Self-Assembly of Mitochondria-Specific Peptide Amphiphiles Amplifying the Lung Cancer Cell Death through Targeting the VDAC1-Hexokinase-II Complex

International audienceMitochondria-targeting peptides represent an emergent approach for cancer inhibition. Here supramolecular assemblies of novel amphiphilic cell-penetrating peptides for targeting cancer cells mitochondria are reported. The employed strategy aims at amplifying the apoptotic stimuli by weakening the mitochondrial VDAC1 (voltage-dependent anion channel-1)-hexokinase-II (HK-II) interaction. Peptide engineering is performed with the N-terminus of the HK-II protein, which binds to VDAC1. First, a designed positively-charged segment (pKV) is anchored to the specific 15 aminoacid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV). Second, a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV in order to enhance the intracellular delivery of the HK-II scaffold. The self-assembly properties of these two synthetic peptides are investigated by synchrotron small-angle X-ray scattering (BioSAXS) and cryogenic transmission electron (cryo-TEM) imaging, which evidence the formation of nanoassemblies of ellipsoid-like shapes. Circular dichroism (CD) spectroscopy demonstrates the induction of partial α-helical structures in the amphiphilic peptides. Confocal microscopy reveals the specific mitochondrial location of Pal-pHK-pKV assemblies in human non-small cell lung cancer (NSCLC) A549 cells. The cytotoxicity and apoptotic studies indicate the enhanced bioactivity of Pal-pHK-pKV self-assembled reservoirs, which cause massive A549 cell death with regard to pHK-pKV. Whereas the half maximum inhibitory concentration (IC 50) of the Pal-pHK-pKV peptide conjugates is 6.5 μM in the A549 cancer cell line, it is higher than 50 μM for healthy human mucosal epithelial cells such as the non-cancerous NCM460 cells. The results demonstrate the potential of self-assembled lipo-peptide (HK-II-derived) conjugates as a promising strategy in cancer therapy.

Network-based Management on Repairing Tool Kits of Civil Aviation Engineering Maintenance

Based on features of high speed of network transmission and easy operations, this thesis covers two aspects to realize network-based management on repairing tool kits of civil aviation engineering maintenance. Firstly, develop a network inquiry system, which can help employees and administrators inquire tool borrowing information. Secondly, a module is designed that has functions to transmit text messages to tool kits borrowers prompting them to return tools at times when the returning date approaches

Passport series: China and Brazil

Come and hear about international studetns' lives before coming to UAA and the challenges they face living in Anchorage and going to school at UAA. China and Brazil with Yuqing Wang, Xinlei Na, and Ana Spaic Rodrigues

Modeling of Concrete-Frozen Soil Interface from Direct Shear Test Results

The shear behaviors of concrete-frozen soil interface are important for analyzing the performance of engineering structures buried in the frozen ground. In this paper, a series of direct shear tests were carried out to determine the concrete-soil interface behaviors at different test temperatures (19°C, −1°C, −3°C, and −5°C) and initial water contents (9.2%, 13.1%, 17.1%, and 20.8%) of soils. The interface shear behaviors, including the shear stress versus horizontal displacement, interface cohesion, and interface friction coefficient, were analyzed based on the test results. Then, a simple, nonlinear model was proposed and verified for the interface shear behaviors. The results show that the effect of initial water content and test temperature on the interface shear behavior is significant, and the peak stress increases with the increasing initial water content and decreasing test temperature. The interface cohesion is sensitive to the test temperature and initial water content, while the interface friction coefficient is insensitive to both the factors. The parameters of the simple nonlinear model can be gained by back-analyzing the test results. The predictions made by the proposed model are found to be in good agreement with the experimental results

Experimental Study on Frost-Heaving Force Development of Tibetan Clay Subjected to One-Directional Freezing in an Open System

Frost heave of soils involves complex coupled interactions among moisture, heat, and stress, which can cause serious damage to cold regions engineering. In this paper, a series of one-directional freezing experiments were implemented for the Tibetan clay with rigid restraint in an open system. The varying characteristics of the temperature, frost-heaving force, and water replenishment during the freezing process were analyzed under different freezing temperatures (−5, −7, and − 9°C), dry densities (1.65, 1.7, and 1.75 g cm−3), and initial moisture contents (11, 14, and 17%) of the soil samples. It was concluded that the freezing of soil samples mainly occurred within 10–25 hours from the beginning of the experiment; hereafter, the soil temperatures tended to be stable. The development of frost-heaving force could be divided into three stages as slow increase, quick increase, and relative stable stages. Low freezing temperature, large dry density, and high moisture content were all the contributors to the frost-heaving process of the soil, which could increase the freezing depth, magnitude of the frost-heaving force, and amount of water replenishment. The variations in water replenishment from the open system corresponded to the three stages of the frost-heaving force but had time lags. The moisture contents at different layers of soil samples were measured after the freezing experiment. The results showed that the freeze part of soil samples experienced a significant wetting, while the unfrozen part experienced drying during the experiment. The degrees of wetting and drying were related to the freezing temperature, dry density, and initial moisture content of the soil samples. The experiment results could provide data support for theoretical study on moisture, heat, and stress coupling in freezing soil

Stochastic geometry based analysis for heterogeneous networks : a perspective on meta distribution

The meta distribution as a new performance metric can provide much more fine-grained information about the individual link reliability, and is of great value for the analysis and design of the future cellular networks. In this paper, we investigate the stochastic geometry based analysis for heterogeneous networks from the perspective on the meta distribution. The comprehensive overview for the fundamental framework of the meta distribution is provided, which involves the concepts of the meta distribution and its related performance metric (e.g., mean local delay and spatial outage capacity) and the efficient calculation methods of the meta distribution. The insights of the meta distribution are also stated by the comparison with standard success probability. The various applications of the meta distribution to heterogeneous networks are summarized and categorized by different types of technologies. Furthermore, some open issues and future work are discussed to promote the development and application of the meta distribution.acceptedVersionPeer reviewe

Dewatering-Induced Stratified Settlement around Deep Excavation: Physical Model Study

The multi-aquifer and multi-aquitard system (MAMA) is a typical geological structure in deltas. Thus, the risks and challenges to settlement control and environmental protection are increased when demand for underground space extends to deeper strata. In this study, dewatering-induced stratified settlement in MAMA is divided into three stages according to whether the overlying aquitard is coupled with groundwater seepage. Subsequently, large physical model tests were carried out. Seepage and compression in the overlying strata come after the compression in the confined aquifer and the coordinated deformation in the overlying strata. The soil is compressed under the seepage drive within the hydraulic gradient range, while the soil above it is still affected by coordinated deformation and shows expansion. Dewatering-induced uneven settlement will cause damage to existing foundations and underground structures. Large-scale and uninterrupted excavation and dewatering are the main reasons for the continuous development of land subsidence. Although artificial groundwater recharging can reduce the settlement of the existing building, underground structure, and surrounding strata, a reasonable space arrangement is needed

Numerical Simulation of Forming MICP Horizontal Seepage Reducing Body in Confined Aquifer for Deep Excavation

The drawdown outside of a deep foundation pit has to be controlled during excavation. However, the vertical curtain cannot cutoff a deep and thick confined aquifer during deep excavation. In this study, a microbial-induced carbonate precipitation (MICP) horizontal seepage reducing body (HSRB) was proposed to control drawdown combined with a partially penetrating curtain. MICP HSRB is formed by using the seepage field generated by the recharge wells to drive the migration of a Sporosarcina pasteurii solution, stationary solution, and cementation solution into the deep confined aquifer. The migration of each solution was numerically simulated to study the HSRB formation process. The influence of different factors on solute migration was studied. The results show that the solutes in the fixed fluid and cementation fluid can reach the area under the driving of the seepage field, which proves that MICP HSRB can be formed. The calcium ions and urea in the cementation solution are more likely to migrate to the designated area than the bacterial solution. Increasing the injection rate of bacterial solution and adding recharge wells both made the bacterial solution migrate more quickly to the designated area. In the case of multiple grouting, the solute migration in the later stage will be hindered by the plugging of pores caused by calcium carbonate generated in the earlier stage. Therefore, different grouting methods need to be designed to drive the seepage field so that the solute injected in the later stage can continue to migrate. The MICP HSRB grouting technology can be used in foundation pit dewatering, providing reference for similar engineering