Synthesis and biological evaluation of novel F-18 labeled pyrazolo[1,5-a]pyrimidine derivatives: potential PET imaging agents for tumor detection

Two novel pyrazolo[1,5-a]pyrimidine derivatives, 7-(2-[¹⁸F]fluoroethylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile ([¹⁸F]FEMPPC, [¹⁸F]1) and N-(2-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)-2-[¹⁸F]fluoro-4-nitrobenzamide ([¹⁸F]FCMPPN, [¹⁸F]2), have been designed and successively labeled with ¹⁸F by the nucleophilic substitution employing tosylate and nitryl as leaving groups, respectively. The radiochemical synthesis of both compounds was completed within 60 min with final high-performance liquid chromatography purification included. The corresponding radiochemical yields (without decay correction) were approximately 35% and 30%, respectively. Meanwhile, we compared the uptake characteristics of [¹⁸F]1 and [¹⁸F]2 with those of [¹⁸F]FDG and L-[¹⁸F]FET in S180 tumor cells. Furthermore, the tumor uptake of [¹⁸F]1 and [¹⁸F]2 was assessed in mice bearing S180 tumor and compared with [¹⁸F]FDG and L-[¹⁸F]FET in the same animal model. In vitro cell uptake studies showed [¹⁸F]1 had higher uptake than [¹⁸F]FDG, [¹⁸F]2 and L-[¹⁸F]FET over the 2 h period. In ex vivo biodistribution showed tumor/brain uptake ratios of [¹⁸F]2 were 12.35, 10.44, 8.69 and 5.13 at 15 min, 30 min, 60 min and 120 min post-injection, much higher than those of L-[¹⁸F]FET (2.43, 2.54, 2.93 and 2.95) and [¹⁸F]FDG (0.59, 0.61, 1.02 and 1.33) at the same time point. What’s more, the uptake of [¹⁸F]1 in tumor was 1.88, 4.37, 5.51, 2.95 and 2.88 at 5 min, 15 min, 30 min, 60 min and 120 min post-injection, respectively. There was a remarkable increasing trend before 30 min. The same trend was present for L-[¹⁸F]FET before 30 min and [¹⁸F]FDG before 60 min. Additionally, the tumor/brain uptake ratios of [¹⁸F]1 were superior to those of [¹⁸F]FDG at all the selected time points, the tumor/muscle and tumor/blood uptake ratios of [¹⁸F]1 at 30 min were higher than those of L-[¹⁸F]FET at the same time point. MicroPET image of [¹⁸F]1 administered into S180 tumor-bearing mouse acquired at 30 min post-injection illustrated that the uptake in S180 tumor was obvious. These results suggest that compound [¹⁸F]1 could be a new probe for PET tumor imaging.     

Optimal conditions of LDR to protect the kidney from diabetes: Exposure to 12.5 mGy X-rays for 8 weeks efficiently protects the kidney from diabetes

Aims

We reported the attenuation of diabetes-induced renal dysfunction by exposure to multiple low-dose radiation (LDR) at 25 mGy every other day by suppressing renal oxidative damage. We here explored the optimal conditions of LDR to protect the kidney from diabetes.

Main methods

Male C57BL/6J mice with type 1 diabetes were induced with multiple injections of low-dose streptozotocin. Diabetic mice received whole body X-irradiation at a dose of 12.5, 25 or 50 mGy every other day for either 4 or 8 weeks. Age-matched normal mice were similarly irradiated at the dose of 25 mGy for 4 or 8 weeks. The renal function and histopathological changes were examined at the 4th and 8th weeks of the study.

Key findings

Diabetes induced renal dysfunction is shown by the decreased creatinine and increased microalbumin in the urine. Renal oxidative damage, detected by protein nitration and lipid oxidation, and remodeling, reflected by increased expression of connective tissue growth factor, collagen IV and fibronectin, were significantly increased in diabetic mice. All these renal pathological and function changes in diabetic mice were significantly attenuated by exposure to LDR at all regimens, among which, however, exposure to LDR at 12.5 mGy for 8 weeks provided the best protective effect on the kidney of diabetic mice.

Significance

Our results suggest that whole-body LDR at 12.5 mGy every other day for 8 weeks is the optimal condition of LDR to protect the kidney from diabetes.     

Discovery of a Novel Polyomavirus in Acute Diarrheal Samples from Children

Polyomaviruses are small circular DNA viruses associated with chronic infections and tumors in both human and animal hosts. Using an unbiased deep sequencing approach, we identified a novel, highly divergent polyomavirus, provisionally named MX polyomavirus (MXPyV), in stool samples from children. The ∼5.0 kB viral genome exhibits little overall homology (<46% amino acid identity) to known polyomaviruses, and, due to phylogenetic variation among its individual proteins, cannot be placed in any existing taxonomic group. PCR-based screening detected MXPyV in 28 of 834 (3.4%) fecal samples collected from California, Mexico, and Chile, and 1 of 136 (0.74%) of respiratory samples from Mexico, but not in blood or urine samples from immunocompromised patients. By quantitative PCR, the measured titers of MXPyV in human stool at 10% (weight/volume) were as high as 15,075 copies. No association was found between the presence of MXPyV and diarrhea, although girls were more likely to shed MXPyV in the stool than boys (p = 0.012). In one child, viral shedding was observed in two stools obtained 91 days apart, raising the possibility of chronic infection by MXPyV. A multiple sequence alignment revealed that MXPyV is a closely related variant of the recently reported MWPyV and HPyV10 polyomaviruses. Further studies will be important to determine the association, if any, of MXPyV with disease in humans.     

Insights into the interactions between HIV-1 integrase and human LEDGF/p75 by molecular dynamics simulation and free energy calculation

Human cellular protein LEDGF/p75 (lens epithelium-derived growth factor) is an important binding partner of human immunodeficiency virus type 1 (HIV-1) integrase (IN). Without LEDGF/p75, HIV-1 can not complete its life cycle. To study the detailed interactions between LEDGF/p75 and HIV-1 IN, and then obtain the hotspots at the binding interface, 13 ns molecular dynamics simulations were carried out here. One-hundred snapshots extracted from the last 4 ns trajectories were used for calculation of binding free energy and decomposition of the energy by residue. First, the structural changes and their dynamic interactions were investigated focused on the production stage. And then, the free energy was discussed. On the basis of the above results, it could be suggested that residues Gln168, Glu170, and Thr174 in chain A of IN, Thr125, and Trp131 in chain B of IN as well as Ile365, Asp366, Phe406, and Val408 in LEDGF/p75 were responsible for their binding. These results might be helpful for discovery and design of small molecules to interrupt the interaction between HIV-1 IN and LEDGF/p75.     

Effects of adult neighbour and gap size on seedling emergence and early growth of <Emphasis Type="Italic">Bromus inermis</Emphasis> Leyss

A field study was conducted to determine the effects of neighbour root exclusion and gap size on the seedling emergence and early growth of Bromus inermis. Seeds of B. inermis were added to artificially created gaps in an improved shortgrass steppe in northern China. Neighbour root exclusion was accomplished using PVC tubes sunk in the soil of gaps. Emergence and survival of seedlings were greater in all gaps than in the control (0-cm diameter), but better growth performance (height of seedling, leaves, tillers and dry weight per seedling) was observed only in large gaps (20- and 40-cm diameter) with neighbour root present and gaps without neighbour root presence. Seedling growth performance was improved by reducing root and shoot competition. Neighbour root exclusion provided a favourable environment for seedling establishment. Differences between gaps in light levels and topsoil temperature can explain the patterns of germination. These results confirm that B. inermis is a gap-enhanced species. Our study strongly suggests that asymmetric competition by adult neighbour plants negatively influences the establishment of B. inermis.     

The effects of gap disturbance on the seedling emergence,survival and growth of two different native species in Inner Mongolia

A field study was conducted to investigate the effects of gap disturbance on the seedling establishment process of two native species. Seeds of Agropyron cristatum and Stipa krylovii were reseeded to artificially created gaps in a degraded steppe in North China. There were seven treatments: shoot gaps and root gaps (10 cm, 20 cm and 40 cm in diameters), no gaps (control). Shoot gaps were formed by removing above ground vegetation and below ground biomass without restricting the re-growth of neighbor roots back into the gap. The root gaps were accomplished by using polyvinyl chloride pipes sunk in the soil of shoot gaps to exclude neighboring roots. Seedling emergence, survival and growth performance after 90 days of growing were recorded for both species. Gap significantly increased soil moisture, especially for root gaps. Emergence increased significantly for both species as gap size increased. Seedling emergence and survivorship of both species were greater in gaps than in controls. However, the gap size showed a significantly negative effect on Agropyron cristatum's survivorship. Growth performance of Agropyron cristatum and Stipa krylovii differ in their response to gap disturbance. Gap had positive effects on seedling growth (including seedling height, dry weight, and numbers of tillers and leaves) of Stipa krylovii, but had negative effects on seedling growth of Agropyron cristatum. The two species have significantly different responses to gap disturbance. All results suggest that Stipa krylovii is a gap-enhanced species, and Agropyron cristatum is not. Predation by insects may be one of the key reasons to explain the stand dominance in this grassland.     

放牧和刈割条件下草山草坡群落空间异质性分析

采用变异矩分析和分形方法,研究了草山草坡群落在放牧和刈割条件下的空间异质性及空间自相关性,结果表明,群落空间格局有尺度依赖性,刈割条件下空物异质性及空间相关性弱,多样性梯度即β多样性小,放牧消除地形引起的样地差异,因而使空间异质性简单化。     

黄河三角洲盐碱地不同造林模式下的土壤碳氮分布特征

为了探讨不同造林模式对土壤碳氮影响的生态效应,以黄河三角洲盐碱地白蜡+棉花(FC)、香花槐+棉花(RC)、竹柳+棉花(SC)、白蜡林(F)、竹柳林(S)等5种造林模式为研究对象,分析比较各造林模式土壤的碳氮形态及分布特征,为重度退化刺槐林的经营改造和造林模式选择提供理论依据。结果显示:(1)不同造林模式下土壤的可溶性总碳和可溶性有机碳含量均高于裸地,农林间作高于纯林,其中SC模式含量最高,其次为FC和RC模式,而F和S纯林模式较低;5种造林模式不同土层可溶性有机碳含量均表现为0—20 cm高于20—40 cm。(2)农林间作模式0—40 cm土层的可溶性全氮和可溶性有机氮平均含量均高于纯林模式,其中SC模式的含量最高。FC、SC和S纯林模式0—20 cm土层可溶性有机氮含量显著高于20—40 cm土层,分别为其1.4、1.5和2.7倍;而RC模式20—40 cm土层可溶性有机氮含量显著高于0—20 cm土层。(3)5种造林模式中,除F纯林土壤硝态氮低于裸地外,其他造林模式下的土壤各种氮养分含量均显著高于裸地。土壤可溶性有机碳与全氮和铵态氮的相关性达到极显著水平(P0.01)。研究表明农林间作模式可显著提高重度退化刺槐林皆伐后土壤中有效态碳、氮含量,其中SC模式改良效果较好,而纯林模式较差。     

植物进化发育生物学的形成与研究进展

植物进化发育生物学是最近十几年来才兴起的一门学科,它是进化发育生物学的主要分支之一。进化发育生物学的产生经历了进化生物学与胚胎学、遗传学和发育生物学的三次大的综合,其历史可追溯到19世纪初冯.贝尔所创立的比较胚胎学。相关研究曾沉寂了近一个世纪,直到20世纪80年代早期,动物中homeobox基因被发现,90年代初花发育的ABC模型被提出,加之对发育相关基因研究的不断深入,才使基因型与表型联系了起来,进而促进了进化发育生物学的飞速发展。目前进化发育生物学已成为21世纪生命科学领域的研究热点之一。本文详细阐述了进化发育生物学产生和发展的历程,综述了最近十几年来植物进化发育生物学的主要研究进展。文中重点介绍了与植物发育密切相关的MADS-box基因在植物各大类群中的研究现状,讨论了植物进化发育生物学领域的研究成果对花被演化、花对称性以及叶的进化等重要问题的启示。