Targeted Disruption of β-Arrestin 2-Mediated Signaling Pathways by Aptamer Chimeras Leads to Inhibition of Leukemic Cell Growth

β-arrestins, ubiquitous cellular scaffolding proteins that act as signaling mediators of numerous critical cellular pathways, are attractive therapeutic targets because they promote tumorigenesis in several tumor models. However, targeting scaffolding proteins with traditional small molecule drugs has been challenging. Inhibition of β-arrestin 2 with a novel aptamer impedes multiple oncogenic signaling pathways simultaneously. Additionally, delivery of the β-arrestin 2-targeting aptamer into leukemia cells through coupling to a recently described cancer cell-specific delivery aptamer, inhibits multiple β-arrestin-mediated signaling pathways known to be required for chronic myelogenous leukemia (CML) disease progression, and impairs tumorigenic growth in CML patient samples. The ability to target scaffolding proteins such as β-arrestin 2 with RNA aptamers may prove beneficial as a therapeutic strategy.

Highlights

• An RNA aptamer inhibits β-arrestin 2 activity.
• Inhibiting β-arrestin 2 impedes multiple tumorigenic pathways simultaneously.
• The therapeutic aptamer is delivered to cancer cells using a cell-specific DNA aptamer.
• Targeting β-arrestin 2 inhibits tumor progression in CML models and patient samples.

     

Genetic mapping of a fertile tiller inhibition gene, ftin, in wheat

Increased fertile tiller number is a very important trait in high-yielding wheat (Triticum aestivum L.) lines. Uncovering the fundamental biological progress of fertile tiller formation would improve our understanding of the genetic nature of this trait and increase wheat yield. However, there is no suitable genetic material for studying the genetic mechanism of wheat fertile tiller formation. We report here the development of a fertile tiller inhibition line, Pubing3558, which was derived from a cross between common wheat and wild grass Agropyron cristatum. Pubing3558 possesses normal tillering ability in the seedling stage but reduced fertile tiller formation in the reproductive growth phase. A cross between Pubing3558 and the wheat cultivar Jing4841 with multiple fertile tillers was performed in order to map the fertile tiller inhibition gene (ftin). The F₁ population of the cross between Pubing3558 and Jing4841 showed a normal phenotype similar to that of the parent Jing4841. The F₂ population segregated with a 3:1 Mendelian ratio in 2-year replicates, which was further proven by the segregation ratio of the F₃ population. Genetic analysis uncovered that the fertile tiller inhibition trait in Pubing3558 is controlled by a single recessive gene. Using bulked segregant analysis methods, we located the ftin gene on wheat chromosome 1AS, which is linked closely to markers Xcfa2153 at a genetic distance of 1.0 cM. A combination of phenotype tests and genetic mapping demonstrated that the ftin gene is a newly identified gene in wheat. Overall, our results suggest that Pubing3558 will be valuable genetic source for studying the biological process of fertile tiller formation.     

Co-transplantation of mesenchymal stromal cells and cord blood cells in treatment of diabetes

Background aimsStem cells provide a promising source for treatment of type 1 diabetes, but the treatment strategy and mechanism remain unclear. The aims of this study were to investigate whether co-transplantation of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) and cord blood mononuclear cells (CB-MNCs) could reverse hyperglycemia in type 1 diabetic mice and to determine the appropriate ratio for co-transplantation. The treatment mechanism was also studied.MethodsA simple and efficient isolation method was developed to generate qualified UC-MSCs. UC-MSCs and CB-MNCs were then transplanted into type 1 diabetic mice at different ratios (UC-MSCs to CB-MNCs = 1:1, 1:4, 1:10) to observe the change in blood glucose concentration. Histology, immunohistochemistry, and human Alu polymerase chain reaction assay were performed to evaluate for the presence of donor-derived cells and the repair of endogenous islets. We also induced UC-MSCs into islet-like cells under specific culture conditions to determine their differentiate potential in vitro.ResultsCo-transplantation of UC-MSCs and CB-MNCs at a ratio of 1:4 effectively reversed hyperglycemia in diabetic mice. The detection of human Alu sequence indicated that the engraftment of donor-derived cells had homed into the recipient's pancreas and kidney. Although neither human insulin nor human nuclei antigen was detected in the regenerated pancreas, UC-MSCs could differentiate into insulin-secreted cells in vitro.ConclusionsCo-transplantation of UC-MSCs and CB-MNCs at a ratio of 1:4 could efficiently reverse hyperglycemia and repair pancreatic tissue.     

宁夏典型天然草地土壤团聚体稳定性及其有机碳分布特征

土壤团聚体作为土壤结构的基本单元和土壤有机碳存在的重要场所,对维系土壤质量和生态环境可持续发展具有重要作用。为探究宁夏天然草地土壤团聚体稳定性及其有机碳分布特征,以宁夏4种典型的天然草地（草甸草原、温性草原、草原化荒漠和荒漠草原）为研究对象,系统开展研究。结果表明：草甸草原、温性草原和草原化荒漠各粒级机械团聚体和水稳性团聚体含量均呈现随粒径减小而先减小后增大趋势,荒漠草原机械团聚体含量呈现随粒径减小而先减小后增大的趋势,水稳性团聚体含量呈现随粒径减小逐渐增大的趋势;且草甸草原和温性草原机械稳定性和水稳性团聚体在0-10 cm、10-20 cm和20-40 cm 3个土层均以>0.25 mm大团聚体为主,草原化荒漠和荒漠草原水稳性团聚体均以<0.25 mm的微团聚体为主。4种草地类型机械团聚体和水稳性团聚体MWD和GMD,以及各粒级土壤团聚体有机碳含量均表现为草甸草原和温性草原显著高于草原化荒漠和荒漠草原。草甸草原和温性草原在3个土层深度均以>0.25 mm的大团聚体对有机碳的贡献率最高,分别达到43.86%、59.26%、58.89%和58.02%、54.03%、57.15%;草原化荒漠和荒漠草原在3个土层深度,均以<0.25 mm的微团聚体贡献率高,分别达到了60.37%、55.86%、54.33%和75.61%、78.34%、78.74%。结果表明：草甸草原和温性草原较草原化荒漠和荒漠草原土壤团聚体稳定性更高,更有利于土壤有机碳累积。     

Multiple ligand-specific conformations of the β2-adrenergic receptor

Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adaptor proteins β-arrestins. Moreover, several receptor ligands with differential efficacies toward these distinct signaling pathways have been identified. However, the structural basis and mechanism underlying this 'biased agonism' remains largely unknown. Here, we develop a quantitative mass spectrometry strategy that measures specific reactivities of individual side chains to investigate dynamic conformational changes in the β(2)-adrenergic receptor occupied by nine functionally distinct ligands. Unexpectedly, only a minority of residues showed reactivity patterns consistent with classical agonism, whereas the majority showed distinct patterns of reactivity even between functionally similar ligands. These findings demonstrate, contrary to two-state models for receptor activity, that there is significant variability in receptor conformations induced by different ligands, which has significant implications for the design of new therapeutic agents.     

Kinetic theory approach to modeling of cellular repair mechanisms under genome stress

Under acute perturbations from outer environment, a normal cell can trigger cellular self-defense mechanism in response to genome stress. To investigate the kinetics of cellular self-repair process at single cell level further, a model of DNA damage generating and repair is proposed under acute Ion Radiation (IR) by using mathematical framework of kinetic theory of active particles (KTAP). Firstly, we focus on illustrating the profile of Cellular Repair System (CRS) instituted by two sub-populations, each of which is made up of the active particles with different discrete states. Then, we implement the mathematical framework of cellular self-repair mechanism, and illustrate the dynamic processes of Double Strand Breaks (DSBs) and Repair Protein (RP) generating, DSB-protein complexes (DSBCs) synthesizing, and toxins accumulating. Finally, we roughly analyze the capability of cellular self-repair mechanism, cellular activity of transferring DNA damage, and genome stability, especially the different fates of a certain cell before and after the time thresholds of IR perturbations that a cell can tolerate maximally under different IR perturbation circumstances.     

Paleo-polyploidization in Lycophytes

Lycophytes and seed plants constitute the typical vascular plants. Lycophytes have been thought to have no paleo-polyploidization although the event is known to be critical for the fast expansion of seed plants. Here, genomic analyses including the homologous gene dot plot analysis detected multiple paleo-polyploidization events, with one occurring approximately 13–15 million years ago (MYA) and another about 125–142 MYA, during the evolution of the genome of Selaginella moellendorffii, a model lycophyte. In addition, comparative analysis of reconstructed ancestral genomes of lycophytes and angiosperms suggested that lycophytes were affected by more paleo-polyploidization events than seed plants. Results from the present genomic analyses indicate that paleo-polyploidization has contributed to the successful establishment of both lineages—lycophytes and seed plants—of vascular plants.     

Cultivation of Chlorella pyrenoidosa in soybean processing wastewater

Chlorella pyrenoidosa was cultivated in soybean processing wastewater (SPW) in batch and fed-batch cultures without a supply of additional nutrients. The alga was able to remove 77.8 ± 5.7%, 88.8 ± 1.0%, 89.1 ± 0.6% and 70.3 ± 11.4% of soluble chemical oxygen demand (SCOD_Cr), total nitrogen (TN), NH₄⁺-N and total phosphate (TP), respectively, after 120 h in fed-batch culture. C. pyrenoidosa attained an average biomass productivity of 0.64 g L⁻¹ d⁻¹, an average lipid content of 37.00 ± 9.34%, and a high lipid productivity of 0.40 g L⁻¹ d⁻¹. Therefore, cultivation of C. pyrenoidosa in SPW could yield cleaner water and useful biomass.