Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke:a special outlook on mitochondrial delivery

Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke.However,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency.By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly improved.Furthermore,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic stroke.Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke therapy.In this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies.Given the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process.Moreover,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases

Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.

Noise Control of a Two Stroke Engine Car

Aim To control the noise of two stroke engine Methods On the basis of noise identification,a new muffler and acoustic shield were designed,Results the car's pass-by noise below the national limit Conclusion through proper noise controlling measures,the pass-by noise of two stroke engines could be reduced under national permitting limit.

Experimental study on compression stroke characteristics of free- piston engine generator

The compression stroke characteristics of free-piston engine generator were studied. The numerical model of the compression stroke was established based on thermodynamics and dynamics equation,and the leak loss,heat loss and friction loss were considered. Through solving numerical equations,the in-cylinder pressure of compression stroke under different compression ratios was calculated,energy transfer and conversion process was analyzed,and the calculated results were experimentally verified. The results showed that the actual effective output of electronic energy and the compression energy stored in the com-pressed gas accounted for about 70%. The compression energy gradually increased with the increasing com-pression ratio. When the compression ratio was more than 7. 5,the actual compression energy increased slowly and the energy error between simulation and test decreased.

A High-Efficiency Two-Stroke Engine Concept: The Boosted Uniflow Scavenged Direct-Injection Gasoline (BUSDIG) Engine with Air Hybrid Operation

A novel two-stroke boosted uniflow scavenged direct-injection gasoline (BUSDIG) engine has been proposed and designed in order to achieve aggressive engine downsizing and down-speeding for higher engine performance and efficiency. In this paper, the design and development of the BUSDIG engine are outlined discussed and the key findings are summarized to highlight the progress of the development of the proposed two-stroke BUSDIG engine. In order to maximize the scavenging performance and produce sufficient in-cylinder flow motions for the fuel/air mixing process in the two-stroke BUSDIG engine, the engine bore/stroke ratio, intake scavenge port angles, and intake plenum design were optimized by three-dimensional (3D) computational fluid dynamics (CFD) simulations. The effects of the opening profiles of the scavenge ports and exhaust valves on controlling the scavenging process were also investigated. In order to achieve optimal in-cylinder fuel stratification, the mixture-formation processes by different injection strategies were studied by using CFD simulations with a calibrated Reitz–Diwakar breakup model. Based on the optimal design of the BUSDIG engine, one-dimensional (1D) engine simulations were performed in Ricardo WAVE. The results showed that a maximum brake thermal efficiency of 47.2% can be achieved for the two-stroke BUSDIG engine with lean combustion and water injection. A peak brake toque of 379 N·m and a peak brake power density of 112 kW·L^-1 were achieved at 1600 and 4000 r·min^-1, respectively, in the BUSDIG engine with the stoichiometric condition.

Numerical Simulation of a Spark Ignited Two-Stroke Free-Piston Engine Generator

A numerical program is built to simulate the performance of a spark ignited two-stroke free-piston engine coupled with a linear generator. The computational model combines a series of dynamic and thermodynamic equations that are solved simultaneously to predict the performances of the engines. The dynamic analysis performed consists of an evaluation of the frictional force and load force introduced by the generator. The thermodynamic analysis used a single zone model to describe the engine＇ s working cycle which includes intake, scavenging, compression, combustion and expansion, and to evaluate the effect of heat transfer based on the first law of thermodynamics and the ideal gas state equation. Because there is no crankshaft, a time based Wiebe equation was used to express the fraction of fuel burned in the combustion. The calculated results were validated by using the experimental data from another research group. The results indicate that the free-piston generator has some advantages over conventional engines.

Exosomes:the next-generation therapeutic platform for ischemic stroke

Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery.Therefore,there is an urgent need to develop new methods for the treatment of this condition.Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions.They have low immunogenicity,good stability,high delivery efficiency,and the ability to cross the blood–brain barrier.These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke.The rapid development of nanotechnology has advanced the application of engineered exosomes,which can effectively improve targeting ability,enhance therapeutic efficacy,and minimize the dosages needed.Advances in technology have also driven clinical translational research on exosomes.In this review,we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke,including their antiinflammation,anti-apoptosis,autophagy-regulation,angiogenesis,neurogenesis,and glial scar formation reduction effects.However,it is worth noting that,despite their significant therapeutic potential,there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes.Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke.Ultimately,our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.

Impact of Degrees of Freedom of Polyatomic Ideal Gas on Efficiency of Three-Stroke-Cycle Heat Engines

It is customary to evaluate the efficiency of four-stroke-cycle heat engines such as Carnot, Otto and Diesel with a working ideal gas [1] [2] [3]. Here we consider various three-stroke-cycle heat engines that are composed of three out of four special processes: adiabatic, isothermal, isobaric and isochoric. We deviate from the customary norm considering the working material to be a polyatomic ideal gas with various degrees of freedom. We develop analytic expressions for the efficiency of each design as a function of degrees of freedom. For suitable practical values of relevant (V, P, T), we evaluate the corresponding efficiencies.

Frequency compensation control method for opposedpiston two-stroke folded-cranktrain engine's common rail system by loop-shaping theory

A frequency compensation control method for the opposed-piston two-stroke folded-cranktrain（ OPFC） diesel engine＇s common rail system is presented as a result of the study of the loop-shaping theory. A common rail working process and the classical frequency control theory are combined to construct a frequency restriction of common rail pressure. A frequency compensator is utilized to improve the robustness of multiplicative perturbations and disturbance. The loop-shaping method has been applied to design the common rail pressure controller of the OPFC diesel engine. Simulation and bench test results show that in the condition of perturbation that comes from the effect of injection,multi-injection,fuel pumping of a pre-cylinder,and instantaneous pressure fluctuation,the controller indicates high precision. Compared with the original controller,this method improves the control precision by 67. 3%.

Emerging strategies for nerve repair and regeneration in ischemic stroke:neural stem cell therapy

Ischemic stroke is a major cause of mortality and disability worldwide,with limited treatment options available in clinical practice.The emergence of stem cell therapy has provided new hope to the field of stroke treatment via the restoration of brain neuron function.Exogenous neural stem cells are beneficial not only in cell replacement but also through the bystander effect.Neural stem cells regulate multiple physiological responses,including nerve repair,endogenous regeneration,immune function,and blood-brain barrier permeability,through the secretion of bioactive substances,including extracellular vesicles/exosomes.However,due to the complex microenvironment of ischemic cerebrovascular events and the low survival rate of neural stem cells following transplantation,limitations in the treatment effect remain unresolved.In this paper,we provide a detailed summary of the potential mechanisms of neural stem cell therapy for the treatment of ischemic stroke,review current neural stem cell therapeutic strategies and clinical trial results,and summarize the latest advancements in neural stem cell engineering to improve the survival rate of neural stem cells.We hope that this review could help provide insight into the therapeutic potential of neural stem cells and guide future scientific endeavors on neural stem cells.

Influence of Combustion Chamber Design Parameters and Intake Environments on Spark Ignition Engine Performance and Exhaust Gas Emission

In the present paper, the effect of the combustion chamber design parameters on the improvement of combustion efficiency (the heat generated inside the combustion chamber) and the enhancement in the pollution rates (heat emissions) from a four-stroke, spark-ignition engine has been studied experimentally and theoretically. Two different programs, Gaseq and Ansys, were used to simulate the effect of the combustion chamber shape, turbulent kinetic energy, intake temperature, intake pressure, parity ratio, compression ratio, and engine speed on reducing specific fuel consumption in the engine, reducing carbon dioxide emissions, and increasing overall engine efficiency. The results showed increasing the intake temperature increased the amount of heat produced in the combustion chamber. This leads to increases in the overall efficiency of the engine, but leads to increasing the carbon dioxide and nitrogen oxide emissions. Increasing the intake pressure has a positive effect on the combustion temperature and pressure, but it has a negative effect on carbon dioxide and nitrogen oxides. Raising the pressure ratio improved the overall efficiency of the engine by increasing the combustion heat, but increasing specific fuel consumption and emissions. Also, increasing the engine speed above the permissible limit has an adverse effect on the spraying speed due to the piston speed being higher than the flame speed, which leads to a reduction in the engine brake torque. An increase in the compression ratio leads to higher fluid pressure and output capacity, but combustion methods occur. An increase in the kinetic energy of the turbulence leads to good combustion. A bowl in a piston has the highest rate of rotation and rotation compared to flat and hemispherical pistons. That is, the design of the cylinder head of this type leads to an improvement in the combustion efficiency and thus the efficiency of the engine.

INVESTIGATION IN REDUCING EXHAUST EMISSIONS FROM TWO STROKE MOTORCYCLES

Test results of reducing two stroke motorcycle emissions with new type carburettors and electronic fuel injection systems are presented. Analyses and comparison between different systems are discussed. The adoption of electronically controlled injection and corresponding electronic control technique is an effective measure of prolonged vitality to improve emissions from two stroke motorcycles. Suggestions about the strategic steps of China′s motorcycle emission control are proposed.

Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis

Mesenchymal stem cells(MSCs)experience substantial viability issues in the stroke infarct region,limiting their therapeutic efficacy and clinical translation.High levels of deadly reactive oxygen radicals(ROS)and proinflammatory cytokines(PC)in the infarct milieu kill transplanted MSCs,whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs’viability.Based on the intrinsic hormesis effects in cellular biology,we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy.This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer.In this system,extracellular ROSscavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a microlivable niche at the level of a single MSC for transplantation.Meanwhile,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing.The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days.This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.

补阳还五汤及主要成分对大脑中动脉阻塞再灌注大鼠脑组织细胞焦亡的影响

背景:细胞焦亡是脑缺血再灌注损伤的重要病理机制,补阳还五汤是中医临床治疗缺血性脑卒中的经典方剂,细胞焦亡可能是补阳还五汤治疗脑缺血再灌注损伤的有效作用靶点。目的:观察补阳还五汤对大脑中动脉阻塞再灌注大鼠脑组织细胞焦亡的影响及作用机制。方法:将48只SD大鼠随机分为假手术组、模型组、黄芪组及补阳还五汤组。除假手术组外,其余各组均进行大脑中动脉阻塞缺血2 h再灌注72 h处理,黄芪组和补阳还五汤组大鼠均于缺血2 h再灌注后开始连续灌胃相应体积的药物至缺血再灌注72 h,早晚各1次。Zea Longa评分观察大鼠神经功能缺损情况,TTC染色观察大鼠脑梗死体积,苏木精-伊红染色观察大鼠脑组织病理损伤变化,免疫荧光观察脑组织Tunel和Cleaved Caspase-1共表达以及接头蛋白ASC表达情况,免疫组化及Western blot检测大鼠脑组织焦亡相关蛋白表达。结果与结论:①与假手术组相比,模型组大鼠神经功能缺损评分显著升高(P<0.01),与模型组相比,补阳还五汤组及黄芪组大鼠神经功能缺损评分显著下降(P<0.01);②与模型组相比,黄芪组和补阳还五汤组脑梗死体积占比下降(P<0.01);③模型组脑组织神经细胞胞核固缩深染或溶解消失,细胞排列紊乱,与模型组比较,补阳还五汤组及黄芪组脑组织病理损伤较轻;④与假手术组相比,模型组大鼠脑组织Tunel与Cleaved Caspase-1双染色阳性细胞数及ASC免疫荧光表达强度显著增加,Cleaved Caspase-1、NLRP3、白细胞介素18和白细胞介素1β焦亡蛋白表达显著升高(P<0.01);与模型组相比,补阳还五汤组及黄芪组Cleaved Caspase-1与Tunel双染色阳性细胞数、ASC免疫荧光表达强度及Cleaved Caspase-1、NLRP3、白细胞介素18、白细胞介素1β焦亡蛋白表达均明显下降(P<0.01)。结果表明,补阳还五汤及其君药黄芪可有效缓解大脑中动脉阻塞再灌注大鼠脑组织损伤,其机制可能与抑制神经细胞焦亡有关。

The use of hydrogel-delivered extracellular vesicles in recovery of motor function in stroke:a testable experimental hypothesis for clinical translation including behavioral and neuroimaging assessment approaches

Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)repair.It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes,making development of CNS therapeutics challenging.Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society,it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels.Extracellular vesicles(EVs),also known as exosomes,when derived from mesenchymal stem cells,are one of the most promising approaches that have been attempted thus far,as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation.At the same time,advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur,as well as the release of biomolecules facilitating or inducing the reparative processes.This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels.The rationale behind this hypothesis is presented,analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain.This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur.Finally,the importance of including nonhuman primate models in the clinical translation pipeline,as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive,in vivo,quantifiable imagingbased biomarkers for CNS repair are discussed,aiming for more effective and safe clinical translation of such regenerative therapies to humans.

二冲程半直喷航空发动机喷油策略研究

基于自主研发的二冲程低压半直喷航空发动机及控制系统,开展喷油控制策略及对发动机性能影响规律的研究。结果表明:对于不同的发动机运行工况,需要采取不同的喷油策略组合。在起动和怠速工况,采用进气道喷射的独立供油方式;在部分负荷及高负荷工况,采用进气道喷射和缸内直喷协同供油方式,随着发动机直喷比例的提高,燃油消耗率相应减小;与采用进气道喷射供油相比较,采用低压半直喷供油可以获得较理想的燃油经济性。

动态气门运行特性及二冲程制动性能耦合研究

基于自主研发的变模式气门驱动装置,进行发动机和该气门驱动装置联合仿真,研究了二者的强耦合运行特性,为该装置的装机应用提供理论依据.研究结果表明:缸内压力和气门运行之间的强耦合关系在上止点附近排气门运行阶段尤为明显,尤其是在2300 r/min以下,发动机转速越高,气门动态升程损失程度越大,最大缸内压力越高;高于该转速后,二者变化程度逐渐减小;排气制动凸轮在上止点后设置过渡升程可消除排气门反跳的问题,并且可进一步改善制动功率和最大缸内压力之间的矛盾关系;与理想四冲程制动相比,二冲程制动的制动功率明显增加,最大缸内压力明显降低,发动机转速分别为1600、1900和2400 r/min时,实际二冲程制动功率分别提高了35.94%、45.61%和27.54%,最大缸内压力分别降低了45.42%、27.20%和7.35%.

压燃式二冲程对置活塞转盘发动机一维性能仿真

二冲程对置活塞转盘(2S-OPCP)发动机是一种新型发动机.该发动机使用凸轮转盘机构替代了传统发动机中的曲柄连杆机构,这种特殊的结构使转盘发动机具有功率密度高、体积小和结构简单等优点.发动机两侧的凸轮转盘存在相对转角,通过改变凸轮相对转角θ可以改变发动机的有效压缩比及换气正时,从而影响发动机的性能.根据转盘发动机的结构特点及工作过程搭建了一维热力学仿真模型,并使用试验数据对模型的缸内压力曲线进行了标定.随着θ改变,发动机的扫气过程及性能表现都会发生变化.当θ在0°~10°内变化时,发动机的换气过程有所改善,给气比在θ=7°时最高,提升了3.5%.同时,在θ达到4°后,指示燃油消耗率(ISFC)开始逐渐增加,ISFC最高增加了3.5%(θ=10°);而平均有效压力(IMEP)最高增加了3.3%(θ=4°),之后随着θ的上升,IMEP开始降低.

干细胞来源的细胞外囊泡治疗急性缺血性卒中的研究进展

急性缺血性卒中(AIS)具有致残率高、病死率高、复发率高的特点。基于细胞外囊泡的无细胞疗法,尤其是干细胞来源的细胞外囊泡(SC-EVs),由于具有与干细胞相似的再生能力及优于干细胞的血脑屏障穿透力和低免疫原性,为AIS的治疗提供了新的视角。本文将对SC-EVs治疗AIS的作用机制和临床研究进展作一述评,以期为AIS的治疗提供新的思路。

环境背压和喷射压力对航空重油空气辅助喷射喷雾特性影响

单一重油燃料的战场作战要求使航空重油活塞发动机的研发提升到一个新的高度。本文基于点燃式四冲程航空重油活塞发动机的空气辅助喷射技术,重点研究了环境背压和喷射压力对喷雾宏观形态发展和喷雾微观粒径分布的影响。结果表明,喷雾横向贯穿距和纵向贯穿距与环境背压成反比,且呈两个阶段的发展趋势,第一阶段横向和纵向贯穿距呈线性增加;第二阶段的贯穿距增加速度放缓。喷雾纵向贯穿距随喷射压力升高而增加,不同喷射压力的喷雾锥角均是先急速增加到一定值后开始回落,慢慢趋于稳定。随环境背压的降低和喷射压力的升高,小粒径的波峰逐渐增加,大粒径的波峰逐渐降低。不同喷射压力的喷雾粒径相对频率分布趋势均呈双峰分布。