BMP signaling in vascular biology and dysfunction

The vascular system is critical for developmental growth, tissue homeostasis and repair but also for tumor development. Bone morphogenetic protein (BMP) signaling has recently emerged as a fundamental pathway of the endothelium by regulating cardiovascular and lymphatic development and by being causative for several vascular dysfunctions. Two vascular disorders have been directly linked to impaired BMP signaling: pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia. Endothelial BMP signaling critically depends on the cellular context, which includes among others vascular heterogeneity, exposure to flow, and the intertwining with other signaling cascades (Notch, WNT, Hippo and hypoxia). The purpose of this review is to highlight the most recent findings illustrating the clear need for reconsidering the role of BMPs in vascular biology.     

Structure–activity relationships (SAR) and structure–kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists III: The role of a hydrogen-bond acceptor in long receptor residence times

The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R^core ≠ H) gives access to compounds with dissociation half-lives of ⩾24 h.     

Synthesis and in vitro evaluation of small-molecule [18F] labeled gonadotropin-releasing hormone (GnRH) receptor antagonists as potential PET imaging agents for GnRH receptor expression

Two novel small molecule gonadotropin-releasing hormone (GnRH) receptor antagonists (12 and 13) of the furamide-class were synthesized and evaluated in vitro for their receptor binding affinities for the rat GnRH receptor. Radiolabeling with no carrier added fluorine-18 of the appropriate precursors was investigated in a one-step reaction. Log P (Octanol/PBS pH 7.4) and serum stability of the compounds were investigated. The antagonists showed low nM affinity for the rat GnRH receptor. ¹⁸F-radiolabled compounds were obtained in high radiochemical purity (>95%) and specific activity (>75 GBq/μmol). These findings suggest this class of compounds holds promise as potential probes for PET targeting of GnRH-receptor expression.     

Regeneration of a Gentiana pneumonanthe population in an oligotrophic wet meadow

Abstract. The aim of this study was to evaluate the critical phases of the life cycle of Gentiana pneumonanthe, the marsh gentian, a threatened species of the Bohemian flora. The effect of various conditions on germination and seedling establishment and the possible effect of competition on the performance of the species were tested. Seeds were sown in plots which were subjected to four treatments in a randomized complete blocks experiment: unmanaged meadow, mown meadow, burned meadow, and meadow with cut sod. The significantly highest recruitment was found in plots with cut sod, the lowest in the unmanaged control plots. Seedling survival also differed among the treatments. In the following year surviving individuals were only found in plots with cut sod. The influence of neighbouring vegetation on target gentian individuals was evaluated by removing the surrounding vegetation and comparing the performance of these individuals with controls. The initial height of each individual was measured and used as a covariable. No significant effect of neighbouring vegetation on performance was detected. Thus, the establishment phase appears to be critical for population persistence and is also more influenced by the management regime than other stages of the life cycle.     

Cub growth and maternal care in cheetahs

Using cub growth as an index, I examine the influence of maternalnutrition, litter size, and cub sex on maternal care in cheetahs(Acinonyx jubatus) and compare cub and litter growth rates withthose of other large feilds. Seventy-nine free-living cheetahcubs in 21 litters from 15 mothers were weighed at least oncebetween 6 and 48 days of age. Eleven litters were weighed atthe beginning and end of a 5-day observation of their mothers.The mean cub growth rate varied significantly between litters,due primarily to differences in maternal food intake. Growthdeclined sharply when maternal food intake was less than 1.5kg/ day, but did not increase with greater levels of food intake.Lower limits of growth rates may therefore have been set bythe mother's food intake, whereas upper limits may be set bythe intrinsic physiological ability of cubs to grow. Althoughmale cubs were heavier than female cubs in the same litter whenfirst weighed, major differences in growth rate between thesexes were not apparent at this stage. Both cheetah cubs andlitters grow fast relative to other large felids, and I arguethat this may be an adaptation to the high rate of cheetah juvenilemortality from predation.     

基于指标自动筛选的新疆开孔河流域生态健康评价

生态健康评价对了解区域生态健康状况和促进区域可持续发展具有重要意义,如何自动筛选出能反映生态系统特性的重要指标,是生态健康定量评估的关键问题。基于压力-状态-响应(PSR,Press-State-Response)框架和生态等级网络框架(EHN,Ecological Hierarchy Network),通过文献调研和因果分析建立要素层与指标层之间的交叉联系,构建了生态健康评价"网状"指标体系;在保证指标体系完备性基础上,通过结合主成分分析和熵权法的候选指标权重的客观计算,基于目标优化理论构建了评价指标的自动筛选模型,并基于中选指标计算了新疆开孔河流域2001—2017年生态健康指数(EHCI,Ecological Health Comprehensive Indexes),分析其空间分异和时间变化特征。结果表明:利用所建立的评价指标自动筛选模型,开孔河流域生态健康评价指标由31个候选指标自动筛选出了17个中选指标,用54.8%的指标表达了85.98%的信息,中选的17个指标在干旱/半干旱区域有关文献中应用较多,使用频次比例都在20%以上,其中归一化植被指数(NDVI,Normalized Difference Vegetation Index)、年降水量和植被覆盖度(FVC,Fractional Vegetation Coverage)3个指标的使用频次百分比均超过了50%,说明指标自动筛选模型的合理性;开孔河流域空间分布差异显著,总体上西北高、东南低,东南部和中部绿洲区外围生态健康状况较差,西北部河谷地带和中部两大绿洲区生态健康状况较好;17年来,流域生态质量整体趋于改善,显著改善区域占10.26%,远高于显著退化的1.61%,显著改善区域以孔雀河绿洲最为明显。开孔河流域生态健康的总体好转趋势说明区域生态综合治理取得一定成效。     

厚壳贻贝whirlin类贝壳基质蛋白的重组表达与功能分析

贝壳历来是生物工程和材料学研究的重要对象。贝壳中的贝壳基质蛋白质在贝壳的形成与发育过程中具有重要的调控作用。Whirlin类蛋白质(Whirlin-like protein,WLP)是一种从厚壳贻贝(Mytilus coruscus)中鉴定的新型贝壳基质蛋白质。序列分析结果显示,该蛋白质含有PDZ(postsynaptic density/Discs large/Zonula occludens)结构域,而该结构域对贝壳生物矿化的影响目前尚无报道。为深入了解WLP在贝壳形成中对碳酸钙晶体的影响,在序列分析基础上,采用密码子优化结合原核重组表达,获得其重组表达产物后,开展了重组WLP对碳酸钙晶体形貌及晶型的影响研究,结晶速度抑制以及碳酸钙晶体结合分析。分析结果表明,重组WLP能诱导文石型碳酸钙晶体的形貌和方解石型碳酸钙晶体的晶型发生改变;同时重组WLP对碳酸钙晶体具有结合作用,且能抑制碳酸钙晶体的结晶速度。上述结果表明,WLP对贝壳的形成及发育具有重要影响,并可能在贝壳肌棱柱层的形成中发挥了重要作用。     

A DEVD-Inhibited Caspase Other than CPP32 Is Involved in the Commitment of Cerebellar Granule Neurons to Apoptosis Induced by K+ Deprivation

Abstract: Cultured cerebellar granule neurons undergo apoptosis when switched from a medium containing depolarizing levels of K⁺ (25 mM KCI) to medium containing lower levels of K⁺ (5 mM KCI). We used this paradigm to investigate the role of caspases in the death process. Two broad-spectrum caspase inhibitors, tert-butoxycarbonyl-Asp·(O-methyl)·fluoromethyl ketone and benzyloxycarbonyl-Val-Ala-Asp·fluoromethyl ketone, significantly reduced cell death (90 and 60%, respectively) at relatively low concentrations (10–25 µM), suggesting that caspase activation is involved in the apoptotic process. DNA fragmentation, a hallmark of apoptosis, was also reduced by these caspase inhibitors, suggesting that caspase activation occurred upstream of DNA cleavage in the sequence of events leading to cell death. As a step toward identifying the caspase(s) involved, the effects of N-acetyl Tyr-Val-Ala-Asp·chloromethyl ketone (YVAD·cmk), an interleukin-1β converting enzyme-preferring inhibitor, and N-acetyl Asp-Glu-Val-Asp·fluoromethyl ketone (DEVD·fmk), a CPP32-preferring inhibitor, were also evaluated. YVAD·cmk provided only modest (<20%) protection and only at the highest concentration (100 µM) tested, suggesting that interleukin-1β converting enzyme and/or closely related caspases were not involved. In comparison, DEVD·fmk inhibited cell death by up to 50%. Western blot analyses, however, failed to detect an increase in processing/activation of CPP32 or in the proteolysis of a CPP32 substrate, poly(ADP-ribose) polymerase, during the induction of apoptosis in granule neurons. Similarly, the levels of Nedd2, a caspase that is highly expressed in the brain and that is partially inhibited by DEVD·fmk, also remained unaffected in apoptotic neurons undergoing apoptosis. These results suggest that a DEVD-sensitive caspase other than CPP32 or Nedd2 mediates the induction of apoptosis in K⁺-deprived granule neurons.