Dual mTOR/PI3K inhibition limits PI3K-dependent pathways activated upon mTOR inhibition in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of kidney cysts leading to kidney failure in adulthood. Inhibition of mammalian target of rapamycin (mTOR) slows polycystic kidney disease (PKD) progression in animal models, but randomized controlled trials failed to prove efficacy of mTOR inhibitor treatment. Here, we demonstrate that treatment with mTOR inhibitors result in the removal of negative feedback loops and up-regulates pro-proliferative phosphatidylinositol 3-kinase (PI3K)-Akt and PI3K-extracellular signal-regulated kinase (ERK) signaling in rat and mouse PKD models. Dual mTOR/PI3K inhibition with NVP-BEZ235 abrogated these pro-proliferative signals and normalized kidney morphology and function by blocking proliferation and fibrosis. Our findings suggest that multi-target PI3K/mTOR inhibition may represent a potential treatment for ADPKD

DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses-Inflammations and Cancers Can Have High Genomic Risks.

Under inflammatory conditions, inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) which cause DNA damage. If not appropriately repaired, DNA damage leads to gene mutations and genomic instability. DNA damage checkpoint factors (DDCF) and DNA damage repair factors (DDRF) play a vital role in maintaining genomic integrity. However, how DDCFs and DDRFs are modulated under physiological and pathological conditions are not fully known. We took an experimental database analysis to determine the expression of 26 DNA D

Investigating the Vascularization of Tissue-Engineered Bone Constructs Using Dental Pulp Cells and 45S5 Bioglass(®) Scaffolds.

Identification of a suitable cell source combined with an appropriate 3D scaffold is an essential prerequisite for successful engineering of skeletal tissues. Both osteogenesis and angiogenesis are key processes for bone regeneration. This study investigated the vascularization potential of a novel combination of human dental pulp stromal cells (HDPSCs) with 45S5 Bioglass(®) scaffolds for tissue-engineered mineral constructs in vivo and in vitro. 45S5 Bioglass scaffolds were produced by the foam replication technique with the standard composition of 45 wt% SiO2, 24.5 wt% Na2O, 24.5 wt% CaO, and 6 wt% P2O5. HDPSCs were cultured in monolayers and on porous 45S5 Bioglass scaffolds under angiogenic and osteogenic conditions for 2-4 weeks. HDPSCs expressed endothelial gene markers (CD34, CD31/PECAM1, and VEGFR2) under both conditions in the monolayer. A combination of HDPSCs with 45S5 Bioglass enhanced the expression of these gene markers. Positive immunostaining for CD31/PECAM1 and VEGFR2 and negative staining for CD34 supported the gene expression data, while histology revealed evidence of endothelial cell-like morphology within the constructs. More organized tubular structures, resembling microvessels, were seen in the constructs after 8 weeks of implantation in vivo. In conclusion, this study suggests that the combination of HDPSCs with 45S5 Bioglass scaffolds offers a promising strategy for regenerating vascularized bone grafts

The Study on Translation of Culture-loaded Words in Aerial ChinaⅠ- Jiangxi from the Perspective of Semantic and Communicative Translation

Aerial ChinaⅠ- Jiangxi has been widely accepted by foreign audiences. In this documentary, there are many culture-loaded words with Jiangxi cultural characteristics. We all know that the translation of Chinese culturally-loaded words has long been a tricky problem. Take the translation of culture loaded words in Aerial ChinaⅠ- Jiangxi as an example, this paper discusses how Newmark's communicative translation and semantic translation theory are applied to the translation of Chinese culture loaded words. It is considered that semantic translation and communicative translation are not completely opposite but complement each other. Good translation works are usually the perfect combination of the two. In order to help translators better translate culture loaded words and achieve the real purpose of cross-cultural communication

Research on Texas savannas : fractional woody cover mapping, potential woody cover modelling, and woody plant encroachment analysis

Tested in Texas savannas of a wide rainfall gradient, this dissertation endeavors to (1) map fractional woody cover at Landsat scale, for close and continuous woody plant encroachment monitoring, (2) model the pattern of potential woody cover over the present rainfall gradient, for implication of the end-point of woody plant encroachment, (3) analyze the rate and effect factors of woody plant encroachment under the regional context, for pertinent savanna management strategy. Web-Enabled Landsat Data (WELD) was used to calibrate the Salford Systems’ Classification and Regression Trees (CART) against training data of fractional woody cover derived from 1m resolution digital orthophotos. The CART model output was verified against an independent test data. This study provides a way to accurately monitor woody plant encroachment across savanna ecosystems at a fine spatial scale, and sets up a protocol for landscape components mapping at sub-pixel level in other ecosystems. The pattern of potential woody cover was modelled over the wide rainfall gradient at Landsat scale (30m) and MODIS scale (500m) respectively. While a positive linear relationship between potential woody cover and mean annual precipitation (MAP) was revealed at Landsat scale, a prominent three-segment relationship was observed at MODIS scale. This discrepancy corroborates the scale dependency of the primary determinants of savanna woody plant density. According to the three-segment pattern at MODIS scale, Texas savannas are divided into arid savanna (MAP 735mm). Analysis of the encroachment of Ashe juniper at its early life stage (initial ~20 years) at local (hectare) scale suggests that water availability has a significant positive effect on the encroachment rate in semi-arid savanna, but not in mesic savanna. In addition, a quadratic relationship was revealed between the encroachment rate and woody plant density in mesic savanna. That is, the encroachment rate increases with woody plant density by a threshold density, then starts decreasing with woody plant density. These results demonstrate that regional context such as rainfall and biological traits of woody species is critical to understand the trend of woody plant encroachment.Geography and the Environmen

Automated electrophysiological and pharmacological evaluation of human pluripotent stem cell-derived cardiomyocytes

Automated planar patch clamp systems are widely used in drug evaluation studies because of their ability to provide accurate, reliable, and reproducible data in a high-throughput manner. Typically, CHO and HEK tumorigenic cell lines overexpressing single ion channels are used since they can be harvested as high-density, homogenous, single-cell suspensions. While human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are physiologically more relevant, these cells are fragile, have complex culture requirements, are inherently heterogeneous, and are expensive to produce, which has restricted their use on automated patch clamp (APC) devices. Here, we used high efficiency differentiation protocols to produce cardiomyocytes from six different hPSC lines for analysis on the Patchliner (Nanion Technologies GmbH) APC platform. We developed a two-step cell preparation protocol that yielded cell catch rates and whole-cell breakthroughs of ∼80%, with ∼40% of these cells allowing electrical activity to be recorded. The protocol permitted formation of long-lasting (>15 min), high quality seals (>2 GΩ) in both voltage- and current-clamp modes. This enabled density of sodium, calcium, and potassium currents to be evaluated, along with dose–response curves to their respective channel inhibitors, tetrodotoxin, nifedipine, and E-4031. Thus, we show the feasibility of using the Patchliner platform for automated evaluation of the electrophysiology and pharmacology of hPSC-CMs, which will enable considerable increase in throughput for reliable and efficient drug evaluation