抗真菌感染新药研究进展

随着免疫功能缺陷人群的增多,侵袭性真菌感染（invasive fungal infections,IFIs）的发病率和死亡率逐年上升,严重威胁人类健康。目前临床常用抗侵袭性真菌感染药物有三唑类（氟康唑）、多烯类（两性霉素B）、棘白菌素类（卡泊芬净）等,然而这些药物并不能满足临床需要,侵袭性真菌感染的死亡率仍居高不下。因此,本文着重于目前处于临床研究阶段的抗真菌感染新药,根据作用靶点不同依次介绍：作用于细胞壁的新型葡聚糖合成酶抑制剂CD101和SCY-078、几丁质合成酶抑制剂尼可霉素Z、GPI锚定蛋白抑制剂APX001;作用于细胞膜的CYP51抑制剂VT-1161和VT-1129、破坏细胞膜通透性药物CAmB;影响细胞代谢的嘧啶合成抑制剂F901318,以及生物制剂包括细胞表面凝集素样序列3蛋白疫苗（NDV-3）和抗真菌感染抗体Mycograb。本文主要综述了上述新药的研究进展,包括作用机制、体内外活性、临床研究结果等,为相关药物的研发与未来的临床应用提供参考。     

Animal movements in fire‐prone landscapes

Movement is a trait of fundamental importance in ecosystems subject to frequent disturbances, such as fire‐prone ecosystems. Despite this, the role of movement in facilitating responses to fire has received little attention. Herein, we consider how animal movement interacts with fire history to shape species distributions. We consider how fire affects movement between habitat patches of differing fire histories that occur across a range of spatial and temporal scales, from daily foraging bouts to infrequent dispersal events, and annual migrations. We review animal movements in response to the immediate and abrupt impacts of fire, and the longer‐term successional changes that fires set in train. We discuss how the novel threats of altered fire regimes, landscape fragmentation, and invasive species result in suboptimal movements that drive populations downwards. We then outline the types of data needed to study animal movements in relation to fire and novel threats, to hasten the integration of movement ecology and fire ecology. We conclude by outlining a research agenda for the integration of movement ecology and fire ecology by identifying key research questions that emerge from our synthesis of animal movements in fire‐prone ecosystems.     

Heterocyclic lactam derivatives containing piperonyl moiety as potential antifungal agents

To study the novel functionalized heterocyclic molecules with highly potential biological activity, two series of heterocyclic lactam derivatives containing the piperonyl moiety were designed and synthesized. The newly obtained compounds have been identified on the basis of analytical spectral data, including ¹H NMR, ¹³C NMR, and ESI-MS. The target compounds were evaluated for their potential antifungal activities in vitro against twelve species of the plant pathogen fungi (Sclerotinia sclerotiorum, Rhizoctonia solani, Rap Sclerotinia stemrot, Fusarium graminearum, Phomopsis adianticola, Pestallozzia theae, Pestalotiopsis guepinii, Alternaria tenuis Nees, Monilinia fructicola, Colletotrichum gloeosporioides, Phytophthora capsici, Magnaporthe oryzae). Preliminary bioassays suggested that all prepared compounds I1–14 displayed broad-spectrum and moderate antifungal activities compared with the positive control hymexazol, especially for Sclerotinia sclerotiorum, Rap Sclerotinia stemrot, and Monilinia fructicola. In particular, the inhibition rate of compound I9 exhibited good inhibition activity reached 95.16% against Sclerotinia sclerotiorum, and compounds I5, I12 against Phytophthora capsici were 93.44%, 91.25%. Further studies revealed that compounds I5 (IC₅₀ = 19.13 µM) and I12 (IC₅₀ = 9.12 µM) exhibited obviously antifungal activities against Phytophthora capsici, which were better than that of commercial agricultural fungicide hymexazol (IC₅₀ = 325.45 µM). Therefore, these target compounds could be further studied and explored as a lead skeleton for discovery of novel antifungal agents.     

Chemical synthesis,microbial transformation and biological evaluation of tetrahydroprotoberberines as dopamine D1/D2 receptor ligands

Dopamine D1/D2 receptors are important targets for drug discovery in the treatment of central nervous system diseases. To discover new and potential D1/D2 ligands, 17 derivatives of tetrahydroprotoberberine (THPB) with various substituents were prepared by chemical synthesis or microbial transformation using Streptomyces griseus ATCC 13273. Their functional activities on D1 and D2 receptors were determined by cAMP assay and calcium flux assay. Seven compounds showed high activity on D1/D2 receptor with low IC₅₀ values less than 1?µM. Especially, top compound 5 showed strong antagonistic activity on both D1 and D2 receptor with an IC₅₀ of 0.391 and 0.0757?µM, respectively. Five compounds displayed selective antagonistic activity on D1 and D2 receptor. The SAR studies revealed that (1) the hydroxyl group at C-9 position plays an important role in keeping a good activity and small or fewer substituents on ring D of THPBs may also stimulate their effects, (2) the absence of substituents at C-9 position tends to be more selective for D2 receptor, and (3) hydroxyl substitution at C-2 position and the substitution at C-9 position may facilitate the conversion of D1 receptor from antagonist to agonist. Molecular docking simulations found that Asp 103/Asp 114, Ser 107/Cys 118, and Trp 285/ Trp 386 of D1/ D2 receptors are the key residues, which have strong interactions with the active D1/D2 compounds and may influence their functional profiles.     

Design,synthesis and biological evaluation of novel 2,3-indolinedione derivatives against mantle cell lymphoma

2,3-Indolinedione derivatives have been identified as a novel class of promising agents for cancer treatment. In this study, eighteen 2,3-indolinedione derivatives were designed and synthesized, and their anticancer activities against mantle cell lymphoma (MCL) cells were evaluated. Most of them exhibited significant antiproliferative activity against the tested cell lines, and compound K5 was the most potent (MCL cellular IC₅₀ = 0.4–0.7 μM). Further, compound K5 could induce cell apoptosis and cell cycle arrest in G2/M phase. Additionally, the results of drug-likeness analysis demonstrated that these novel 2,3-indolinedione derivatives could have potential as novel treatment strategies for MCL.     

Design,synthesis and algicides activities of thiourea derivatives as the novel scaffold aldolase inhibitors

By using a new Fragment-Based Virtual Screen strategy, two series of novel FBA-II inhibitors (thiourea derivatives) were de novo discovered based on the active site of fructose-1, 6-bisphosphate aldolase from Cyanobacterial (CyFBA). In comparison, most of the N-(2-benzoylhydrazine-1-carbonothioyl) benzamide derivatives (L14～L22) exhibit higher CyFBA-II inhibitory activities compared to N-(phenylcarbamothioyl) benzamide derivatives (L1～L13). Especially, compound L14 not only shows higher CyFBA-II activity (K_i?=?0.65?μM), but also exhibits most potent in vivo activity against Synechocystis sp. PCC 6803 (EC₅₀?=?0.09?ppm), higher (7-fold) than that of our previous inhibitor (EC₅₀?=?0.6?ppm). The binding modes of compound L14 and CyFBA-II were further elucidated by jointly using DOX computational protocol, MM-PBSA and site-directed mutagenesis assays. The positive results suggest that strategy adopted in this study was promising to rapidly discovery the potent inhibitors with novel scaffolds. The satisfactory algicide activities suggest that the thiourea derivatives is very likely to be a promising lead for the development of novel specific algicides to solve Cyanobacterial harmful algal blooms (CHABs).     

天然间苯三酚的化学结构和药理活性研究进展

天然的间苯三酚类化合物来源广泛、结构新颖,具有多种药理活性,是目前天然药物化学的研究热点之一。本文对近十年发现的天然间苯三酚类化合物的化学结构和药理活性的研究进展做了调研和综述,以期对该类化合物进一步的研究提供参考。     

疏勒河流域气候变化和人类活动对植被NPP的相对影响评价

气候变化和人类活动是对陆地生态系统碳循环产生重要影响的两个因素,定量评估气候变化与人类活动对植被净初级生产力(NPP)的相对影响,对深入理解其驱动机制和控制荒漠化发展具有重要意义。以疏勒河流域为研究区,利用遥感和气象数据计算潜在NPP(PNPP)及其与实际NPP(ANPP)之间的差值,分别衡量了气候变化和人类活动对流域NPP的相对影响。研究结果表明:(1)2001—2015年疏勒河流域年ANPP整体呈缓慢增加趋势,与全国和西北地区相比,普遍较低,流域植被整体生产力水平不高。流域年ANPP空间分布呈现上游祁连山区和中下游绿洲区ANPP较高,而中下游荒漠戈壁区ANPP较低的分布格局。(2)2001—2015年流域年PNPP的变化趋势表明,降水量的变化是导致疏勒河流域植被退化加剧或缓解的主要气候驱动因素,但气温的变化对植被的影响较为复杂。(3)2001—2015年流域大部分地区植被退化系人类活动造成的,但人类活动的负向影响力在减弱。(4)气候变化和人类活动对植被NPP的相对影响均表现出明显的空间异质性,其中人类活动是疏勒河流域植被变化的主要驱动因素。     

Kin recognition and co‐operative foraging in Drosophila melanogaster larvae

A long‐standing goal for biologists and social scientists is to understand the factors that lead to the evolution and maintenance of co‐operative behaviour between conspecifics. To that end, the fruit fly, Drosophila melanogaster, is becoming an increasingly popular model species to study sociality; however, most of the research to date has focused on adult behaviours. In this study, we set out to examine group‐feeding behaviour by larvae and to determine whether the degree of relatedness between individuals mediates the expression co‐operation. In a series of assays, we manipulated the average degree of relatedness in groups of third‐instar larvae that were faced with resource scarcity, and measured the size, frequency and composition of feeding clusters, as well as the fitness benefits associated with co‐operation. Our results suggest that larval D. melanogaster are capable of kin recognition (something that has not been previously described in this species), as clusters were more numerous, larger and involved more larvae, when more closely related kin were present in the social environment. These findings are discussed in the context of the correlated fitness‐associated benefits of co‐operation, the potential mechanisms by which individuals may recognize kin, and how that kinship may play an important role in facilitating the manifestation of this co‐operative behaviour.