Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity

Interleukin-2(IL-2)is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells(Tregs)and effector cells,leading to paradoxical consequences.Here,we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine(FSY)into IL-2 for proximity-enabled covalent binding to IL-2Rαto selectively promote Treg activation.We found that FSY-bearing IL-2 variants,such as L72-FSY,covalently bound to IL-2Rαvia sulfur-fluoride exchange when in proximity,resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells.Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation,as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3(LAG-3)and enhanced expression of programmed cell death protein-1(PD-1).Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease(GvHD)resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment.The efficacy of L72-FSY was further improved by N-terminal PEGylation,which increased its circulatory retention for preferential and sustained effects.This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.

靶向流感病毒进入(细胞)抑制剂研究进展

目前临床上抗流感病毒感染的药物主要有M2离子通道抑制剂及神经氨酸酶抑制剂两大类.随着流行性感冒、季节性流感、高致病性禽流感的爆发以及耐药流感病毒株的出现,使得对具有新作用机制的抗流感药物的需求更加紧迫.近年来,随着流感病毒进入细胞分子机制研究的深入,为以"病毒进入细胞为靶"的抗流感抑制剂的研究带来了契机.本文在介绍流感病毒进入细胞分子机制的基础上,重点介绍了靶向流感病毒进入的抑制剂及其作用机制的最新研究进展.

China's wetland change (1990-2000) determined by remote sensing

Two wetland maps for the entire China have been produced based on Landsat data acquired around 1990 and 2000. Wetlands in China have been divided into 3 broad categories with 15 sub-categories except rice fields. In 1990, the total wetland area in China was 355208 km2 whereas in 2000 it dropped to 304849 km2 with a net loss of 50360 km2. During an approximate 10-year period, inland wetland reduced from 318326 to 257922 km2, coastal wetland dropped from 14335 to 12015 km2, while artificial wetland increased from 22546 to 34911 km2. The greatest natural wetland loss occurred in Heilongjiang, Inner Mon- golia, and Jilin with a total loss of over 57000 km2 of wetland. In western China, over 13000 km2 of wetlands were newly formed in Xinjiang, Tibet, and Qinghai. About 12000 km2 of artificial wetlands were also added for fish farm and reservoir constructions. The newly formed wetlands in western China were caused primarily by climate warming over that region whereas the newly created artificial wetlands were caused by economic developments. China’s wetland loss is caused mainly by human activities.

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Dimers as HCV Entry Inhibitors

A series of triterpene dimers bearing different scaffold were designed and synthesized via CuAAC reaction. Their anti-HCV entry activities were evaluated by HCVpp and VSVpp entry assays. It was found that echinocystic acid （EA） and its dimer were still necessary for maintaining anti-HCV entry activity, and replacement of EA by other triterpenes might significantly decrease its anti-viral activities. Using a linker bearing a piperazine group, compound 14 dramatically increased its potency with IC50 at 2.87 nmol/L. In addition, the undesired hemolytic effect of all these compounds was removed.

Heat Health Risk and Adaptability Assessments at the Subdistrict Scale in Metropolitan Beijing

Against the background of global climate change, the increasing heat health risk from the combined effect of changes in high temperature, exposure, vulnerability, and other factors has become a growing concern.Yet the low number of temperature observation stations is insufficient to represent the complex changes in urban heatwaves, and subdistrict-scale(town, township, neighborhood committee, and equivalent) heat health risk and adaptability assessments are still limited. In this study, we built daytime and nighttime high-temperature interpolation models supported by data from 225 meteorological stations in Beijing.The models performed well at interpolating the cumulative hours of high temperature and the interpolation quality at night was better than that during the day. We further established a methodological framework for heat health risk and adaptability assessments based on heat hazard, population exposure, social vulnerability, and adaptability at the subdistrict scale in Beijing. Our results show that the heat health risk hotspots were mainly located in the central urban area,with 81 hotspots during the day and 76 at night. The average value of the heat health risk index of urban areas was 5.60 times higher than that of suburban areas in the daytime,and 6.70 times higher than that of suburban areas in the night. Greater population density and higher intensity of heat hazards were the main reasons for the high risk in most heat health risk hotspots. Combined with a heat-adaptive-capacity evaluation for hotspot areas, this study suggests that 11high-risk and low-adaptation subdistricts are priority areas for government action to reduce heat health risk in policy formulation and urban development.

Selective and facile deacetylation of pentacyclic triterpenoid under methanolic ammonia condition and unambiguous NMR analysis

The acetyl ester plays an important role for protection of the hydroxyl groups in carbohydrates synthesis.In the present study,we described an efficient deprotection of acetyl group of pentacyclic triterpenoid by using methanolic ammonia in THF solution.Good selectivity for cleaving gal-C2-OAc group of 3β-hydroxy-olean-12-en-28-oic acid 28-N-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside(3) was achieved in the presence of methanolic ammonia within 4 h at low temperature(-60℃) in a yield of 56%.The reaction disclosed here provides a new method for the synthesis of C2 selective modified carbohydrates,which is more useful than conventional synthesis procedure that usually requires many steps including temporary regioselective protection and deprotection.When the reaction temperature was increased from -60℃ to room temperature,the cleavage of the other three acetyl groups of galactose in an order of C4-OAc>C3-OAc>C6-OAc was observed.Based on this study,a plausible route for the deacetylation reaction has been proposed.

Facile preparation and characterization of novel oleanane-type triterpene functionalized β-cyclodextrin conjugates

Oleanolic acid(OA) and echinocystic acid(EA), two naturally occurring pentacyclic oleanane triterpenes,are gaining increasing attention due to their promising pharmacological activities. Conjugation with amphiphilic α(β)-cyclodextrin(CD) via "click chemistry" can improve their solubility and anti-HCV entry potency. In the present work,four water-soluble β-CD-pentacyclic triterpene conjugates were designed and synthesized, in which OA and EA was coupled to one of the primary hydroxyl groups of β-CD via ester and amide bonds. The structures of the conjugates were unambiguously determined by ~1H NMR, ^(13)C NMR and HRMS or MALDI-TOF-MS. All the conjugates showed lower hydrophobicity(AlogP) than their parent compounds and no significant cytotoxicity was found to HL-60, A549, Hela and Bel-7402 cells at concentrations up to 10 μmol/L. Further anti-HCV entry activity and mechanism studies are under way in our laboratory.