Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84?nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.     

Forward chemical genetic screens in Arabidopsis identify genes that influence sensitivity to the phytotoxic compound sulfamethoxazole

The rise of high mountain chains is widely seen as one of the factors driving rapid diversification of land plants and the formation of biodiversity hotspots. Supporting evidence was reported for the impact of the rapid rise of the Andean mountains but this hypothesis has so far been less explored for the impact of the “roof of the world”. The formation of the Himalaya, and especially the rise of the Qinghai–Tibetan Plateau in the recent 20 million years, altered the monsoon regimes that dominate the current climates of South East Asia. Here, we infer the hypothesis that the rise of Himalaya had a strong impact on the plant diversity in the biodiversity hotspot of the Southwest Chinese Mountains. Our analyses of the diversification pattern of the derived fern genus Lepisorus recovered evidence for changes in plant diversity that correlated with the strengthening of South East Asian monsoon. Southwest China or Southwest China and Japan was recovered as the putative area of origin of Lepisorus and enhancing monsoon regime were found to shape the early diversification of the genus as well as subsequent radiations during the late Miocene and Pliocene. We report new evidence for a coincidence of plant diversification and changes of the climate caused by the uplift of the Himalaya. These results are discussed in the context of the impact of incomplete taxon sampling, uncertainty of divergence time estimates, and limitations of current methods used to assess diversification rates.     

Strong Genetic Differentiation of Primula sikkimensis in the East Himalaya–Hengduan Mountains

The East Himalaya-Hengduan Mountains region is the center of diversity of the genus Primula, and P. sikkimensis is one of the most common members of the genus in the region. In this study, the genetic diversity and structure of P. sikkimensis populations in China were assessed using inter-simple sequence repeat (ISSR) and chloroplast microsatellite markers. The 254 individuals analyzed represented 13 populations. High levels of genetic diversity were revealed by ISSR markers. At the species level, the expected heterozygosity and Shannon’s index were 0.4032 and 0.5576, respectively. AMOVA analysis showed that 50.3% of the total genetic diversity was partitioned among populations. Three pairs of chloroplast microsatellite primers tested yielded a total of 12 size variants and 15 chloroplast haplotypes. Strong cpDNA genetic differentiation (G _ST = 0.697) and evidence for phylogeographic structure were detected (N _ST = 0.788, significantly higher than G _ST). Estimated rates of pollen-mediated gene flow are approximately 27% greater than estimated rates of seed-mediated gene flow in P. sikkimensis. Both seed and pollen dispersal, however, are limited, and gene flow among populations appears to be hindered by the patchiness of the species’ habitats and their geographic isolation. These features may have played important roles in shaping the genetic structure of P. sikkimensis. A minimum-spanning tree of chloroplast DNA haplotypes was constructed, and possible glacial refugia of P. sikkimensis were identified.     

抑卵激素对家蝇卵巢周期性发育的调控

抑卵激素是调控家蝇Musca dorncstica vicina卵巢周期性发育的关键因子之一。在家蝇中,当第一个周期的卵母细胞处于卵黄发生期或卵黄发生后期时,其第二个周期的卵母细胞的发育不进入卵黄发生期。本文建立了家蝇抑卵激素的生物测定方法,即用一对卵巢提取物注射1头羽化后12h家蝇,并在羽化后60h观察卵母细胞的发育及卵黄蛋白的沉积情况。抑卵激素的作用首先是延缓了卵母细胞在卵黄发生前期的发育;其次,抑卵激素抑制脂肪体中卵黄蛋白的合成,导致血淋巴中卵黄蛋白含量的下降,从而抑制了卵母细胞的发育。抑卵激素并不抑制卵母细胞对卵黄原蛋白的摄取。卵发育神经激素可以颉抗抑卵激素的抑制作用。抑卵激素无种属特异性。     

BMP-2 promotes osteogenic differentiation of mesenchymal stem cells by enhancing mitochondrial activity

Objectives:Mesenchymal stem cells (MSCs) have become seed cells and basic elements for bone regeneration and bone tissue engineering. The aim of the present study was to investigate the roles and mechanisms of bone morphogenetic protein 2 (BMP-2) on osteogenic differentiation of MSCs.Methods:Primary MSCs were isolated from the femur and tibia bone of rats and then transfected with BMP-2 and PGC-1α adenovirus vectors. Alkaline phosphatase (ALP) activity and alizarin red staining were used to measure osteogenic differentiation of MSCs. Real-time PCR and western blot assays were performed to assess osteogenic differentiation-related proteins levels. The activities of mitochondrial respiratory chain complexes I and II and mitochondrial fluorescence intensity were used to explore mitochondria status during osteogenic differentiation of MSCs.Results:We found that the ability of BMP-2 overexpressed (OE) group osteogenic differentiation was significantly improved, compared with the negative control (NC) group. The results also indicated that BMP-2 can promote the activity of mitochondria. We further used the gain- and loss-of-function approaches to demonstrate that BMP-2 promotes mitochondrial activity by up-regulating PGC-1α to promote osteogenic differentiation of MSCs.Conclusions:These results explored the important role of BMP-2 in the osteoblast differentiation of MSCs from a new perspective, providing a theoretical and experimental basis for bone defect and repair.     

Cultivable Fungal Diversity in Deep-Sea Sediment of the East Pacific Ocean

The diversity of fungi in the marine environment has been extensively studied, but their denitrification activity has rarely been reported to date. In the present study, we used six different media to isolate fungi from 10 sediment samples collected at five different locations of the East Pacific Ocean with water depths ranging from 4545 to 7068?m. Fungal identification and phylogenetic diversity analysis were conducted based on morphological characteristics and internal transcribed spacers of ribosomal DNA (ITS-rRNA) sequencing. A total of 106 fungal isolates, belonging to 12 genera, including Aspergillus (five strains), Aureobasidium (three strains), Candida (two strains), Cladosporium (56 strains), Cystobasidium (one strain), Devriesia (nine strains), Knufia (one strain), Nigrospora (three strains), Penicillium (18 strains), Rhodotorula (four strains), Sarocladium (three strains), and unclassified Xylariales (one strain) were obtained. The most dominant culturable genus was Cladosporium. One possible novel fungal strains showed less than 97% similarity to their closest matches of unclassified Xylariales in the Genbank. In addition, we used nirK gene as the molecular marker to detect denitrifying fungi among the cultivable fungal isolates. The nirK gene was detected in Aspergillus niger and Penicillium chrysogenum. Our research indicated that diverse fungi from the deep sea sediments of the East Pacific Ocean and highlighted the involvement of these fungi in denitrification process.