Safety and efficacy of an anti-human APC antibody for prophylaxis of congenital factor deficiencies in preclinical models.

Rebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia. We engineered a humanized chimeric antibody, SR604, based on a previously published murine antibody, HAPC1573, which selectively blocks the anticoagulant activity of human activated protein C (APC). SR604 effectively blocked the anticoagulation activities of APC in human plasma deficient in various coagulation factors in vitro with affinities ∼60 times greater than that of HAPC1573. SR604 exhibited prophylactic and therapeutic efficacy in the tail-bleeding and knee-injury models of hemophilia A and B mice expressing human APC (humanized hemophilic mice). SR604 did not interfere with the cytoprotection and endothelial barrier function of APC, nor were there obvious toxicity effects in humanized hemophilic mice. Pharmacokinetic study showed a high bioavailability (106%) of subcutaneously injected SR604 in cynomolgus monkeys. These results demonstrate that SR604 is expected to be a safe and effective therapeutic and/or prophylactic agent with a prolonged half-life for patients with congenital factor deficiencies including hemophilia A and B.

The spatiotemporal response of China's vegetation greenness to human socio-economic activities.

Climate change and human socioeconomic activities both strongly impact long-term vegetation greenness. It is more a challenge to evaluate the impacts of socioeconomic activities on vegetative greenness than climate change, partially due to the lack of appropriate quantitative indicators of the former. Here we examined the relationship between the remote sensing nighttime light (NTL) data and the Normalized Difference Vegetation Index (NDVI), which in this study are used as the proxies of socioeconomic activities and vegetation greenness, respectively. We first eliminated the vegetation greenness changes in response to climate change and calculated the human-activities-induced NDVI (HNDVI). After explored the spatiotemporal patterns of the HNDVI and NTL data across China from 1998 to 2018, we studied the relationship between the HNDVI and NTL at the grid and county levels, respectively. Our results show that the mean adjusted DN values of the NTL data (NTLI) continuously increase (+0.2938) across our study area from 1998 to 2018, whereas the HNDVI values fluctuate with a general upward trend (+0.0018). Most grids (91.2%) with increased HNDVI were found in rural areas, particularly in the Northeast forest shelterbelt and the Loess Plateau. By contrast, the HNDVI values in rapidly urbanized areas in Chinese major urban agglomerations mainly show a downward trend, especially in the Yangtze River Delta (YRD) urban agglomeration. The relationships between the NTLI and HNDVI are inconsistent over time and across space, which could be attributed to land use conditions, afforestation projects in rural areas, and greening activities in urban areas over different periods and regions.

Blocking human protein C anticoagulant activity improves clotting defects of hemophilia mice expressing human protein C.

Hemophilia A and B are hereditary coagulation defects resulting in unstable blood clotting and recurrent bleeding. Current factor replacement therapies have major limitations such as the short half-life of the factors and development of inhibitors. Alternative approaches to rebalance the hemostasis by inhibiting the anticoagulant pathways have recently gained considerable interest. In this study, we tested the therapeutic potential of a monoclonal antibody, HAPC1573, that selectively blocks the anticoagulant activity of human activated protein C (APC). We generated F8-/- or F9-/- hemophilia mice expressing human protein C by genetically replacing the murine Proc gene with the human PROC. The resulting PROC+/+;F8-/- or PROC+/+;F9-/- mice had bleeding characteristics similar to their corresponding F8-/- or F9-/- mice. Pretreating the PROC+/+;F8-/- mice with HAPC1573 shortened the tail bleeding time. HAPC1573 pretreatment significantly reduced mortality and alleviated joint swelling, similar to those treated with either FVIII or FIX, of either PROC+/+;F8-/- or PROC+/+;F9-/- mice in a needle puncture-induced knee-joint bleeding model. Additionally, we found that HAPC1573 significantly improved the thrombin generation of PROC+/+;F8-/- mice but not F8-/- mice, indicating that HAPC1573 enhanced the coagulant activity of hemophilia mice by modulating human APC in vivo. We further documented that HAPC1573 inhibited the APC anticoagulant activity to improve the clotting time of human plasma deficient of FVIII, FIX, FXI, FVII, VWF, FV, or FX. These results demonstrate that selectively blocking the anticoagulant activity of human APC may be an effective therapeutic and/or prophylactic approach for bleeding disorders lacking FVIII, FIX, or other clotting factors.

Mapping human's digital footprints on the Tibetan Plateau from multi-source geospatial big data.

It is a challenge to accurately quantify short-term dynamic human impact on the environment, which is the key to ecosystem and biodiversity conservation. Human's digital footprints are widely used as a proxy of dynamic human impact. This study developed a method to accurately and objectively map the dynamic human's digital footprints in the Tibetan Plateau using the geospatial big datasets, including the numbers of smartphone location request, microblog check-ins, and geo-tagged flicker photos. We developed a method to calculate the fused digital footprint intensity (FDFI) by integrating the location information in the three datasets. The magnitude of the FDFI was converted to a footprint intensity score (FIS), which was then used to infer the human impact. Results show that the average FIS values in Qinghai and Tibet are low (0.12 and 0.04, respectively). The grids with a positive FIS only account for 5.99% of the Tibetan Plateau and are mainly found in the cities and along the transportation networks. The FIS is also strongly correlated to land use and the positive values are mainly found in the built-up and agricultural lands. All other land use categories tend to have near zero FIS values. We concluded that human activities overall show very limited impact on the Tibetan Plateau and most of the impact is found in the built-up and agricultural lands.

China's improving inland surface water quality since 2003.

Increased human activity threatens inland water quality in China. Major efforts have been made to alleviate water pollution since 2001. Understanding how water quality responds to these forces can help to guide future efforts to maintain water security and sustainability. We here analyzed the nationwide variability of inland water quality across China from 2003 to 2017 and its responses to anthropogenic discharges. We show that water quality has been improved markedly or was maintained at favorable levels over the country because of reduced discharges in the industrial, rural, and urban residential sectors. However, growing discharges from the agricultural sector threaten these gains. Moreover, the present status of water pollution is relatively severe in north and northeast China. Our findings suggest that China's water quality would further benefit from more flexible strategies for mitigation measures, which respond to regional differences in the factors that influence water pollution levels in specific regions.

Pollution exacerbates China's water scarcity and its regional inequality.

Inadequate water quality can mean that water is unsuitable for a variety of human uses, thus exacerbating freshwater scarcity. Previous large-scale water scarcity assessments mostly focused on the availability of sufficient freshwater quantity for providing supplies, but neglected the quality constraints on water usability. Here we report a comprehensive nationwide water scarcity assessment in China, which explicitly includes quality requirements for human water uses. We highlight the necessity of incorporating water scarcity assessment at multiple temporal and geographic scales. Our results show that inadequate water quality exacerbates China's water scarcity, which is unevenly distributed across the country. North China often suffers water scarcity throughout the year, whereas South China, despite sufficient quantities, experiences seasonal water scarcity due to inadequate quality. Over half of the population are affected by water scarcity, pointing to an urgent need for improving freshwater quantity and quality management to cope with water scarcity.