南宁市湖库型饮用水源景观结构与涵养功能关系耦合优化

为探明湖库型饮用水源景观结构与涵养功能间的内在机理,优化水源涵养林功能,保护水源安全,借助遥感解译技术得到各用地类型面积并计算水源涵养功能指数,依据取水量和水源涵养量间水量平衡模式计算所需最小森林面积,应用多元数量分析方法探究水源涵养功能指数、景观格局指数、水质指标之间的耦合关系。结果表明:(1)水源地3 km缓冲区较500 m缓冲区的水源涵养功能有所下降。(2)用最小面积法优化筛选出以软阔叶林、栎林、硬阔叶林、竹林为主的岸边带森林生态系统可有效提高水源涵养功能,最大限度的满足饮用水源保护区面积、集雨区面积和涵养区面积间的数量关系。(3)水源涵养功能与景观格局、水资源、水质和污染物排放间可建立起通过显著性检验的多元回归拟合模型方程。(4)多维尺度综合分析过程可诊断出南宁市湖库型饮用水源在生态系统稳定性、水资源量和水质方面存在的生态安全与风险隐患问题,建议南宁市开展饮用水源环境综合整治、生态系统保护与修复工作。     

Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer

Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new molecule entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized. After enzymatic evaluations, structure-activity relationships (SAR) were discussed in detailed. Among the screened compounds, derivative 35 showed excellent enzymatic inhibitory activity (IC₅₀, 36?nM). The cellular inhibition results showed that compound 35 had good antiproliferative activity against the non-small cell lung cancer A549 cells (IC₅₀, 1.61?μM). Liver microsome stability showed that the half-life of compound 35 in human liver microsome was 42.3?min, which was more stable than the control CB-5083 (25.8?min). The in vivo pharmacokinetic results showed that the elimination phase half-lives of compound 35 were 4.57?h for ig and 3.64?h for iv, respectively and the oral bioavailability was only 4.5%. These results indicated that compound 35 could be effective for intravenous treatment of non-small cell lung cancer.     

拉萨河流域植物群落的数量分类与排序

青藏高原植物群落空间分异格局是异质生境条件下物种性状、种间相互作用等生态学过程共同作用的结果,对其分析有助于深入理解群落形成与环境因子之间的关系。基于拉萨河流域自然植被样带调查,采用双向指示种分析(TWINSPAN)和典范对应分析(CCA)等方法,探讨了群落的结构组成及影响其结构分异的主导环境因子。结果表明:(1) TWINSPAN数量分类将拉萨河流域草地系统划分成12个群系类型,即圆叶合头菊+唐古拉翠雀花群系;紫花针茅群系;青藏臺草群系;雪层杜鹃+鲜卑花-西藏嵩草群系;高山嵩草群系;小叶金露梅群系;硬叶柳+杯腺柳群系;水栒子+拱枝绣线菊-高山嵩草群系;绢毛蔷薇-冷蒿+白草群系;大果圆柏-垂穗披碱草群系;铺地柏-藏橐吾+高原荨麻群系;醉鱼草+砂生槐群系。12种群系类型包含了较多的植被类型,包括高寒灌丛草甸、高寒灌丛草原、稀树草原、高寒草甸和高寒草原等。(2) CCA排序表明:影响拉萨河流域植物群系分布的主要环境因子是年均温度、海拔和经度和纬度,其次是年均降雨量。(3) TWINSPAN分类与CCA排序结合反映了群系分布格局变异与环境因子之间的关系,可为拉萨河流域草地的保护和可持续利用,以及相关的植被群落研究提供参考。     

生态系统服务权衡与协同关系及驱动力——以江苏省太湖流域为例

生态系统服务权衡与协同关系研究是生态系统综合管理的前提。以太湖流域江苏省为例,通过空间显示的生物物理模型计算氮、磷净化、水量供给及土壤保持4种服务指标,借助GIS空间分析表征氮、磷指标与其他指标之间关系,并利用多元Logistic模型定量识别主导驱动力。结果表明:2000到2010年间,各指标的单位面积年均值呈现不同程度的变化,氮输出指标先增加后略下降,磷输出指标逐渐增加,水量供给先下降后上升,土壤保持逐渐下降,并且服务指标的空间格局显著差异。氮、磷净化与水量供给关系在空间上表现为广泛分布的权衡及协同变化区,但与土壤保持的关系不明显,氮、磷之间主要为协同变化关系。氮净化与水量供给的正向主导驱动力为城镇建设用地和农村居民点密度,而植被覆盖度和水网密度具有显著负作用。氮、磷关系的主要影响因素为植被覆盖度,其次是耕地及林地比例,且均起到正向促进作用。主导驱动力识别有助于明确生态系统服务间关系的作用机制,为区域环境管理及生态保护规划提供科学依据。     

工业蛋白质构效关系的计算生物学解析

工业催化用酶已经成为现代生物制造技术的核心"芯片"。不断设计和研发新型高效的酶催化剂是发展工业生物技术的关键。工业催化剂创新设计的科学基础是对酶与底物的相互作用、结构与功能关系及其调控机制的深入剖析。随着生物信息学和智能计算技术的发展,可以通过计算的方法解析酶的催化反应机理,进而对其结构的特定区域进行理性重构,实现酶催化性能的定向设计与改造,促进其工业应用。聚焦工业酶结构-功能关系解析的计算模拟和理性设计,已成为工业酶高效创制改造不可或缺的关键技术。本文就各种计算方法和设计策略以及未来发展趋势进行简要介绍和讨论。     

Salt stress differentially regulates mobilisation of carbon and nitrogen reserves during seedling establishment of Pityrocarpa moniliformis

• Seedling establishment is a critical step in environment colonisation by higher plants that frequently occurs under adverse conditions. Thus, we carried out an integrated analysis of seedling growth, water status, ion accumulation, reserve mobilisation, metabolite partitioning and hydrolase activity during seedling establishment of the native Caatinga species Piptadenia moniliformis (Benth.) Luckow & R.W. Jobson under salinity.
• Two‐day‐old seedlings were cultivated in vitro for 4 days in water agar (control) or supplemented with 50 or 100 mm NaCl. Biochemical determinations were performed according to standard spectrophotometric protocols.
• We found that 100 mm NaCl stimulated starch degradation, amylase activity and soluble sugar accumulation, but limited storage protein hydrolysis in the cotyledons of P. moniliformis seedlings. Although Na⁺ accumulation in the seedling affected K⁺ partitioning between different organs, it was not possible to associate the salt‐induced changes in reserve mobilisation with Na⁺ toxicity, or water status, in the cotyledons. Remarkably, we found that starch content increased in the roots of P. moniliformis seedlings under 100 mm NaCl, probably in response to the toxic effects of Na⁺.
• The mobilisation of carbon and nitrogen reserves is independently regulated in P. moniliformis seedlings under salt stress. The salt‐induced delay in seedling establishment and the resulting changes in the source–sink relationship may lead to storage protein retention in the cotyledons. Possibly, the intensification of starch mobilisation in the cotyledons supported starch accumulation in the root as a potential mechanism to mitigate Na⁺ toxicity.

     

VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate

This letter describes progress towards an M₄ PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M₄ PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe.     

Design,synthesis and evaluation of biphenyl imidazole analogues as potent antifungal agents

To further explore the structure activity relationships (SARs) of our previously discovered antifungal lead compound (1), a series of biphenyl imidazole analogues were designed, synthesized and evaluated for their in vitro antifungal activity. Many of the synthesized compounds showed excellent activity against Candida albicans and Candida tropicalis. Among these compounds, 2-F substituted analogue 12m displayed the most remarkable in vitro activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and itraconazole. Notably, the compound 12m exhibited low inhibition profiles for various human cytochrome P450 isoforms and showed low toxicity to mammalian A549 cells and U87 cells. The SARs and binding mode established in this study will be useful for further lead optimization.     

Substrate specificity of tuliposide-converting enzyme,a unique non-ester-hydrolyzing carboxylesterase in tulip: Effects of the alcohol moiety of substrate on the enzyme activity

6-Tuliposides A (PosA) and B (PosB) are glucose esters accumulated in tulip (Tulipa gesneriana) as major defensive secondary metabolites. Pos-converting enzymes (TgTCEs), which we discovered previously from tulip, catalyze the conversion reactions of PosA and PosB to antimicrobial tulipalins A (PaA) and B (PaB), respectively. The TgTCEs, belonging to the carboxylesterase family, specifically catalyze intramolecular transesterification, but not hydrolysis. In this report, we synthesized analogues of Pos with various alcohol moieties, and measured the TgTCE activity together with a determination of the kinetic parameters for these analogues with a view to probe the substrate recognition mechanism of the unique non-ester-hydrolyzing TgTCEs. It was found that d-glucose-like structure and number of the hydroxyl group in alcohol moiety are important for substrate recognition by TgTCEs. Among the analogues examined, 1,2-dideoxy analogues of PosA and PosB were found to be recognized by the TgTCEs more specifically than the authentic substrates by lowering K_m values. The present results will provide a basis for designing simple, stable synthetic substrate analogues for crystallographic analysis of TgTCEs.     

Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants

Obsessive‐compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical‐striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3^?/?) exhibit compulsive behavior (grooming), anxiety and dysregulated cortical‐striatal function. However, it is unknown whether SAPAP3^?/? display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3^?/? and wild‐type (WT) littermates were trained in a Pavlovian conditioning task pairing visual cues with the delivery of sucrose solution. After mice learned to discriminate between a reward‐predicting conditioned stimulus (CS+) and a non‐reward stimulus (CS?), contingencies were reversed (CS+ became CS? and vice versa). Additionally, we assessed grooming, anxiety and general activity. SAPAP3^?/? acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3^?/? were unable to adapt their behavior after contingency reversal, exemplified by a lack of re‐establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming and anxiety were unrelated. This study shows that SAPAP3^?/? are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3^?/? not only display compulsive‐like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3^?/? as a suitable model for the study of OCD. The observation that compulsive‐like behavior, anxiety and behavioral inflexibility were unrelated suggests a non‐causal relationship between these traits and may be of clinical relevance for the treatment of OCD.