knockdown PDAC cells.Fig. S8. STAT3 depletion inhibited the growth of PDAC cellsFig. S9. WB436B suppressed STAT3 nuclear translocation and the binding to the targetgenes in pancreatic cancer cellsFig. S10. WB436B was well-tolerated in vivoFig. S11. WB436B was well-tolerated in pancreatic cancer metastatic mouse model.Fig. S12. WB436B inhibited PDAC tumor metastasis in vivoFig. S13. WB436B decreased PDAC tumors angiogenesis, inhibited tumor-associatedmacrophage infiltration and induced apoptosis in vivo

Purpose:Pancreatic cancer is the worst prognosis among all human cancers, and novel effective treatments are urgently needed. Signal transducer and activator of transcription 3 (STAT3) has been demonstrated as a promising target for pancreatic cancer. Meanwhile, selectively targeted STAT3 with small molecule remains been challenging.Experimental Design:To specifically identify STAT3 inhibitors, more than 1.3 million compounds were screened by structure-based virtual screening and confirmed with the direct binding assay. The amino acid residues that WB436B bound to were verified by induced-fit molecular docking simulation, RosettaLigand computations, and site-directed mutagenesis. On-target effects of WB436B were examined by microscale thermophoresis, surface plasmon resonance, in vitro kinase assay, RNA sequencing, and selective cell growth inhibition assessment. In vivo studies were performed in four animal models to evaluate effects of WB436B on tumor growth and metastasis. Kaplan–Meier analyses were used to assess survival.Results:WB436B selectively bound to STAT3 over other STAT families protein, and in vitro antitumor activities were improved by 10 to 1,000 fold than the representative STAT3 inhibitors. WB436B selectively inhibits STAT3-Tyr705 phosphorylation, STAT3 target gene expression, and the viability of STAT3-dependent pancreatic cancer cells. WB436B significantly suppresses tumor growth and metastasis in vivo and prolongs survival of tumor-bearing mice. Mechanistic studies showed that WB436B have unique binding sites located in STAT3 Src homology 2 domain.Conclusions:Our work presents the first-in-class selective STAT3 inhibitor WB436B as a potential therapeutic candidate for the treatment of pancreatic cancer.

Supplementary Methods

Table S1. List of antibodies used and their technical information Table S2. The sequence of Real-time PCR primersTable S3. The sequence of shRNAs for silencing STAT3 Table S4. The sequence of ChromatinImmunoprecipitation (Ch-IP) PCRTable S5. The binding affinities of WB436B towards STAT member protein in SPR assay Table S6. Selectivity profiling of WB436B in a kinase panel

Atherosclerosis (AS) is a primary cause of cardiovascular diseases. This study investigated the mechanism of methyltransferase-like 3 (METTL3) in AS plaques via modulating the phenotypic transformation of vascular smooth muscle cells (VSMCs).AS mouse models and MOVAS cell models were established through high-fat diet and the treatment of ox-LDL, respectively. METTL3 expression in AS models was detected via RT-qPCR and Western blot. The AS plaques, lipid deposition, and collagen fibers were examined via histological staining. The levels of Ly-6c, α-SMA, and OPN were examined via Western blot. The blood lipid indexes in mouse aortic tissues were determined using kits. The proliferation and migration of MOVAS cells were detected via CCK-8 and Transwell assays. The mMETTL3 was highly expressed in AS. Silencing METTL3 alleviated AS progression and stabilized AS plaques in mice, and limited the phenotypic transformation of VSMCs induced by ox-LDL. Silencing METTL3 inhibited mMETTL3-mediated m

PDF file - 904K, Restoring HIC1 expression prevents PCa metastasis by intracardiac and tail vein injections in BALB/c Nude mice

PDF file - 281K, HIC1 expression had a significant effect on reducing osseous destruction of PCa cells

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PDF file - 247K, CXCR7 expression regulated by HIC1 in PCa cells

Purpose: Prostate cancer is the second leading cause of cancer deaths among men in Western counties, which has also occurred in Chinese male with markedly increasing incidence in recent years. Although the mechanism underlying its progression still remains unclear, epigenetic modifications are important ethological parameters. The purpose of this study is to determine the methylation status and function of hypermethylatioted in cancer 1 (HIC1) in prostate cancer progression.Experimental Design: The methylation status of HIC1 promoter was assayed in cell lines, tissues, and plasma of patients with prostate cancer by using methylation-specific PCR and bisulfate sequencing PCR. The ability of HIC1 to regulate proliferation, migration, and invasion was assessed by MTT, scratch-healing assay, and reconstituted extracellular matrices in porous culture chambers. Tumorigenesis, metastases, and bone destruction were analyzed in mice bearing prostate cancer cells restoring HIC1 by using Xenogen IVIS with radiographic system and small-animal positron emission tomography computed tomographic images. Microarrays were searched for genes that had correlated expression with HIC1 mRNA. Reporter gene assays were used to determine whether HIC1 affected the expression of CXCR7, and chromatin immunoprecipitation was used to determine whether HIC1 bound to CXCR7 promoters. All P values were determined using 2-sided tests.Results: The methylation status of 11 CpG sites within HIC1 promoter was abundantly methylated in cell lines, tissues, and plasma of patients with prostate cancer compared with those of respective normal controls. Restoring HIC1 expression in prostate cancer cells markedly inhibited proliferation, migration, and invasion and induced the apoptosis in these cells. Moreover, mice bearing prostate cancer–restoring HIC1 cells had a marked effect on reducing tumor growth, multiple tissue metastases, and bone destruction. Notably, we also identified that the chemokine receptor CXCR7 is a direct downstream target gene of HIC1. Finally, we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression.Conclusions: Our data show for the first time that hypermethylation of HIC1 promoter results in loss of its repressive function, responsible for prostate cancer progression and invasion. These findings suggest that therapies targeting epigenetic events regulating HIC1 expression may provide a more effective strategy for prostate cancer treatment. Clin Cancer Res; 19(6); 1400–10. ©2012 AACR.

PDF file - 488K, Effects in PCa cells after knockdown of expression of HIC1

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PDF file - 53K, Part of genes regulated more than 2-fold in PC3HIC1 and C4-2BHIC1 cells comparison with the control

PDF file - 416K, Methylation status of HIC1 promoter in plasma DNA from PCa patients and healthy controls.

PDF file - 255K, CXCR7 is direct HIC1 target genes

PDF file - 35K, Clinical information and body tumor methylation status of prostate cancer patients

Purpose:Pancreatic cancer is the worst prognosis among all human cancers, and novel effective treatments are urgently needed. Signal transducer and activator of transcription 3 (STAT3) has been demonstrated as a promising target for pancreatic cancer. Meanwhile, selectively targeted STAT3 with small molecule remains been challenging.Experimental Design:To specifically identify STAT3 inhibitors, more than 1.3 million compounds were screened by structure-based virtual screening and confirmed with the direct binding assay. The amino acid residues that WB436B bound to were verified by induced-fit molecular docking simulation, RosettaLigand computations, and site-directed mutagenesis. On-target effects of WB436B were examined by microscale thermophoresis, surface plasmon resonance, in vitro kinase assay, RNA sequencing, and selective cell growth inhibition assessment. In vivo studies were performed in four animal models to evaluate effects of WB436B on tumor growth and metastasis. Kaplan–Meier analyses were used to assess survival.Results:WB436B selectively bound to STAT3 over other STAT families protein, and in vitro antitumor activities were improved by 10 to 1,000 fold than the representative STAT3 inhibitors. WB436B selectively inhibits STAT3-Tyr705 phosphorylation, STAT3 target gene expression, and the viability of STAT3-dependent pancreatic cancer cells. WB436B significantly suppresses tumor growth and metastasis in vivo and prolongs survival of tumor-bearing mice. Mechanistic studies showed that WB436B have unique binding sites located in STAT3 Src homology 2 domain.Conclusions:Our work presents the first-in-class selective STAT3 inhibitor WB436B as a potential therapeutic candidate for the treatment of pancreatic cancer.

Climate change, especially climate extremes, can increase the uncertainty of locust outbreaks. The Italian locust(Calliptamus italicus L.), Asian Migratory locust (Locusta migratoria migratoria L.), and Siberian locust(Gomphocerus sibiricus) are common pests widely distributed in the semidesert grasslands of Central Asia and its surrounding regions.Predicting locust geographic distribution changes and future habitats accounting for climate warming is essential to effectively prevent large and sudden locust outbreaks. The MaxEnt model was used in this study to identify environmental factors that impact the distribution of the three typical locust species and to display the probable appropriate regions and uncertainty of typical locust species habitats under different current and future climatic scenarios. Our results showed that soil surface sand content, slope, mean precipitation during the hottest season, and precipitation seasonality were the key environmental variables affecting locust distribution in the region. The three locust species are mainly distributed in the upstream region of the Irtysh River, the Alatao Mountain region, the northern slopes of the Tianshan Mountains, around Sayram Lake, the eastern part of the Alakol Lake region, the Tekes River region, the western part of Ulungur Lake, the Ili River, the upstream region of the Tarim River. According to several climate projections, the area of potential habitat for the three most common locust species will decrease by 3.9 x 104 − 4.6 x 104 km2 by the 2030s and by 6.4 x 104 − 10.6 x 104 km2 by the 2050s. Although the suitable area is shrinking, the climate is becoming more extreme, and the high suitability area is expanding, so the risk of infestation should be taken seriously. This study on locust habitat change under climate change provides a scientific basis for the scientific prevention and control of locust disasters and the sustainable development of the grassland environment in China and Kazakhstan in the context of global warming and intergovernmental cooperation measures.

Ecological security and ecosystem stability in Central Asia depend heavily on the local vegetation. Vegetation dynamics and the response and hysteresis relationships to climate factors and drought on multiple scales over long time series in the region still need to be further explored. Using the net primary productivity (NPP) values as the vegetation change index of interest, in this study, we analyzed vegetation dynamics in Central Asia from 1982 to 2020 and assessed the responses and time lags of vegetation to climate factors and drought. The results showed that NPP gradually decreased from north to south and from east to west. Vegetation was distributed along both sides of the mountains. The temperatures rose from northeast to southwest, while precipitation gradually increased from southwest to northeast. The proportion of dry and wet years was as follows: normal (56.41%) slightly dry (28.2%) slightly humid (15.39%). Precipitation and drought conditions were positively correlated with NPP during the growing season, while temperature was negatively correlated with NPP. Increased spring temperature, precipitation, and drought conditions positively affected vegetation, while sustained summer temperature resulted in suppressed vegetation growth. Autumn vegetation was positively affected by temperature and drought, and precipitation was negatively correlated with autumn vegetation. Increasing winter temperatures promoted vegetation growth. The time lag between NPP and temperature gradually increased from northeast to southwest, and the time lag between NPP and precipitation gradually increased from south to north. Spring temperatures had the greatest beneficial impact on forestlands; summer climatic factors and drought had little effect on shrublands; the autumn climate exhibited small differences in its influence of each plant type; and winter temperatures had the greatest positive effect on grasslands. No time lag effect was found between any of the four vegetation types and precipitation. A one-month lag was found between cultivated lands and temperature; a two-month lag was found between forestlands and temperature; and a one-month lag was found between forestlands and drought and between shrublands and drought. The results can provide a scientific foundation for the sustainable development and management of ecosystems.

The rapid development of urbanization, population growth, and unreasonable use of land resources have made the contradiction between human beings and land increasingly prominent, and the carrying capacity of land resources has become an important factor affecting the sustainable development of a city or even a country. Based on the carrying capacity of agricultural land, construction land, and ecological land in 31 provinces of China, this paper analyzed the spatiotemporal characteristics of the carrying capacity of land resources in 31 provinces of China from 2008 to 2016 by using single-factor carrying capacity evaluation and comprehensive carrying capacity evaluation methods. The evaluation results were divided into six levels (No pressure, Lower pressure, Low pressure, Medium pressure, High pressure, Higher pressure), and the ArcGIS10.2 software was used for visualization, and the carrying capacity prediction model was constructed to predict the development trend of the comprehensive carrying capacity of land resources in 2020 and 2025. The results showed that China’s land carrying capacity is extremely unbalanced. Whether from the evaluation results of single-factor carrying capacity or comprehensive carrying capacity, we showed the characteristics of high pressure in the east and low pressure in the west, and that the regional land resources have a deteriorating trend. Through the prediction of the future land resource carrying capacity index, it was found that the comprehensive carrying capacity index of land resources in 31 provinces of China will still show an upward trend in the future.

Modeling and forecasting tourism demand across destinations has become a priority in tourism research. Most tourism demand studies rely on annual statistics with small sample sizes and lack research on spatial heterogeneity and drivers of tourism demand. This study proposes a new framework for measuring inter-provincial tourism demand's spatiotemporal distribution using search engine indices based on a geographic perspective. A combination of spatial autocorrelation and Geodetector is utilized to recognize the spatiotemporal distribution patterns of tourism demand in 2011 and 2018 in 31 provinces of mainland China and detect its driving mechanisms. The results reveal that the spatial distribution of tourism demand manifests a vital stratification phenomenon with significant spatial aggregation in the southwest and northeast of China. Traffic conditions, social-economic development level, and physical conditions compose a constant and robust interaction network, which dominates the spatial distribution of tourism demand in different development stages through different interactions.

Background Angiotensin-converting enzyme 2 (ACE2) is implicated as a host cell receptor that causes infection in the pathogenesis of Coronavirus disease 2019 (COVID-19), and its genetic polymorphisms in the ACE2 gene may promote cardiovascular disease and systemic inflammatory injury in COVID-19. Hence, genetic background may potentially explain the broad inter-individual variation of disease susceptibility and/or severity. Methods The genetic susceptibility to COVID-19 by examining single-nucleotide polymorphisms (SNPs) of ACE2 was analyzed in 196 patients with COVID-19 and 210 normal controls using TaqMan genotyping assay. Results We demonstrated that ACE2 SNP rs4646142, rs6632677, and rs2074192 were associated with COVID-19 (all P < 0.05), and the differences of ACE2 SNPs rs4646142 and rs6632677 were correlated with COVID-19 related systemic inflammatory injury and cardiovascular risk. Specially, rs4646142 was associated with high-sensitive C-reactive protein (hs-CRP), prealbumin (PAB), apolipoprotein A (APOA), high-density lipoprotein (HDL), and acid glycoprotein (AGP). Rs6632677 was also associated with elevated CRP and haptoglobin (HPT). Conclusions Our results suggest that early identification of these individuals can provide a possible strategy for preventing the spread of the COVID-19, and ACE2 SNPs rs4646142 and rs6632677 may be a common genetic loci and optimal early identification genetic marker for COVID-19 with cardiovascular risks.

The dynamics of the ecosystem represented by vegetation under the influence of human activities have become an important issue in the study of the regional ecological environment. Xinjiang is one of the most ecologically fragile areas in the world, and vegetation changes have received extensive attention. Xinjiang is one of the most ecologically fragile areas in the world, and vegetation changes have received extensive attention. However, the spatiotemporal patterns and evolutionary trends of anthropogenic impacts on vegetation dynamics in Xinjiang are still unclear. In this study, the anthropogenic impacts on vegetation dynamics were quantitatively assessed by combining the improved normalized difference vegetation index (NDVI) prediction model and the residual analysis method in Xinjiang, China. The human driving factors were analyzed with the support of a stepwise multiple regression model for vegetation changes at the county scale. Based on trend analysis and the Hurst exponent, the spatiotemporal characteristics and evolutionary trends of the impact of human activities on vegetation change were discussed. The results show that (1) the NDVI values in Xinjiang showed a gradually increasing trend at a rate of 0.005/10 years from 1982 to 2018, and the vegetation dynamics mainly showed significant improvements (57.09% of the vegetated areas), especially for crops. (2) The anthropogenic effects of vegetation changes in Xinjiang mainly included positive impact increases (43.22% of the vegetated areas) from 2000 to 2018. Human activities promoted the increase in the NDVI of various vegetation types. Both the positive and negative impacts of human activities increased over the study period, and the growth rate of the positive influence (0.08%/10 years) was higher than that of the negative influence (0.04%/10 years). (3) The cultivated area, GDP of primary industry, and population are the main anthropogenic factors causing the increase in NDVI, which dominate the vegetation greening in 30.34%, 29.22%, and 28.09% of the counties in Xinjiang, respectively. The animal husbandry population, agricultural population, and livestock number are the main anthropogenic factors causing the decrease in NDVI, which dominate the vegetation degradation in 23.60%, 21.35%, and 17.98% of the counties in Xinjiang, respectively. (4) The evolutionary trend of the anthropogenic impact on vegetation dynamics in Xinjiang will be dominated by anti-persistence (53.84% of the vegetated areas), thereby mainly showing that the positive impacts continued to increase (22.56% of the vegetated areas), especially for crops, shrubs, grasslands, and alpine vegetation. Our results are helpful in understanding the characteristics and evolutionary trends of vegetation changes in arid areas caused by human activities and are of significance as a reference for policymakers to appropriately adjust policy guidance in a timely manner to promote the protection and sustainable development of fragile ecosystems.

Pulmonary thromboembolism (PTE) is a fatal clinical syndrome that usually occurs in elderly individuals. The present study aimed to identify functional and key genes involved in the early diagnosis of PTE using bioinformatics analysis. The GSE84738 dataset was retrieved from the Gene Expression Omnibus database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were subsequently performed. In addition, Cytoscape software v.3.7.2 was used to construct a protein-protein interaction (PPI) network. Serum samples from patients with PTE and healthy individuals were collected and the expression levels of Toll-like receptor (TLR)4, TLR2, IL-1β, JUN, prostaglandin-endoperoxide synthase 2 (PTGS2), osteopontin (SPP1) and endothelin-1 (ET-1) were analyzed by reverse transcription-quantitative PCR. A total of 160 upregulated and 159 downregulated differentially expressed genes were identified between patients with PTE and healthy individuals. TNF, IL-1β, JUN, TLR4, PTGS2, vascular cell adhesion molecule 1, SPP1, ryanodine receptor 2, TLR2 and ET-1 were considered as hub genes, which are defined as the genes with the highest degree of interaction in the enrichment and PPI network analyses. The top 10 common genes with the highest degree in the PPI network and the top 10 genes in modules 1 and 2 were TLR4, TLR2, IL-1β, JUN, PTGS2, SPP1 and ET-1. Taken together, the present study suggested that TLR4, TLR2, IL-1β and SPP1 were enriched in patients with PTE, thus providing novel potential biomarkers for the diagnosis of PTE.

The arid area of Northwest China provides a unique terrestrial ecosystem for identifying the response of vegetation activities to natural changes. In order to reveal the influence of climate factors on vegetation, the normalized difference V vegetation index (NDVI), climate data and land use and land cover change (LUCC) map were used to study. The spatial and temporal variation characteristics of NDVI from 2000 to 2015 were analyzed.