Heparan Sulfate Facilitates Spike Protein-Mediated SARS-CoV-2 Host Cell Invasion and Contributes to Increased Infection of SARS-CoV-2 G614 Mutant and in Lung Cancer

The severe acute respiratory syndrome (SARS)-like coronavirus disease (COVID-19) is caused by SARS-CoV-2 and has been a serious threat to global public health with limited treatment. Cellular heparan sulfate (HS) has been found to bind SARS-CoV-2 spike protein (SV2-S) and co-operate with cell surface receptor angiotensin-converting enzyme 2 (ACE2) to mediate SARS-CoV-2 infection of host cells. In this study, we determined that host cell surface SV2-S binding depends on and correlates with host cell surface HS expression. This binding is required for SARS-Cov-2 virus to infect host cells and can be blocked by heparin lyase, HS antagonist surfen, heparin, and heparin derivatives. The binding of heparin/HS to SV2-S is mainly determined by its overall sulfation with potential, minor contribution of specific SV2-S binding motifs. The higher binding affinity of SV2-S G614 mutant to heparin and upregulated HS expression may be one of the mechanisms underlying the higher infectivity of the SARS-CoV-2 G614 variant and the high vulnerability of lung cancer patients to SARS-CoV-2 infection, respectively. The higher host cell infection by SARS-CoV-2 G614 variant pseudovirus and the increased infection caused by upregulated HS expression both can be effectively blocked by heparin lyase and heparin, and possibly surfen and heparin derivatives too. Our findings support blocking HS-SV2-S interaction may provide one addition to achieve effective prevention and/treatment of COVID-19

Madden–Julian Oscillation simulated in BCC climate models

AbstractThis study evaluates the ability of four versions BCC (Beijing Climate Center or National Climate Center) models (BCC_AGCM2.1, BCC_AGCM2.2, BCC_CSM1.1 and BCC_CSM1.1m) in simulating the MJO phenomenon using the outputs of the AMIP (Atmospheric Model Intercomparison Project) and historical runs. In general, the models can simulate some major characteristics of the MJO, such as the intensity, the periodicity, the propagation, and the temporal/spatial evolution of the MJO signals in the tropics. There are still some biases between the models and the observation/reanalysis data, such as the overestimated total intraseasonal variability, but underestimated MJO intensity, shorter significant periodicity, and excessive westward propagation. The differences in the ability of simulating the MJO between AMIP and historical experiments are also significant. Compared to the AMIP runs, the total intraseasonal variability is reduced and more realistic, however the ratio between the MJO and its westward counterpart decreases in the historical runs. This unrealistic simulation of the zonal propagation might have been associated with the greater mean precipitation over the Pacific and corresponded to the exaggeration of the South Pacific Convergence Zone structure in precipitation mean state. In contrast to the T42 versions, the improvement of model resolution demonstrate more elaborate topography, but the enhanced westward propagation signals over the Arabia Sea followed. The underestimated (overestimated) MJO variability over eastern Indian Ocean (Pacific) was assumed to be associated with the mean state. Three sets of sensitive experiments using BCC_CSM1.1m turn out to support this argument

Improving China’s Resilience to Climate-Related Risks: The China Framework for Climate Services

The primary needs for climate services in China, in the form of climate information for decision-making, are to better prepare for and manage meteorological-related disasters, adaptation to climate change, and sustainable development. In this paper, the vision, structure, content, and governance of the China Framework for Climate Services, which is designed to respond to these primary needs, is described. This paper reflects on practice, lessons, and experience developing and delivering climate services in China for disaster risk reduction, agriculture, water, energy, urbanization, and major engineering projects. Four key aspects of successful climate services are highlighted: the transition of climate research to operational climate services; delivering relevant, tailored, and usable climate information; effective engagement between users and providers of climate services; and building interdisciplinary professional teams. Key challenges and opportunities for climate services are recognized in this paper: a growing gap between climate science and services capability and societal need, a lack of awareness in user communities of the climate service value for their activities, and the important need for closer and more meaningful interactions between users and providers of climate services. The delivery and uptake of high-quality, relevant, usable, and effective climate services will facilitate climate-smart decisions that will reduce climate risks and improve Chinese societal resilience

3-O-Sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake

International audiencePrion-like transcellular spreading of tau in Alz-heimersD isease (AD) is mediated by tau binding to cell surface heparan sulfate (HS). However,t he structural determinants for tau-HS interaction are not well understood. Microarraya nd SPR assays of structurally defined HS oligosaccharides showt hat ar are 3-O-sulfation (3-O-S) of HS significantly enhances tau binding. In Hs3st1 À/À (HS 3-O-sulfotransferase-1 knockout) cells,reduced 3-O-S levels of HS diminished both cell surface binding and internalization of tau. In ac ell culture,t he addition of a3-O-S HS 12-mer reduced both tau cell surface binding and cellular uptake.N MR titrations mapped 3-O-S binding sites to the microtubule binding repeat 2(R2) and proline-richregion 2(PRR2) of tau. Taui so nly the seventh protein currently knownt or ecognize HS 3-O-sulfation. Our work demonstrates that this rare 3-O-sulfation enhances tau-HS binding and likely the transcellular spread of tau, providing an ovel target for disease-modifying treatment of AD and other tauopathies

FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels

<div><p>The M2 subtype Acute Myeloid Leukemia (AML-M2) with t(8;21) represents an unmet challenge because of poor clinical outcomes in a sizable portion of patients. In this study,we report that FTY720 (Fingolimod), a sphingosine analogue and an FDA approved drug for treating of multiple sclerosis, shows antitumorigenic activity against the Kasumi-1 cell line, xenograft mouse models and leukemic blasts isolated from AML-M2 patients with t(8;21) translocation. Primary investigation indicated that FTY720 caused cell apoptosis through caspases and protein phosphatase 2A (PP2A) activation. Transcriptomic profiling further revealed that FTY720 treatment could upregulate AML1 target genes and interfere with genes involved in ceramide synthesis. Treatment with FTY720 led to the elimination of AML1-ETO oncoprotein and caused cell cycle arrest. More importantly, FTY720 treatment resulted in rapid and significant increase of pro-apoptotic ceramide levels, determined by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry based lipidomic approaches. Structural simulation model had also indicated that the direct binding of ceramide to inhibitor 2 of PP2A (I2PP2A) could reactivate PP2A and cause cell death. This study demonstrates, for the first time, that accumulation of ceramide plays a central role in FTY720 induced cell death of AML-M2 with t(8;21). Targeting sphingolipid metabolism by using FTY720 may provide novel insight for the drug development of treatment for AML-M2 leukemia.</p></div

Guiding the creation of a comprehensive surface temperature resource for 21st century climate science

Surface temperature data – observed primarily for weather-related purposes – are disparate, originating from ever evolving instrument types and observational practices. Although several global databases are in use internationally, no comprehensive global repository exists and many data are undigitized or restricted. Scientists have painstakingly obtained vast quantities of data, carefully removed random errors and accounted for systematic biases. The 21st Century demands go further - requiring highly detailed (spatially and temporally), globally complete, long-term products, with quantified uncertainties, and created from freely available, fully traceable data. Many decisions of substantial socio-economic importance rely on the accuracy of such products. An international meeting was held to plan how best to facilitate such efforts. A central repository is to be created, where data are traceable from their origins to final product. Strategies are outlined to rescue non-digitized data and move towards entirely freely available data. Creation of multiple methodologically independent products is recommended for quantifying uncertainty. Methods of benchmarking and assessing multiple products to aid inter-comparison and end-user product selection are described. Data-products would be obtained and visualized using in-house tools from the planned data-portal. Structure and governance include engagement with bodies such as WMO and, importantly, with experts other than climatologists

<i>In vitro</i> efficacy of FTY720 on Kasumi-1 cells and fresh leukemic cells.

<p>(A) Kasumi-1 and SKNO-1 cells were treated with indicated concentration of FTY720 for 48 h, and the cell viability was determined with a CCK-8 kit. (B) Kasumi-1 cells were grown in methylcellulose for 14 d in presence of FTY720. **P<0.01, student's <i>t</i> test compared with untreated. (C) PBMCs from leukemia patients or healthy donor were treated with or without FTY720 for 24 h, and then subjected to apoptosis analysis by flow cytometry. *P<0.05, **P<0.01. (D) Kasumi-1 (top panel) and fresh leukemic cells (bottom panel) from AML-M2 patient were treated or untreated with FTY720 (7.5 µM), and analyzed by wright staining. Partial apoptotic cells were indicated by red arrows, and blue arrow presented cells might undergo differentiation.</p