Piperazine-derived ionizable lipids for enhanced mRNA delivery and cancer immunotherapy

Messenger ribonucleic acid(mRNA)-based therapeutics hold great prospects in disease treatment and lipid nanoparticles(LNPs)are the most extensively applied non-viral platform for RNA delivery in clinics.Despite the clinical success of LNPs as vehicles have been achieved,developing LNPs with enhanced mRNA transmembrane delivery and transfection efficiency in a non-toxic manner is highly desirable and challenging.In this study,we designed a series of new ionizable amino lipids with piperazinederived headgroups and constructed a group of LNPs to promote the transfection activity of mRNA cargos.Among them,LNP formulated with lipid 10(L10-LNP)can efficiently package mRNA and perform superior transfection efficiency both in vitro and in vivo,which is mainly attributed to the improved intracellular uptake and effective endosomal escape.We verified that a single administration of L10-LNP packaging interleukin(IL)-12 mRNA induced tumor shrink and even regression by robust activation of immune effector CD8^(+)T cells and stimulating the generation of IFN-γwithout causing systemic toxicity,which provides a promising platform for clinical cancer immunotherapy.

RNF6 promotes chronic myelogenous leukemia cell proliferation and migration by stabilizing vimentin via multiple atypical ubiquitinations

Chronic myelogenous leukemia(CML)is a malignancy from bone marrow myeloid stem cells mainly driven by the fusion gene BCR-ABL.In addition to BCR-ABL,other genes including RNF6 are also dysregulated in CML cells.1 RNF6,a ubiquitin ligase of the RING family,promotes various cancer cell proliferation,chemoresistance,and tumor growth in vivo by targeting various proteins for ubiquitination and degradation,including SHP1,TLE3,FOXA1,and MAD1.^(2) However,its specific mechanism in CML is not known.

Feasibility assessment of up-flow anaerobic sludge blanket treatment of sulfamethoxazole pharmaceutical wastewater

Treatment of sulfamethoxazole pharmaceutical wastewater is a big challenge.In this study,a series of anaerobic evaluation tests on pharmaceutical wastewater from different operating units was conducted to evaluate the feasibility of using anaerobic digestion,and the results indicated that the key refractory factor for anaerobic treatment of this wastewater was the high sulfate concentration.A laboratory-scale up-flow anaerobic sludge blanket(UASB)reactor was operated for 195 days to investigate the effects of the influent chemical oxygen demand(COD),organic loading rate(OLR),and COD/SO_(4)^(2-) ratio on the biodegradation of sulfamethoxazole in pharmaceutical wastewater and the process performance.The electron flow indicated that methanogenesis was still the dominant reaction although sulfidogenesis was enhanced with a stepwise decrease in the influent COD/SO_(4)^(2-) ratio.For the treated sulfamethoxazole pharmaceutical wastewater,a COD of 4983 mg/L(diluted by 50%),OLR of 2.5 kg COD/(m^(3)·d),and COD/SO_(4)^(2-) ratio of more than 5 were suitable for practical applications.The recovery performance indicated that the system could resume operation quickly even if production was halted for a few days.

Designing HVDC GIS/GIL spacer to suppress charge accumulation

To suppress the charge accumulation on the spacer surface in direct current(DC)gas insulated transmission line(GIL)is an important and emergent issue for the development of a clean,safe and economic smart grid.A design method of the DC spacer is proposed,and a spacer prototype is prepared and evaluated both by simulation and type test.The DC withstand voltage test and polarity reversal test are performed using the new DC spacer compared with a commercialised 220 kVAC spacer.The simulation results indicate that the surface electric field and surface charge of the DC spacer are lower than those of the alternating current(AC)spacer under DC voltage.The test results verify that the surface flashover voltage of this DC spacer is higher than that of the AC spacer.The potential feasibility of the spacer design for HVDC is discussed.It is hoped that the content of this paper can bring new ideas in the development of HVDC gas insulated equipment.