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SummaryGenetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival. We performed RNA-seq and ATAC-seq on hESC-β cells from each knockout line. Analyses of T2D GWAS signals overlapping with HNF4A-dependent ATAC peaks identified a specific SNP as a likely causal variant. In addition, we performed integrative association analyses and identified four genes (CP, RNASE1, PCSK1NandGSTA2) associated with insulin production, and two genes (TAGLN3andDHRS2) associated with sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental hESC line, to identify a single likely functional variant at each of 23 T2D GWAS signals.

Scientific understanding of regional wind speed variation characteristics and driving mechanisms is of great practical significance to the management and rational utilization of wind energy resources, ecological protection and governance, and sustainable development of agriculture. Taking the Shiyang River Basin in inland river basin of monsoon marginal zone as the study area, this paper analyzed wind speed changes and influencing factors at different time and space scales. The results showed that, first of all, the annual average wind speed showed a downward trend as a whole in Shiyang River Basin, and the change of spring wind speed and the decreasing frequency of daily max-wind speed above Grade 5 were the main contributors. The turning point of annual average wind speed was consistent with that in spring and autumn (1981) and earlier than that in winter and summer (1982). Secondly, as far as the wind speed change tendency rate is concerned, before the turning point, Yongchang area had the largest decline rate with obvious “2000 m effect”, while after the turning point, Wuwei Basin had the largest rise rate with obvious “basin effect”. Focusing on the downstream desert oasis region, the sand-driving wind speed showed a decreasing trend as a whole, and showed a “cliff-like” decline after 1988. The rising trend of sand-driving wind speed after 2014 will pose greater challenges to ecological governance. Finally, under the background of unbalanced global warming, the wind speed changes in different periods were driven by the circulation system changes. In 1970–1981, the decline of the wind speed was the result of the combined action of Arctic Oscillation and Asia Polar Vortex. However, after 1981, it was affected by North Atlantic Oscillation, Asian Meridional Circulation, Tibet Plateau Circulation, India-Burma Trough, Western Pacific Subtropical High and Northern Hemisphere Subtropical High.

The Sugan Lake Basin is located in the inland arid region of northwestern China, in which groundwater is of great significance to human and ecology. Therefore, it is necessary to understand the chemical characteristics and quality of groundwater in the basin. Based on samples collected from 35 groundwater wells in Sugan Lake Basin, the spatial distribution characteristics of groundwater chemistry, main hydrogeochemical processes and groundwater quality have been discussed in this paper by using the multivariate statistics and hydrochemistry analysis methods. The results showed that the groundwater is weakly alkaline, and its total dissolved solid (TDS) and total hardness (TH) are high, with the average values of 1244.03 mg/L and 492.10 mg/L, respectively. The types of groundwater are mainly HCO3−-SO42−-Ca2+ type in the runoff area and Cl−-SO42−-Na+ type in the catchment area. Rock weathering and ion exchange are the main controlling factors of regional groundwater chemistry, followed by evaporative crystallization, and human activities have less impact on groundwater. The spatial difference of groundwater quality is obvious, the water quality of the catchment area is not suitable for drinking, and the suitability for plant growth is also poor. The groundwater in the runoff area can be used for drinking, but the hardness is slightly higher, which is more suitable for ecological purpose.

Soil, as the largest organic carbon pool of terrestrial ecosystem, plays a significant role in regulating the global carbon cycle, atmospheric carbon dioxide (CO2) levels, and global climate change. It is of great significance to scientifically understand the change rule and influence mechanism of soil organic carbon (SOC) to further understand the "source&ndash, sink" transformation of SOC and its influence on climate change. In this paper, the spatiotemporal distribution characteristics and influencing mechanism of SOC were analyzed by means of field investigation and laboratory analysis and the measured data in the Eastern Qilian Mountains. The results showed that the average SOC content of 0&ndash, 50 cm was 35.74 &plusmn, 4.15 g/kg and the range of coefficients of variation (CV) between 48.84% and 75.84%, which suggested that the SOC content exhibited moderate heterogeneity at each soil layer of the Eastern Qilian Mountains. In four land cover types, the SOC content of forestland was the highest, followed by alpine meadow, grassland, and wilderness, which presented surface enrichment, and there was a decreasing trend with the soil depth. From the perspective of seasonal dynamics, there was a uniform pattern of SOC content in different land cover types, shown to be the highest in winter, followed by autumn, spring, and summer, and with the biggest difference between winter and summer appearing in the surface layer. At the same time, our study suggested that the SOC content of different land cover types was closely related to aboveground biomass and negatively related to both the mean monthly temperature and the mean monthly precipitation. Therefore, the distribution and variation of SOC was the result of a combination of climate, vegetation, and other factors.

Groundwater chemistry has an important impact on the vegetation distribution in inland areas. An in-depth understanding of the impact of groundwater chemistry on vegetation can help in developing an effective management strategy to protect the inland ecosystem. The aim of this study was to identify the influence of groundwater chemicals on species diversity and the distribution characteristics of wetland plants at multiple scales based on the groundwater chemical data from 15 sampling points and the distribution data of 13 plants in the Sugan Lake Wetland in 2016. The results show that the groundwater of the Sugan Lake Wetland is weakly alkaline, with high salinity and hardness, the water chemical type is Na-SO4-Cl, the concentration of the major water chemical parameters is significantly different and is the highest in the northwest, followed by the southwest, and is the lowest in the east, with an increase in the groundwater depth, the concentration of major water chemical parameters first showed an increasing trend followed by a decreasing trend, Artemisia frigida Willd, Poa annua L and Triglochin maritimum L were adapted to the environment with a higher ion concentration of the groundwater, and their salt resistance was the strongest, Blysmus sinocompressus and Polygonum are more adapted to the environment with lower salinity and hardness of groundwater, Thermopsis lanceolata has stronger adaptability to the ion concentration, salinity, and hardness of groundwater, other plants are adapted to environments where the ion concentration, salinity, and hardness of the groundwater are moderate.

Quantifying the influence of human activities on hydrological drought is of great significance to sustainable water resource management, but it remains difficult. The key to solving this problem is determining how to scientifically select the natural reference tributary. On the basis of existing research, this paper puts forward a tributary-comparison method that combines the Drought Propagation Intensity Index (DPI) with the human activity index to preliminarily and quantitatively determine the natural reference tributary from among all tributaries and then quantify the influence of human activities on hydrological drought in other tributaries. The empirical research was carried out in the upper reaches of the Shiyang River in the eastern area of Qilian Mountain. The results showed that, firstly, at the annual and seasonal scales, the tributaries in the upper reaches of the Shiyang River changed from hydrological humidification to hydrological aridification, from west to east, from 1961 to 2016. On the whole, the hydrological aridification of Huangyang River in the central part was the most serious, but its hydrological drought duration and drought Intensity showed a downward trend at a monthly scale. Secondly, using the tributary-comparison method, Xiying River was quantitatively selected as the natural reference tributary, and the influence of human activities on hydrological drought in other tributaries was quantified. On the whole, human activities will reduce hydrological drought duration and enhance hydrological drought intensity. The empirical study further proved that the tributary-comparison method has strong applicability in multi-tributary areas with obvious differences in human activities and provides a useful supplement to existing research methods. According to this method, tributaries that are weakly affected by human activity (or not affected at all) can be selected, and the tributaries least affected by human activity can also be identified. On this basis, the influence degree and direction of human activities in other tributaries on hydrological drought can be quantified.

The Shiyang River Basin is a typical arid watershed in Northwest China. Scientific understanding of the driving mechanism of runoff change is the basis of scientific utilization of water resources and regional sustainable development. In this study, runoff changes at different time scales were analyzed for the period 1960–2018, and the impacts of climate variability and human activities on runoff were investigated in the middle and lower reaches of the Shiyang River Basin (SRB). A combination of mutation analysis and human-designed analysis was adopted to divide the study period into the baseline period and the variation period. The Mann–Kendall test (M−K) and Double Mass Curve method (DMC) were used to detect abrupt changes and quantify the relative effects of climate change and human activities on runoff. The results reveal a significant declining trend in annual runoff on the whole in the middle and lower reaches of the SRB, and there was an obvious recovery trend after the implementation of the Comprehensive Treatment Program of the SRB (CTSRB) in 2007. Abrupt changes occurred in 1976, 1991 and 2007, which divided the study period into the baseline period (1960–1975), the Variation Ⅰ period (1976–1990), the Variation Ⅱ period (1991–2006) and the Variation III period (2007–2018). The contribution of human activities to runoff reduction was 88.72%, whereas the contribution of climate change to runoff reduction was only 11.28%. Furthermore, the contribution of human activities to runoff reduction in the Variation Ⅰ period, Variation Ⅱ period and Variation III period was 89.44%, 93.02% and 83.69%, respectively. Therefore, human activities played the most dominant role in the variation of runoff, followed by climate change and upstream runoff. Further analysis of the impact of human activities on runoff indicated that agricultural irrigation was the dominant factor of runoff reduction. This study can provide detailed information on water resources and a scientific basis for the development and utilization of water resources in the future.

We present herein a novel dissection-then-evolution strategy for ligand optimization., We present herein a novel dissection-then-evolution strategy for ligand optimization. Using the co-crystal structure of the smoothened receptor (SMO) as a guide, we studied the modular contribution of LY2940680 by systematically “silencing” the specific interaction between the individual residue(s) and the fragment in the ligand. Following evolution by focusing on the benzoyl part finally yielded an improved ligand 21.

As an important means to cope with global climate change, ecological restoration projects have a huge impact on ecosystem carbon storage functions. Scientifically evaluating the response process and mechanism of basin ecosystem carbon storage functions in ecological restoration projects is beneficial to the improvement of regional ecosystems. Taking Shiyang River Basin (SRB) as an example, and based on the perspective of “carbon sink–carbon source” mutual transformation, the current study utilized the InVEST (Integrated Valuation of Ecosystem Services and Tradeoffs) model to analyze the spatio-temporal dynamics of carbon storage in SRB, quantified the effect of ecological restoration projects on the ecosystem carbon fixation capacity, and identified sensitive and vulnerable areas of carbon loss against the background of climate and land use/cover change (LUCC). The results show that the ecosystem carbon storage in SRB changed significantly before and after the ecological project implementation, with a decrease of 5.71 Tg in 1986–2000 and an increase of 14.11 Tg in 2000–2016. The proportion of carbon sink enhancement areas was only 7.46% in 1986–2000, which increased to 15.04% in 2000–2016, indicating that the ecological restoration effect of the watershed was obvious as a result of the ecological management. The contribution of LUCC brought about by the ecological restoration project to the increase in ecosystem carbon storage was as high as 103.71%, for which the increase in woodland and grassland was the key. However, in 2000–2016, low carbon optimization areas accounted for 4.17% and carbon emission control areas for 6.16% of the total area of SRB. The carbon fixation capacity of these areas declined, and carbon emissions were elevated, especially in carbon emission control areas. These were mainly distributed in the oasis–desert transition zone in the mid-lower reaches, which are sensitive and vulnerable areas for carbon loss. Therefore, in future ecological restoration and protection processes, these areas should be given more attention and protection.

Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival. We performed RNA-seq and ATAC-seq on hESC-β cells from each knockout line. Analyses of T2D GWAS signals overlapping with HNF4A-dependent ATAC peaks identified a specific SNP as a likely causal variant. In addition, we performed integrative association analyses and identified four genes ( CP, RNASE1, PCSK1N and GSTA2 ) associated with insulin production, and two genes ( TAGLN3 and DHRS2 ) associated with sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental hESC line, to identify a single likely functional variant at each of 23 T2D GWAS signals.