ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLC beta 3 Catalysis : Targeting It Eradicates Leukemia Stem Cells

Leukemia stem cells (LSCs) are a rare subpopulation of abnormal hematopoietic stem cells (HSCs) that propagates leukemia and are responsible for the high frequency of relapse in therapies. Detailed insights into LSCs' survival will facilitate the identification of targets for therapeutic approaches. Here, we develop an inhibitor, LYZ-81, which targets ORP4L with high affinity and specificity and selectively eradicates LCSs in vitro and in vivo. ORP4L is expressed in LSCs but not in normal HSCs and is essential for LSC bioenergetics and survival. It extracts PIP2 from the plasma membrane and presents it to PLC beta 3, enabling IP3 generation and subsequentCa(2+)-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP2 and blocks PIP2 hydrolysis, resulting in defective Ca2+ signaling. The results provide evidence that LSCs can be eradicated through the inhibition of ORP4L by LYZ-81, which may serve as a starting point of drug development for the elimination of LSCs to eventually cure leukemia.Peer reviewe

Species packing and the latitudinal gradient in beta-diversity

Acknowledgements We thank Dingliang Xing, Tak Fung, Fangliang He and Gabriel Arellano for comments on the earlier draft. We thank Alex Karolus for leading the census in the Danum Valley forest plot, and we are grateful to Mike Bernados and Bill McDonald for species identifications, to Fangliang He, Stuart Davies and Shameema Esufali for advice and training, to Qianjiangyuan National Park, the Center for Forest Science at Morton Arboretum, Fushan Research Center, Lienhuachih Research Center and Sri Lankan Forest Department for logistical support and the hundreds of fieldworkers and students who measured and mapped the trees analysed in this study. Funding. This work was financially supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB31000000) and National Natural Science Foundation of China (NSFC 31770478). Data collection was funded by many organizations,principally, NSFC 31470490, 31470487, 41475123, 31570426, 31570432, 31570486, 31622014, 31660130, 31670441, 31670628, 31700356, 31760141, 31870404 and 32061123003, the Southeast Asia Rain Forest Research Programme (SEARRP), National Key Basic Research Program of China (Grant No. 2014CB954100), SEARRP partners especially Yayasan Sabah, HSBC Malaysia, financial project of Heilongjiang Pro- vince (XKLY2018ZR01), National Key R&D Program of China (2016YFC1201102 and 2016YFC0502405), the Central Public-interest Scientific Institution Basal Research Fund (CAFYBB2017ZE001), CTFS Forest GEO for funding for Sinharaja forest plot, the Taiwan For- estry Bureau (92-00-2-06 and tfbm960226), the Taiwan Forestry Research Institute (93AS-2.4.2-FI-G1, 94AS-11.1.2-FI-G1, and 97AS- 7.1.1.F1-G1) and the Ministry of Science and Technology of Taiwan (NSC92-3114-B002-009) for funding the Fushan and Lienhuachih plots, Scientific Research Funds of Heilongjiang Provincial Research Institutes (CZKYF2021B006). J.C.S. considers this work a contribution to his VILLUM Investigator project ‘Biodiversity Dynamics in a Changing World’ funded by VILLUM FONDEN (grant no. 16549).Peer reviewedPostprin

ForestGEO: understanding forest diversity and dynamics through a global observatory network

ForestGEO is a network of scientists and long-term forest dynamics plots (FDPs) spanning the Earth's major forest types. ForestGEO's mission is to advance understanding of the diversity and dynamics of forests and to strengthen global capacity for forest science research. ForestGEO is unique among forest plot networks in its large-scale plot dimensions, censusing of all stems ≥1 cm in diameter, inclusion of tropical, temperate and boreal forests, and investigation of additional biotic (e.g., arthropods) and abiotic (e.g., soils) drivers, which together provide a holistic view of forest functioning. The 71 FDPs in 27 countries include approximately 7.33 million living trees and about 12,000 species, representing 20% of the world's known tree diversity. With >1300 published papers, ForestGEO researchers have made significant contributions in two fundamental areas: species coexistence and diversity, and ecosystem functioning. Specifically, defining the major biotic and abiotic controls on the distribution and coexistence of species and functional types and on variation in species' demography has led to improved understanding of how the multiple dimensions of forest diversity are structured across space and time and how this diversity relates to the processes controlling the role of forests in the Earth system. Nevertheless, knowledge gaps remain that impede our ability to predict how forest diversity and function will respond to climate change and other stressors. Meeting these global research challenges requires major advances in standardizing taxonomy of tropical species, resolving the main drivers of forest dynamics, and integrating plot-based ground and remote sensing observations to scale up estimates of forest diversity and function, coupled with improved predictive models. However, they cannot be met without greater financial commitment to sustain the long-term research of ForestGEO and other forest plot networks, greatly expanded scientific capacity across the world's forested nations, and increased collaboration and integration among research networks and disciplines addressing forest science