Engineered fibrotic liver-targeted truncated transforming growth factor ß receptor type II variant for superior anti-liver fibrosis therapy.

Truncated transforming growth factor ß receptor type II (tTßRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-ß1 by means of competing with wild type TßRII (wtTßRII). However, the widespread application of tTßRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTßRII variant Z-tTßRII by fusing the platelet-derived growth factor ß receptor (PDGFßR)-specific affibody ZPDGFßR to the N-terminus of tTßRII. The target protein Z-tTßRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTßRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFßR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTßRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-ß1/Smad pathway-related protein levels in TGF-ß1-stimiluated HSC-T6 cells. Furthermore, Z-tTßRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-ß1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTßRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTßRII or former variant BiPPB-tTßRII (PDGFßR-binding peptide BiPPB modified tTßRII). In addition, Z-tTßRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTßRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.

Overexpression of the Long Noncoding RNA HIF2PUT Inhibits Non-Small Cell Lung Cancer Cell Proliferation and Invasion Through HIF-2a Pathway.

Objective: The role and molecular mechanism of long-chain noncoding RNAs (lncRNAs) in lung cancer remain to be elucidated. The aim of this study was to investigate the association between a long coding RNA hypoxia-inducible factor-2α (HIF-2α) promoter upstream transcript (HIF2PUT) and clinical characteristics of non-small cell lung cancer (NSCLC) and its regulatory role in NSCLC. Materials and Methods: The correlation between HIF2PUT expression and pathological features of NSCLC was analyzed in NSCLC patient samples. Real-time polymerase chain reaction and Western blot were used to detect genes' mRNA and protein expression, respectively. Cell proliferation assay, invasion, and transwell assay were performed to determine the effects of HIF2PUT on NSCLC cells. Results: lncRNA HIF2PUT was downregulated in NSCLC tissues and cell lines. The authors found that HIF2PUT was mainly expressed in cytoplasm and overexpression of HIF2PUT attenuates cell proliferation and invasion in NSCLC cells. Moreover, low expression of HIF2PUT was significantly related to TNM stage (p = 0.045) and histological type (p = 0.025). Furthermore, HIF2PUT was found to play a role in cell proliferation and invasion in NSCLC through regulating HIF-2a. Conclusion: Based on this study, the inhibitory role of HIF2PUT on NSCLC proliferation, invasion could be blocked by HIF-2a silencing. In summary, this study suggests that HIF2PUT and HIF-2a may play an important role in the regulation of NSCLC progression, which provides new insights for clinical treatment.

Propagation and Diffusion of Fluorescent Substances with Footprints in Indoor Environments.

Some studies have shown that contaminants can be transferred between floors and the soles, and there are few studies on pollutant propagation caused by human walking in real-life situations. This study explored the propagation and diffusion law of ground pollutants from rubber soles to poly vinyl chloride (PVC) floor during indoor walking through employing a fluorescent solution as a simulant. The footprint decay (D) and transfer efficiency (τ) of the fluorescent solution transferred from the sole to the indoor floor during walking were analyzed based on the fluorescent footprint imaging. The effects of namely body weight (50-75 kg), walking frequency (80-120 steps/min), and solution viscosity (oil and water) were also investigated. It was found that the total fluorescence gray value on the ground decreased exponentially as the number of walking steps (i) increased. The relationship between the normalized gray value of the fluorescent solution (D) on each floor panel i was Di=aebi,2.1≤a≤3.8,-1.4≤b≤-0.7, and τ was distributed in the range of 0.51-0.72. All influencing factors had a significant effect on a, and a greater body weight resulted in a smaller a value, while only the body weight had a significant effect on b and τ, and a greater body weight led to larger b and lower τ values.

Enhanced Glioblastoma Selectivity of Harmine via the Albumin Carrier.

Glioblastoma, the most common tumor in the brain, has witnessed very little clinical progress over the last decades. Exploring and discovering new therapeutic strategies for glioblastoma has become a critical problem. Harmine (HM), belonging to the beta-carboline alkaloid, is a natural product and isolated from the seeds of Peganum harmala L., which own notable antitumor activity in vitro. However, the poor water solubility and less selectivity of HM severely limit its clinical use. For enhancing its selective ability to tumor cells, we fabricated a kind of protein nanoparticles (BSA-HM NPs), composed of the modified bovine serum albumin (BSA) and HM. It was substantiated through in vitro and in vivo experiment that BSA-HM NPs could predominantly accumulate in tumor tissues and exhibited remarkably enhanced antitumor efficacy. This study provides a promising strategy to improve the bioavailability and avoid side effects of HM as antitumor agents by choosing BSA as carriers.

Chemical Buffer Layer Enabled Highly Reversible Zn Anode for Deeply Discharging and Long-Life Zn-Air Battery.

Rechargeable alkaline Zn-air batteries (ZABs) are attracting extensive attention owing to their high energy density and environmental friendliness. However, the dilemma of Zn anode, composed of ineluctable passivation and dissolution problems, severely hinders the discharge and cycling performance of the battery. Herein, the authors propose a chemical buffer layer coated on Zn metal (CBL@Zn) anode, in which ZnO nanorods are uniformly dispersed in graphene oxide (GO), to improve the reversibility of Zn↔ZnO electrochemical conversion process. Benefiting from the cooperative effect of ZnO nanorods' nuclei role and GO's adsorption affinity, the electrochemical precipitation-dissolution behavior of insulated ZnO is chemically regulated and the Zn(OH)4 2- ions are effectively confined in the chemical buffer layer. Therefore, the symmetrical CBL@Zn-CBL@Zn coin cell achieves a superior stability of 100 cycles with quite low overpotential (30 mv). When paired with commercial catalysts to assemble alkaline ZABs for practical use, an ultra high depth of discharge (DODZn ) >98% and excellent 450-h long-term cycling performance are realized. This chemical buffer strategy can potentially provide a new insight for developing other highly reversible alkaline Zn-metal batteries.

Ion transport in electrolytes of dielectric nanodevices.

Ion transport in electrolytes with nanoscale confinements is of great importance in many fields such as nanofluidics and electrochemical energy devices. The mobility and conductance for ions are often described by the classical Debye-Hückel-Onsager (DHO) theory but this theory fails for ions near dielectric interfaces. We propose a generalized DHO theory by using the Wentzel-Kramers-Brillouin techniques for the solution of the Onsager-Fuoss equation with variable coefficients. The theory allows to quantitatively measure physical quantities of ion transport in nanodevices and is demonstrated to well explain the abnormal increase or decrease of the ionic mobility tuned via the dielectric mismatch. By numerical calculations, our theory unravels the crucial role of the size of confinements and the ionic concentration on the ion transport, and demonstrates that the dielectric polarization can provide a giant enhancement on the conductance of electrolytes in nanodevices. This mechanism provides a practical guide for related nanoscale technologies with controllable transport properties.

Application value of goal-directed fluid therapy with ERAS in patients undergoing radical lung cancer surgery.

OBJECTIVE: To explore the application value of goal-directed fluid therapy (GDFT) in the enhanced recovery after surgery (ERAS) of patients undergoing radical lung cancer surgery (RLCS). METHODS: A total of 74 patients undergoing elective RLCS based on the enhance recovery after surgery (ERAS) concept in the HanDan Central Hospital between December 2016 and December 2019 were enrolled and assigned to a group treated by regular conventional liquids (regular group, n=34) and a group treated by goal-directed fluid (GDFT group, n=40) according to the fluid infusion scheme. The two groups were compared in intraoperative fluid inflow and outflow, hemodynamic indexes at 30 min (T0) before operation, 4 h (T1) and 24 h (T2) after operation, postoperative complications, postoperative recovery, inflammatory factors at 1 day (d 0) before operation, and at 1 day (d 1) and 7 days (d 3) after operation, as well as for postoperative life quality. RESULTS: Crystalloid fluid input, fluid infusion, and urine output of the GDFT group were all significantly less than those of the regular group (all P<0.05), and the GDFT group showed significantly lower fluctuations of MAP, cardiac index, and stroke volume (SV) than the regular group (all P<0.05). Additionally, the GDFT group showed a significantly lower overall complication rate and experienced notably earlier time to flatus and getting out-of-bed time and notably shorter hospitalization time than the regular group (all P<0.05). Moreover, the GDFT group presented with less fluctuation of IL-10, IL-6, and TNF-α levels and experienced notably higher life quality scores than the regular group. CONCLUSION: GDFT is beneficial to the rapid recovery of patients after RLCS, because it can exert a positive effect on maintaining the stability of hemodynamic indexes and reducing inflammation and postoperative complications.

Targeted truncated TGF-ß receptor type II delivery to fibrotic liver by PDGFß receptor-binding peptide modification for improving the anti-fibrotic activity against hepatic fibrosis in vitro and in vivo.

Truncated transforming growth factor-ß receptor type II (tTßRII) is a promising anti-fibrotic candidate because it attenuates excessive transforming growth factor-ß1 (TGF-ß1) and then blocks TGF-ß1 activity in hepatic fibrosis. However, its use has been greatly limited due to the fact that it is expensive to chemically synthesize and it does not specifically target to the lesion site. In this study, we describe that platelet-derived growth factor ß receptor (PDGFßR)-binding peptide BiPPB modified tTßRII (BiPPB-tTßRII) was prepared from the cleavage of SUMO-BiPPB-tTßRII by digestion with SUMO-specific protease. Moreover, compared to the unmodified tTßRII, the target protein BiPPB-tTßRII not only highly specific targeted activated hepatic stellate cells (HSCs) and fibrotic liver tissue, but also significantly inhibited the protein levels of fibrosis-related genes in TGF-ß1-induced HSC-T6 cells and CCl4-induced liver fibrosis in mice. Furthermore, BiPPB-tTßRII markedly ameliorated liver morphology, fibrotic responses and the damage of liver function in fibrosis animal. More importantly, BiPPB-tTßRII showed a much lesser extent in binding to quiescent HSCs and non-fibrotic liver tissue. Taken together, our results suggested that the target protein BiPPB-tTßRII, with its high specific fibrotic liver-targeting potential and its improved anti-fibrotic activity in liver fibrosis, may be a potential therapeutic agent for liver fibrosis.

Hypoxia and pH co-triggered oxidative stress amplifier for tumor therapy.

To keep fast proliferation, tumor cells are exposed to higher oxidative stress than normal cells and they upregulate the amount of some antioxidants such as glutathione (GSH) against reactive oxygen species to maintain the balance. This phenomenon is severe in hypoxic tumor cells. Although researchers have proposed a series of treatment strategies based on regulating the intracellular reactive oxygen species level, few of them are related to the hypoxic tumor. Herein, a novel organic compound (PLC) was designed by using lysine as a bridge to connect two functional small molecules, a hypoxia-responsive nitroimidazole derivative (pimonidazole) and a pH-responsive cinnamaldehyde (CA) derivative. Then, the oxidative stress amplifying ability of PLC in hypoxic tumor cells was evaluated. The acidic microenvironment of tumor can trigger the release of CA to produce reactive oxygen species. Meanwhile, large amount of nicotinamide adenine dinucleotide phosphate (NADPH) can be consumed to decrease the synthesis of GSH during the bio-reduction process of the nitro group in PLC under hypoxic conditions. Therefore, the lethal effect of CA can be amplified for the decrease of GSH. Our results prove that this strategy can significantly enhance the therapeutic effect of CA in the hypoxic tumor cells.

Effects of Kinetic Dielectric Decrement on Ion Diffusion and Capacitance in Electrochemical Systems.

Diffusion of ionic components in electrolytes not only eliminates the gradients of ionic concentrations but also alters the local dielectric environment, and the coupling effect between kinetic dielectric decrement and ionic concentration gradient on the diffusion dynamics is not well understood. Herein, taking the charging process in electrical double layer systems as a case study, we conduct a multiscale investigation of ion diffusions in aqueous electrolytes by combining the dynamic density functional theory and an ion-concentration-dependent dielectric constant model. By properly considering the time evolutions of local dielectric constant coupled with ion density, we report an interesting phenomenon on the suppression of surface charge density that is not captured by conventional models. In addition, we show that the usage of aqueous electrolyte with small dielectric decrement coefficients promotes the capacitance, in quantitative agreement with experimental measurements.

Planktonic Bacterial and Archaeal Communities in an Artificially Irrigated Estuarine Wetland: Diversity, Distribution, and Responses to Environmental Parameters.

Bacterial and archaeal communities play important roles in wetland ecosystems. Although the microbial communities in the soils and sediments of wetlands have been studied extensively, the comprehensive distributions of planktonic bacterial and archaeal communities and their responses to environmental variables in wetlands remain poorly understood. The present study investigated the spatiotemporal characteristics of the bacterial and archaeal communities in the water of an artificially irrigated estuarine wetland of the Liaohe River, China, explored whether the wetland effluent changed the bacterial and archaeal communities in the Liaohe River, and evaluated the driving environmental factors. Within the study, 16S rRNA quantitative PCR methods and MiSeq high-throughput sequencing were used. The bacterial and archaeal 16S rRNA gene abundances showed significant temporal variation. Meanwhile, the bacterial and archaeal structures showed temporal but not spatial variation in the wetland and did not change in the Liaohe River after wetland drainage. Moreover, the bacterial communities tended to have higher diversity in the wetland water in summer and in the scarce zone, while a relatively higher diversity of archaeal communities was found in autumn and in the intensive zone. DO, pH and PO4-P were proven to be the essential environmental parameters shaping the planktonic bacterial and archaeal community structures in the Liaohe River estuarine wetland (LEW). The LEW had a high potential for methanogenesis, which could be reflected by the composition of the microbial communities.

Ion Structure Near a Core-Shell Dielectric Nanoparticle.

A generalized image charge formulation is proposed for the Green's function of a core-shell dielectric nanoparticle for which theoretical and simulation investigations are rarely reported due to the difficulty of resolving the dielectric heterogeneity. Based on the formulation, an efficient and accurate algorithm is developed for calculating electrostatic polarization charges of mobile ions, allowing us to study related physical systems using the Monte Carlo algorithm. The computer simulations show that a fine-tuning of the shell thickness or the ion-interface correlation strength can greatly alter electric double-layer structures and capacitances, owing to the complicated interplay between dielectric boundary effects and ion-interface correlations.

Hybrid Monte Carlo and continuum modeling of electrolytes with concentration-induced dielectric variations.

The distribution of ions near a charged surface is an important quantity in many biological and material processes, and has been therefore investigated intensively. However, few theoretical and simulation approaches have included the influence of concentration-induced variations in the local dielectric permittivity of an underlying electrolyte solution. Such local variations have long been observed and known to affect the properties of ionic solution in the bulk and around the charged surface. We propose a hybrid computational model that combines Monte Carlo simulations with continuum electrostatic modeling to investigate such properties. A key component in our hybrid model is a semianalytical formula for the ion-ion interaction energy in a dielectrically inhomogeneous environment. This formula is obtained by solving for the Green's function Poisson's equation with ionic-concentration-dependent dielectric permittivity using a harmonic interpolation method and spherical harmonic series. We also construct a self-consistent continuum model of electrostatics to describe the effect of ionic-concentration-dependent dielectric permittivity and the resulting self-energy contribution. With extensive numerical simulations, we verify the convergence of our hybrid simulation scheme, show the qualitatively different structures of ionic distribution due to the concentration-induced dielectric variations, and compare our simulation results with the self-consistent continuum model. In particular, we study the differences between weakly and strongly charged surfaces and multivalencies of counterions. Our hybrid simulations conform particularly the depletion of ionic concentrations near a charged surface and also capture the charge inversion. We discuss several issues and possible further improvement of our approach for simulations of large charged systems.

Density functional formulation of the random-phase approximation for inhomogeneous fluids: Application to the Gaussian core and Coulomb particles.

Using the adiabatic connection, we formulate the free energy in terms of the correlation function of a fictitious system, h_{λ}(r,r^{'}), in which interactions λu(r,r^{'}) are gradually switched on as λ changes from 0 to 1. The function h_{λ}(r,r^{'}) is then obtained from the inhomogeneous Ornstein-Zernike equation and the two equations constitute a general liquid-state framework for treating inhomogeneous fluids. The two equations do not yet constitute a closed set. In the present work we use the closure c_{λ}(r,r^{'})≈-λßu(r,r^{'}), known as the random-phase approximation (RPA). We demonstrate that the RPA is identical with the variational Gaussian approximation derived within the field-theoretical framework, originally derived and used for charged particles. We apply our generalized RPA approximation to the Gaussian core model and Coulomb charges.

Self-energy-modified Poisson-Nernst-Planck equations: WKB approximation and finite-difference approaches.

We propose a modified Poisson-Nernst-Planck (PNP) model to investigate charge transport in electrolytes of inhomogeneous dielectric environment. The model includes the ionic polarization due to the dielectric inhomogeneity and the ion-ion correlation. This is achieved by the self energy of test ions through solving a generalized Debye-Hückel (DH) equation. We develop numerical methods for the system composed of the PNP and DH equations. Particularly, toward the numerical challenge of solving the high-dimensional DH equation, we developed an analytical WKB approximation and a numerical approach based on the selective inversion of sparse matrices. The model and numerical methods are validated by simulating the charge diffusion in electrolytes between two electrodes, for which effects of dielectrics and correlation are investigated by comparing the results with the prediction by the classical PNP theory. We find that, at the length scale of the interface separation comparable to the Bjerrum length, the results of the modified equations are significantly different from the classical PNP predictions mostly due to the dielectric effect. It is also shown that when the ion self energy is in weak or mediate strength, the WKB approximation presents a high accuracy, compared to precise finite-difference results.

Self-consistent field model for strong electrostatic correlations and inhomogeneous dielectric media.

Electrostatic correlations and variable permittivity of electrolytes are essential for exploring many chemical and physical properties of interfaces in aqueous solutions. We propose a continuum electrostatic model for the treatment of these effects in the framework of the self-consistent field theory. The model incorporates a space- or field-dependent dielectric permittivity and an excluded ion-size effect for the correlation energy. This results in a self-energy modified Poisson-Nernst-Planck or Poisson-Boltzmann equation together with state equations for the self energy and the dielectric function. We show that the ionic size is of significant importance in predicting a finite self energy for an ion in an inhomogeneous medium. Asymptotic approximation is proposed for the solution of a generalized Debye-Hückel equation, which has been shown to capture the ionic correlation and dielectric self energy. Through simulating ionic distribution surrounding a macroion, the modified self-consistent field model is shown to agree with particle-based Monte Carlo simulations. Numerical results for symmetric and asymmetric electrolytes demonstrate that the model is able to predict the charge inversion at high correlation regime in the presence of multivalent interfacial ions which is beyond the mean-field theory and also show strong effect to double layer structure due to the space- or field-dependent dielectric permittivity.