Reversed charge transfer induced by nickel in Fe-Ni/Mo_(2)C@nitrogen-doped carbon nanobox for promoted reversible oxygen electrocatalysis

The interaction between metal and support is critical in oxygen catalysis as it governs the charge transfer between these two entities,influences the electronic structures of the supported metal,affects the adsorption energies of reaction intermediates,and ultimately impacts the catalytic performance.In this study,we discovered a unique charge transfer reversal phenomenon in a metal/carbon nanohybrid system.Specifically,electrons were transferred from the metal-based species to N-doped carbon,while the carbon support reciprocally donated electrons to the metal domain upon the introduction of nickel.This led to the exceptional electrocatalytic performances of the resulting Ni-Fe/Mo_(2)C@nitrogen-doped carbon catalyst,with a half-wave potential of 0.91 V towards oxygen reduction reaction(ORR)and a low overpotential of 290 m V at 10 mA cm^(-2)towards oxygen evolution reaction(OER)under alkaline conditions.Additionally,the Fe-Ni/Mo_(2)C@carbon heterojunction catalyst demonstrated high specific capacity(794 mA h g_(Zn)~(-1))and excellent cycling stability(200 h)in a Zn-air battery.Theoretical calculations revealed that Mo_(2)C effectively inhibited charge transfer from Fe to the support,while secondary doping of Ni induced a charge transfer reversal,resulting in electron accumulation in the Fe-Ni alloy region.This local electronic structure modulation significantly reduced energy barriers in the oxygen catalysis process,enhancing the catalytic efficiency of both ORR and OER.Consequently,our findings underscore the potential of manipulating charge transfer reversal between the metal and support as a promising strategy for developing highly-active and durable bi-functional oxygen electrodes.

Electric field optimized LDMOST using multiple decrescent and reverse charge regions

A lateral double-diffused metal-oxide-semiconductor field effect transistor （LDMOST） with multiple n-regions in the p-substrate is investigated in detail. Because of the decrescent n-regions, the electric field distribu- tion is higher and more uniform, and the breakdown voltage of the new structure is increased by 95%, in comparison with that of a conventional counterpart without substrate n-regions. Based on the trade-off between the breakdown voltage and the on-resistance, the optimal number of n-regions and the other key parameters are achieved. Furthermore, sensitivity research shows that the breakdown voltage is relatively sensitive to the drift region doping and the n-regions＇ lengths.

Value-Added Tax （VAT） on Selected Financial Transactions

This paper deals with the approach to imposing value-added tax （VAT） on financial transactions. The VAT is a highly harmonized consumption tax within the European Union （EU）. VAT operational rules have been set down by the relevant directive of the Council of the EU. Under the directive, it is possible to select either exemption or taxation of financial transactions. Only the first option is permitted in the Czech Republic. Pros and cons of both models are described, in particular, the problems with determining the difference between financial transactions and other similar performance that must always be subject to tax. Potential lower VAT revenue or tax base assessment, as appropriate, seems to be crucial in the case of the taxation of financial transactions.

Surface charge adaptive nitric oxide nanogenerator for enhanced photothermal eradication of drug-resistant biofilm infections

Due to protection of extracellular polymeric substances,the therapeutic efficiency of conventional antimicrobial agents is often impeded by their poor infiltration and accumulation in biofilm.Herein,one type of surface charge adaptable nitric oxide(NO)nanogenerator was developed for biofilm permeation,retention and eradication.This nanogenerator(PDG@Au-NO/PBAM)is composed of a core-shell structure:thermo-sensitive NO donor conjugated AuNPs on cationic poly(dopamine-co-glucosamine)nanoparticle(PDG@Au-NO)served as core,and anionic phenylboronic acid-acryloylmorpholine(PBAM)copolymer was employed as a shell.The NO nanogenerator featured long circulation and good biocompatibility.Once the nanogenerator reached acidic biofilm,its surface charge would be switched to positive after shell dissociation and cationic core exposure,which was conducive for the nanogenerator to infiltrate and accumulate in the depth of biofilm.In addition,the nanogenerator could sustainably generate NO to disturb the integrity of biofilm at physiological temperature,then generate hyperthermia and explosive NO release upon NIR irradiation to efficiently eradicate drug-resistant bacteria biofilm.Such rational design offers a promising approach for developing nanosystems against biofilm-associated infections.

Convenient preparation of charge-adaptive chitosan nanomedicines for extended blood circulation and accelerated endosomal escape

A major impediment in the development of chitosan nanoparticles （CTS NPs） as effective drug delivery vesicles is their rapid clearance from blood and endosome entrapment. To overcome these problems, a convenient and promising template system was developed by decorating poly（methacrylic acid） （PMAA） to the surface of 10-hydroxy camptothecin （HCPT）-loaded CTS NPs （HCPT-CTS/ PMAA NPs）. The results show that the presence of negatively charged PMAA significantly elongated the blood circulation time of HCPT-CTS NPs from 12 to 24 h, and reduced the blood clearance （C1） from 30.57 to 6.72 mL/h in vivo. The calculated area under curve （AUC0-24h） and terminal elimination half-life （tl/2） of HCPT-CTS/PMAA NPs were 4.37-fold and 2.48-fold compared with those of HCPT-CTS NPs. Furthermore, the positively charged HCPT-CTS/PMAA NPs triggered by tumor acidic microenvironment （pH 6.5） result in a 453-fold higher cellular uptake than the negatively charged counterparts at pH 7.4. Additionally, HCPT-CTS/PMAA NPs have the ability to escape endosomal entrapment via ＂proton sponge effect＂ after incubation with HepG2 cells for 3 h at pH 6.5. Taken together, these findings open up a convenient, low-cost, but effective way to prepare HCPT-CTS/PMAA NPs as a candidate for developing vectors with enhanced long blood circulation and endosomal escape ability in future clinical experiments.

Enzyme-activatable disk-shaped nanocarriers augment tumor permeability for breast cancer combination therapy

Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic outcomes.Here,we constructed TRAIL-[NDHCPT]^(GAC),a synergistic hydroxycamptothecin(HCPT)and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)protein co-loaded disk-shaped nanocarrier withγ-glutamyl transpeptidase responsiveness.When the novel nanodisks extravasated into the tumor interstitium,theγ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved theγ-glutamyl portions of the nanodisk surface to produce positively charged amino groups.As a result,the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic nanodisks.HCPT and TRAIL exerted synergistic antitumor effects with better overall therapeutic efficacy.This TRAIL-[ND-HCPT]^(GAC)system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.

Multifunctional biodegradable nanoplatform based on oxaliplatin prodrug cross-linked mesoporous polydopamine for enhancing cancer synergetic therapy

Due to the limitations of conventional chemotherapy including side effects,poor prognosis,and drug resistance,there is an urgent need for the development of a novel multi-functional combined therapy strategy.Dopamine-modified oxaliplatin prodrug(OXA-DA)was successfully synthesized in this study to ameliorate the organ distribution of oxaliplatin for improving the drug efficacy and reducing toxic side effects,and OXA-DA was applied to develop a porous oxaliplatin cross-linked polydopamine nanoparticle for loading siPD-L1 to construct multifunctional nanoplatform.The multifunctional nanoplatform was modified with poly(2-ethyl-2-oxazoline)(PEOz),which occurred charge reversal in the tumor microenvironment,and exerted the lysosomal escape effect in tumor cells to improve the bioavailability of small interfering RNA targeting programmed cell death-ligand 1(siPD-L1).The pH-responsive charge reversal,photothermal,biodegradation,lysosomal escape ability,PD-L1 protein degradation,toxicity properties and multiple antitumor effects were comprehensively evaluated in vitro and in vivo experiments.The findings indicated that OXA-DA-siPD-L1@PDA-PEOz excellently induced tumor cell necrosis and apoptosis as a result of the synergistic effect of chemo-photothermal therapy,and upregulated CD8+T cells produced interferon-γ(IFN-γ)to further attack the tumor cells.In conclusion,the novel nanoplatform-mediated chemo/photothermal/immunotherapy has promising clinical applications in the treatment of malignant tumors.

Dual-responsive nanoparticles with transformable shape and reversible charge for amplified chemo-photodynamic therapy of breast cancer

Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.

Co-delivery of photosensitizer and diclofenac through sequentially responsive bilirubin nanocarriers for combating hypoxic tumors

Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.

Integrated prodrug micelles with two-photon bioimaging and pH-triggered drug delivery for cancer theranostics

Nanodrug carriers with fluorescence radiation are widely used in cancer diagnosis and therapy due to their real-time imaging,less side effect,better drug utilization as well as the good bioimaging ability.However,traditional nanocarriers still suffer from unexpectable drug leakage,unsatisfactory tumor-targeted drug delivery and shallow imaging depth,which limit their further application in cancer theranostics.In this study,an integrated nanoplatform is constructed by polymeric prodrug micelles with two-photon and aggregation-induced emission bioimaging,charge reversal and drug delivery triggered by acidic pH.The prodrug micelles can be self-assembled by the TPPEI(DA/DOX)-PEG prodrug polymer,which consists of the two-photon fluorophore(TP),dimethylmaleic anhydride(DA)grafted polyethyleneimine(PEI)and polyethylene glycol(PEG).The PEG segment,DOX and DA are bridged to polymer by acid cleavable bonds,which provides the micelles a‘stealth’property and a satisfactory stability during blood circulation,while the outside PEG segment is abandoned along with the DA protection in the tumor acidic microenvironment,thus leading to charge reversal-mediated accelerated endocytosis and tumor-targeted drug delivery.The great antitumor efficacy and reduced side effect of these pH-sensitive prodrug micelles are confirmed by antitumor assays in vitro and in vivo.Meanwhile,these micelles exhibited great deep-tissue two-photon bioimaging ability up to 150 lm in depth.The great antitumor efficacy,reduced side effect and deep two-photon tissue imaging make the TP-PEI(DA/DOX)-PEG prodrug micelles would be an efficient strategy for theranostic nanoplatform in cancer treatment.

Self-assembled ternary hybrid nanodrugs for overcoming tumor resistance and metastasis

Traditional chemotherapy exhibits a certain therapeutic effect toward malignant cancer,but easily induce tumor multidrug resistance(MDR),thereby resulting in the progress of tumor recurrence or metastasis.In this work,we deigned ternary hybrid nanodrugs(PEI/DOX@CXB-NPs)to simultaneously combat against tumor MDR and metastasis.In vitro results demonstrate this hybrid nanodrugs could efficiently increase cellular uptake at pH 6.8 by the charge reversal,break lysosomal sequestration by the proton sponge effect and trigger drugs release by intracellular GSH,eventually leading to higher drugs accumulation and cell-killing in drug-sensitive/resistant cells.In vivo evaluation revealed that this nanodrugs could significantly inhibit MDR tumor growth and simultaneously prevent A549 tumor liver/lung metastasis owing to the specifically drugs accumulation.Mechanism studies further verified that hybrid nanodrugs were capable of down-regulating the expression of MDR or metastasis-associated proteins,lead to the enhanced anti-MDR and anti-metastasis effect.As a result,the multiple combination strategy provided an option for effective cancer treatment,which could be potentially extended to other therapeutic agents or further use in clinical test.

Some Random Batch Particle Methods for the Poisson-Nernst-Planck and Poisson-Boltzmann Equations

We consider in this paper random batch interacting particle methods forsolving the Poisson-Nernst-Planck (PNP) equations, and thus the Poisson-Boltzmann(PB) equation as the equilibrium, in the external unbounded domain. To justify thesimulation in a truncated domain, an error estimate of the truncation is proved inthe symmetric cases for the PB equation. Then, the random batch interacting particle methods are introduced which are O(N) per time step. The particle methods cannot only be considered as a numerical method for solving the PNP and PB equations,but also can be used as a direct simulation approach for the dynamics of the chargedparticles in solution. The particle methods are preferable due to their simplicity andadaptivity to complicated geometry, and may be interesting in describing the dynamics of the physical process. Moreover, it is feasible to incorporate more physical effectsand interactions in the particle methods and to describe phenomena beyond the scopeof the mean-field equations.

A kind of modified bovine serum albumin with great potential for applying in gene delivery

Bovine serum albumin （BSA） was modified through a facile synthesis method to increase its isoelectric point （pl） from 4.8 to 6.0. When pH is higher than 6.0, the protein shows a negative surface charge, on the contrary, the protein is positively charged. In this study, the charge-reversal modified BSA （crBgA） was utilized to assemble with the binary complexes of pDNA/poly（vinylpyrrolidone）-graft-poly（2- dimethylaminoethyl methacrylate） （pDNA/PVP-g-PDMAEMA） to shield the excess positive charges of complexes at physiological pH （pH 7.4）. When the complex coated with crBSA located in the environment at endosomal pH （pH 5.0）, the charge-reversal of crBSA led to the deviation of crBSA from polyplex by electrostatic repulsion, which would benefit the transfection of the target gene. The crBSA shows great potential for improving the transfection efficiency of ~DNA/PVP-^-PDMAEMA.