sFlt Multivalent Conjugates Inhibit Angiogenesis and Improve Half-Life In Vivo

We would like to thank Jonathan Winger and Xiao Zhu for guidance with the insect cell protein expression system and providing reagents. We would like to acknowledge Ann Fischer for help with expressing the sFlt protein in the Tissue Culture Facility at UC Berkeley and Dawn Spelke and Anusuya Ramasubramanian for help optimizing protein purification from insect cells. We are also grateful for the help from Leah Byrne and John Flannery at in the Helen Wills Neuroscience Institute at UC Berkeley for aiding us in the development of the rat intravitreal residence time model and for allowing us to use their facilities.Current anti-VEGF drugs for patients with diabetic retinopathy suffer from short residence time in the vitreous of the eye. In order to maintain biologically effective doses of drug for inhibiting retinal neovascularization, patients are required to receive regular monthly injections of drug, which often results in low patient compliance and progression of the disease. To improve the intravitreal residence time of anti-VEGF drugs, we have synthesized multivalent bioconjugates of an anti-VEGF protein, soluble fms-like tyrosine kinase-1 (sFlt) that is covalently grafted to chains of hyaluronic acid (HyA), conjugates that are termed mvsFlt. Using a mouse corneal angiogenesis assay, we demonstrate that covalent conjugation to HyA chains does not decrease the bioactivity of sFlt and that mvsFlt is equivalent to sFlt at inhibiting corneal angiogenesis. In a rat vitreous model, we observed that mvsFlt had significantly increased intravitreal residence time compared to the unconjugated sFlt after 2 days. The calculated intravitreal half-lives for sFlt and mvsFlt were 3.3 and 35 hours, respectively. Furthermore, we show that mvsFlt is more effective than the unconjugated form at inhibiting retinal neovascularization in an oxygen-induced retinopathy model, an effect that is most likely due to the longer half-life of mvsFlt in the vitreous. Taken together, our results indicate that conjugation of sFlt to HyA does not affect its affinity for VEGF and this conjugation significantly improves drug half-life. These in vivo results suggest that our strategy of multivalent conjugation could substantially improve upon drug half-life, and thus the efficacy of currently available drugs that are used in diseases such as diabetic retinopathy, thereby improving patient quality of life.Yeshttp://www.plosone.org/static/editorial#pee

WebGIS and Random Forest Model for Assessing the Impact of Landslides in Van Yen District, Yen Bai Province, Vietnam

Van Yen district in Yen Bai province of Vietnam is one of the most affected areas indicating high and very high potential of landslide occurrences. WebGIS technology is useful for dissemination of the geographical information related to landslides. To this aim, this paper provides a landslide information system for Van Yen district of the Yen Bai province. The paper firstly provides a landslide susceptibility map produced using a Random Forest-based model. Along the process, a landslide inventory from three investigations of 2013, 2017, and landslides along national road 32 and provincial road 163 (collected in November 2021) was considered. Additionally, thirteen factors were used in the model as variables including geological data, DEM (digital elevation model), slope, aspect, plan curvature, profile curvature, stream power index, topographic wetness index, fault network, river network, road network, land use-land cover data, and Sentinel-2 based NDVI (normalized difference vegetation index). The model was validated based on confusion matrix, and gave an excellent accuracy of 91.33%. Finally, WebGIS was created using open-source technologies such as Leaflet, Openlayers, Geoserver, PostgreSQL as the database management system, and PostGIS as it is plugin for spatial database management. WebGIS not only contains information relevant to landslides, but it also combines the landslide susceptibility map with population data in order to assess exposure for warning purposes