Simultaneous enhancement of cellular and humoral immunity by the lymph node-targeted cholesterolized TLR7 agonist liposomes

Toll-like receptor(TLR)agonists,as promising adjuvants and immunotherapeutic agents,have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling pathways.However,their clinical application is hindered by uncontrolled systemic inflammatory reactions.Therefore,it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and efficacy.In this study,we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes(1V209-Cho-Lip^(+))to mitigate undesired side effects.Co-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8^(+)T cells.The main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip^(+)in tumor vaccines.Following immunization with 1V209-Cho-Lip^(+)+OVA,we observed a pronounced"depot effect"and enhanced trafficking to secondary lymphoid organs.Prophylactic vaccination with 1V209-Cho-Lip^(+)^(+)OVA significantly delays tumor development,prolongs mouse survival,and establishes durable immunity against tumor recurrence.Additionally,1V209-Cho-Lip^(+)+OVA,while used therapeutic tumor vaccine,has demonstrated its efficacy in inhibiting tumor progression,and when combined with anti-PD-1,it further enhances antitumor effects.Therefore,the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine.

High-dimensional robust inference for censored linear models

Due to the direct statistical interpretation,censored linear regression offers a valuable complement to the Cox proportional hazards regression in survival analysis.We propose a rank-based high-dimensional inference for censored linear regression without imposing any moment condition on the model error.We develop a theory of the high-dimensional U-statistic,circumvent challenges stemming from the non-smoothness of the loss function,and establish the convergence rate of the regularized estimator and the asymptotic normality of the resulting de-biased estimator as well as the consistency of the asymptotic variance estimation.As censoring can be viewed as a way of trimming,it strengthens the robustness of the rank-based high-dimensional inference,particularly for the heavy-tailed model error or the outlier in the presence of the response.We evaluate the finite-sample performance of the proposed method via extensive simulation studies and demonstrate its utility by applying it to a subcohort study from The Cancer Genome Atlas(TCGA).

Predicting tremor improvement after MRgFUS thalamotomy in essential tremor from preoperative spontaneous brain activity:A machine learning approach

Magnetic resonance-guided focused ultrasound surgery(MRgFUS)thalamotomy is an emerging technique for medication-refractory essential tremor(ET),but with variable outcomes.This study used pattern regression analysis to identify brain signatures predictive of tremor improvements.Fifty-four ET patients(mean age=63.06 years,standard deviation(SD)=10.55 years,38 males)underwent unilateral MRg FUS thalamotomy and were scanned for resting-state functional magnetic resonance imaging(rsf MRI).Seventy-four healthy controls(mean age=58.09 years,SD=10.30 years,38 males)were recruited for comparison.Tremor responses at 12 months posttreatment were evaluated by the Clinical Rating Scale for Tremor.The fractional amplitude of low-frequency fluctuations(f ALFF)was calculated from rs-f MRI data.Two-sample t-test was used to generate a disease-specific mask,within which Multivariate Kernel Ridge Regression analyses were conducted.Predicted and actual clinical scores were compared using Pearson's correlation coefficient(r)and normalized mean squared error(Norm.MSE).Permutation test and leave-one-out strategy were applied for results validation.KRR identified f ALFF patterns that significantly predicted the hand tremor improvement(r=0.23,P=0.025;Norm.MSE=0.05,P=0.026)and the postural tremor improvement(r=0.28,P=0.025;Norm.MSE=0.06,P=0.023),but not action tremor improvement.Lobule VI of right cerebellum(Cerebelum_6_R),right superior occipital gyrus(Occipital_Sup_R)and lobule X of vermis(Vermis_10)contributed most for hand tremor prediction(normalized weights(NW):2.77%,2.40%,2.34%)while Vermis_10,left supplementary motor area(Supp_Motor_Area_L)and right hippocampus(Hippocampus_R)for postural tremor prediction(NW:2.69%,2.12%,2.05%).The low contributing NW of the individual brain regions suggested that the f ALFF pattern as a whole is an overall predicting feature.Preoperative f ALFF pattern predicts tremor benefits induced by MRg FUS thalamotomy.Clinical Trials.gov number:NCT04570046.

Concept of radial slippage propagation triggering self-loosening and optimisation design of novel anti-loosening structures

Self-loosening of bolted joints can occur in a vibration environment,and it may induce bolt fatigue fracture with catastrophic consequences.It is essential to clarify the self-loosening mechanism,based on which novel anti-loosening thread structures can be developed.In this paper,we propose the concept of radial slippage propagation and provide new insights into the self-loosening process.The new theory states that the slippage along the radial direction of the thread surface induces more slippage areas(slippage propagation),and self-loosening occurs due to the dynamic evolution and propagation of contact states on the thread and bearing surfaces with an increase in the number of vibration cycles.Finite element analysis(FEA)was used to validate the propagation process of slippage areas on the thread surface.A novel bolted joint with step thread engagement was developed,which could prevent the occurrence of relative motion of the external and internal threads in the radial direction and thus block slippage propagation.A three-dimensional(3D)finite element model(FEM)of the novel thread structure was established,and a test specimen was manufactured using two special tools.FEA and experiments validated its superior anti-loosening and anti-fatigue performances,and the convenience of installation and removal.Experimental validation of the radial slippage propagation theory and the performance optimisation of the step-thread structure should be performed in the future.

Fe-N-C nanostick derived from 1D Fe-ZIFs for electrocatalytic oxygen reduction

The slow oxygen reduction process at the cathode and the scarcity of platinum-based metals lead to limited applications in fuel cells and metal-air cells.Recently,transition metal and nitrogen co-doped carbon-based catalysts(M–N–C)are regarded as the most prospective non-precious metal catalysts for future fuel cell applications.It is verified theoretically and experimentally that the metal and nitrogen coordination structure is the main catalytic activity center of oxygen reduction reaction(ORR),so constructing M–N–C materials with high available surface area and structural stability is an effective way to accelerate ORR.Herein,we deliberately synthesize a one-dimensional ZIF structure to fabricate one-dimensional porous Fe–N–C nanostick via two-step pyrolysis.Excitingly,the as-synthesized exhibited an outstanding ORR activity in alkaline medium(E_(1/2)of 0.928 V),as well as superior stability(only changed 7 mV after 10,000 cycles in alkaline medium).Our results show that the reduction of electrocatalyst dimensionality can promote mass transport and increase the accessibility of active sites,thus optimizing their performance in ORR.This work is a good demonstration of the importance of a rational design of catalyst structure for efficient ORR.

富氧燃烧方式下烟气中SO3和Hg的排放及控制研究进展

富氧燃烧技术可有效控制温室气体排放,是一种具有应用潜力的节能减排技术。本工作系统总结分析了富氧燃烧方式下关键烟气组分(SOx,NOx,H2O,Cl2/HCl等)对SO3和Hg排放规律的影响及飞灰对烟气中SO3吸附去除和Hg富集规律的影响,提出了富氧燃烧方式下较优的具可行性的污染物协同控制技术建议,为富氧燃烧技术工业应用面临的污染物协同控制提供重要参考。分析了目前富氧燃烧方式下SO3和Hg排放规律及优化控制研究存在的问题,对未来的研究方向提出了建议。要点:(1)富氧燃烧方式下烟气中SO3和Hg浓度明显提高。烟气中SOx,NOx,H2O,Cl2/HCl及飞灰等对SO3和Hg排放规律具有重要影响。(2)从脱硝、除尘、脱硫工艺优化方面,提出了富氧燃烧方式下具有可行性的污染物协同控制技术建议,为工业应用面临的污染物协同控制问题提供重要参考。(3)指出了未来富氧燃烧方式下SO3和Hg排放及优化控制的研究方向,如实际工况多因素耦合作用下排放规律、烟气中污染物的协同控制规律、关键污染物的迁移规律及协同控制工艺路线优化研究。

Active oxygen species and oxidation mechanism over Ce-doped LaMn_(0.8)Ni_(0.2)O_(3)/hierarchical ZSM-5 in pentanal oxidation

Hierarchical ZSM-5(HZ)molecular sieves based on fly ash were synthesized using a method combining water heat treatment with step-by-step calcination.The coupling catalysts between La_(1-x)Ce_(x)Mn_(0.8)-Ni_(0.2)O_(3)(x≤0.5)perovskites and HZ were prepared through the impregnation method,which were characterized by X-ray diffraction(XRD),scanning electron microscopy(SEM),high-resolution transmission electron microscopy(HRTEM),N_(2)adsorption,X-ray photoelectron spectroscopy(XPS),NH3-temperature programmed desoprtion(NH3-TPD),H_(2)-temperature programmed reduction(H_(2)-TPR)and O_(2)-TPD techniques and investigated regarding pentanal oxidation at 120-390℃to explore the effects of Ce doping on the catalytic activity and the active oxygen species of the coupling catalysts,meanwhile,the reaction mechanism and pathway of pentanal oxidation were also studied.The results reveal that Ce substitution at La sites can change the electronic interactions between all the elements and promote the electronic transfer among La,Ce,Ni,Mn and HZ,influencing directly the physicochemical characteristics of the catalysts.Moreover,the amount and transfer ability of surface adsorbed oxygen(O_(2)-and O-)regarded as the reactive oxygen species and the low temperature reducibility are the main influence factors in pentanal oxidation.Additionally,La_(0.8)Ce_(0.2)Mn_(0.8)Ni_(0.2)O_(3)/HZ exhibits the best catalytic activity and deep oxidation capacity as well as a better water resistance due to its larger amount of surface adsorbed oxygen species and higher low temperature reducibility.What’s more,appropriate Ce substitution can significantly enhance the amount of O_(2)-ions,which can distinctly enhance the catalytic activity of the catalyst,and moderate acid strength and appropriate acid amount can also facilitate the improvement of the pentanal oxidation activity.It is found that there is a synergic catalytic effect between surface acidity and redox ability of the catalyst.According to the in situ DRIFTS and GC/MS analyses,pentanal can be oxidized gradually to CO_(2)and H_(2)O by the surface oxygen species with the form of adsorption in air following the Langmuir-Hinshelwood(L-H)reaction mechanism.Two reaction pathways for the pentanal oxidation process are proposed,and the conversion of the formates to carbonates may be one of the main rate-determining steps.