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Polyplex interaction strength as a driver of potency during cancer immunotherapy

Nano Research 2018年第10期11卷 5642-5656页

作者： Shannon d. Tsai james I. Andorko Xiangbin Zeng Joshua m. Gammon Christopher m. dewell Fischell Department of Bioengineering University of Marylond 8278 Paint Branch Drive College Park MD 20742 USA Robert E. Fischell Institute for Biomedicol Devices University of Maryland 8278 Paint Branch Drive College Park MD 20742 USA United States Department of Veterans Affairs Maryland VA Health Care System 10 North Greene Street Baltimore MD 21201 USA Deportment of microbiology and Immunology University of Maryland Medical School 685 West Baltimore Street Baltimore MD 21201 USA marlene and Stewart Greenebaum Cancer Center 22 South Greene Street Baltimore MD 21201 USA

many experimental cancer vaccines are exploring toll-like receptor agonists （TLRas） such as CpG, a DNA motif that agonizes toll-like receptor 9 （TLR9）, to trigger immune responses that are potent and molecularly-specific. The ability to tune the immune response is especially important in the immunosuppressive microenvironments of tumors. Because TLR9 is located intracellularly, CpG must be internalized by immune cells for functionality. Polyplexes can be self- assembled through electrostatics using DNA （anionic） condensed by a positively charged carrier. These structures improve cell delivery and have been widely explored for gene therapy. In contrast, here we use cationic poly （^-amino esters）（PBAEs） to assemble polyplexes from CpG as an adjuvant to target and improve immune stimulation in cells and mouse models. Polyplexes were formed over a range of PBAE：CpG ratios, resulting in a library of complexes with increasingly positive charge and stronger binding as PBAE：CpG ratio increased. Although higher PBAE：CpG ratios exhibited improved CpG uptake, lower ratios of PBAE：CpG--which condensed CpG more weakly, activated DCs and tumorspecific T cells more effectively. In a mouse melanoma model, polyplexes with lower binding affinities improved survival more effectively compared with higher binding affinities. These data demonstrate that altering the polyplex interaction strength impacts accessibility of CpG to TLRs in immune cells. Thus, physiochemical properties, particularly the interplay between charge, uptake, and affinity, play a key role in determining the nature and efficacy of the immune response generated. This insight identifies new design considerations that must be balanced for engineering effective immunotherapies and vaccines.

关键词： cancer immunotherapy nanoparticle vaccine polyplex

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A model reference adaptive control based method for actuator delay estimation in real-time testing

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Frontiers of Structural and Civil Engineering 2010年第3期4卷 277-286页

作者： Cheng CHEN james m.RICLES School of Engineering San Francisco State UniversitySan FranciscoCA 94132USA ATLSS Engineering Research Center Lehigh UniversityBethlehemPA 18015USA

Real-time testing provides a viable experimental technique to evaluate the performance of structural systems subjected to dynamic ***-hydraulic actuators are often utilized to apply calculated displacements from an integration algorithm to the experimental structures in a real-time *** compensation of actuator delay is therefore critical to achieve stable and reliable experimental *** advances in compensation methods based on adaptive control theory enable researchers to accommodate variable actuator delay and achieve good actuator control for real-time ***,these adaptive methods all require time duration for actuator delay *** show that a good actuator delay estimate can help optimize the performance of the adaptive compensation *** rate of adaptation also requires that a good actuator delay estimate be acquired especially for the tests where the peak structural response might occur at the beginning of the *** paper presents a model reference adaptive control based method to identify the parameter of a simplified discrete model for servo-hydraulic dynamics and the resulting compensation *** are conducted using both numerical analysis and experimental results to evaluate the effectiveness of the proposed estimation method.

关键词： real-time testing actuator delay compensation adaptive control mIT rule discrete transfer function

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基于CJP模型的疲劳裂纹扩展率曲线及应用方法

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机械工程学报 2018年第18期54卷 76-84页

作者：杨冰 james m N 西南交通大学牵引动力国家重点试验室成都610031 普利茅斯大学工程学院英国普利茅斯PL4 8AA

利用数字图像相关技术开展工业纯钛5种不同高宽比CT试样的疲劳裂纹扩展率试验,分别采用传统应力强度因子范围ΔK和基于CJP模型理论框架的新应力强度因子范围ΔKCJP对数据进行分析,得到的da/d N-ΔK和da/d N-ΔKCJP曲线均有效反映了试验... 详细信息

利用数字图像相关技术开展工业纯钛5种不同高宽比CT试样的疲劳裂纹扩展率试验,分别采用传统应力强度因子范围ΔK和基于CJP模型理论框架的新应力强度因子范围ΔKCJP对数据进行分析,得到的da/d N-ΔK和da/d N-ΔKCJP曲线均有效反映了试验数据分布规律,具有良好的拟合效果。相较于传统参量ΔK,ΔKCJP直接由裂尖位移场求解,无需进行修正即可用于材料疲劳裂纹扩展率描述,具有与CT试样高宽比无关的特性;作为ΔKCJP的两个组成参量,ΔKF、ΔKR与传统ΔK数据间均呈现出某种总体变化趋势,分别可用二次多项式和线性方程表征。构造了ΔKCJP与ΔK的关联函数,并由此推导出ΔKCJP表达式,为da/d N-ΔKCJP曲线在材料与结构的失效分析和安全评价中的应用提供了有效途径,拓宽了CJP模型的工程应用范围。

关键词： CJP模型裂尖位移场数字图像相关裂纹扩展率工业纯钛

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Improving estimates of waning immunity rates in stochastic SIRS models with a hierarchical framework

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Infectious Disease modelling 2023年第4期8卷 1127-1137页

作者： Punya Alahakoon james m.mcCaw Peter GTaylor School of mathematics and Statistics The University of MelbourneMelbourneAustralia Centre for Epidemiology and Biostatistics Melbourne School of Population and Global HealthThe University of MelbourneMelbourneAustralia School of Population Health University of New South WalesSydneyAustralia Kirby Institute University of New South WalesSydneyAustralia

As most disease causing pathogens require transmission from an infectious individual to a susceptible individual,continued persistence of the pathogen within the population requires the replenishment of susceptibles through births,immigration,or waning *** the introduction of an unknown infectious disease into a fully susceptible population where it is not known how long immunity is conferred once an individual recovers from ***,initially,the prevalence of disease increases(that is,the infection takes off),the number of infectives will usually decrease to a low level after the first major *** this post-outbreak period,the disease dynamics may be influenced by stochastic effects and there is a non-zero probability that the epidemic will die *** out in this period following the first major outbreak is known as an epidemic *** the disease does not die out,the susceptible population may be replenished by the waning of immunity,and a second wave may *** this study,we investigate if the rate of waning immunity(and other epidemiological parameters)can be reliably estimated from multiple outbreak data,in which some outbreaks display epidemic fade-out and others do *** generated synthetic outbreak data from independent simulations of stochastic SIRS models in multiple *** outbreaks faded-out and some did *** conducted Bayesian parameter estimation under two alternative approaches:independently on each outbreak and under a hierarchical *** conducting independent estimation,the waning immunity rate was poorly estimated and biased towards zero when an epidemic fade-out was ***,under a hierarchical approach,we obtained more accurate and precise posterior estimates for the rate of waning immunity and other epidemiological *** greatest improvement in estimates was obtained for those communities in which epidemic fade-out was observed.

关键词： estimates stochastic estimation

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Acute worsening of microvascular complications of diabetes mellitus during rapid glycemic control:The pathobiology and therapeutic implications

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World Journal of Diabetes 2024年第3期15卷 311-317页

作者： Dania Blaibel Cornelius james Fernandez Joseph m Pappachan Department of Endocrinology and metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Department of Endocrinology and metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine and HealthThe University of ManchesterManchester M139PLUnited Kingdom

While chronic hyperglycaemia resulting from poorly controlled diabetes mellitus(Dm)is a well-known precursor to complications such as diabetic retinopathy,neuropathy(including autonomic neuropathy),and nephropathy,a paradoxical intensification of these complications can rarely occur with aggressive glycemic management resulting in a rapid reduction of glycated ***,acute onset or worsening of retinopathy and treatment induced neuropathy of diabetes are more common among these complications,rarely other problems such as albuminuria,diabetic kidney disease,Charcot’s neuroarthropathy,gastroparesis,and urinary bladder dysfunction are also *** World Journal of Diabetes recently published a rare case of all these complications,occurring in a young type 1 diabetic female intensely managed during pregnancy,as a case report by Huret et *** is essential to have a comprehensive understanding of the pathobiology,prevalence,predisposing factors,and management strategies for acute onset,or worsening of microvascular complications when rapid glycemic control is achieved,which serves to alleviate patient morbidity,enhance disease management compliance,and possibly to avoid medico-legal issues around this rare clinical *** editorial delves into the dynamics surrounding the acute exacerbation of microvascular complications in poorly controlled Dm during rapid glycaemic control.

关键词： Diabetes mellitus microvascular complications Diabetic retinopathy Treatment induced neuropathy of diabetes Diabetic nephropathy Charcot’s neuropathy

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Combustion analysis of a hydrogen-diesel fuel operated DI diesel engine with exhaust gas recirculation

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Frontiers in Energy 2017年第4期11卷 568-574页

作者： m. LOGANATHAN A. VELmURUGAN TOm PAGE E. james GUNASEKARAN P. TAmILARASAN Department of mechanical Engineering Annamalai University Anna- malainagar 608002 India Product Design and manufacturing Loughborough University Lough- borough LE11 3TU United Kingdom

The rapid depletion of fossil fuel and growing demand necessitates researchers to find alternative fuels which are clean and sustainable. The need for finding renewable, low cost and environmentally friendly fuel resources can never be understated. An efficient method of generation and storage of hydrogen will enable automotive manufacturers to introduce hydrogen fuelled engine in the market. In this paper, a conventional DI diesel engine was modified to operate as gas engine. The intake manifold of the engine was supplied with hydrogen along with recirculated exhaust gas and air. The injection rates of hydrogen were maintained at three levels with 2 L/min, 4 L/min, 6 L/min and 8 L/min and 10 L/min with an injection pressure of 2 bar. many of the combustion parameters like heat release rate （HRR）, ignition delay, combustion duration, rate of pressure rise （ROPR）, cumulative heat release rate （CHR）, and cyclic pressure fluctuations were measured. The HRR peak pressure decreased with the increase in EGR rate, while combustion duration increased with the EGR rate. The cyclic pressure variation also increased with the increase in EGR rate.

关键词： hydrogen exhaust gas recirculation (EGR),diesel combustion heat release rate (HRR) combustionduration

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Diabetic cardiomyopathy:Emerging therapeutic options

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World Journal of Diabetes 2024年第8期15卷 1677-1682页

作者： Cornelius james Fernandez Sahana Shetty Joseph m Pappachan Department of Endocrinology&metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom Department of Endocrinology Kasturba Medical CollegeManipal Academy of Higher EducationManipal 576104KarnatakaIndia Department of Endocrinology and metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine and HealthThe University of ManchesterManchester M139PLUnited Kingdom

Diabetic cardiomyopathy(DbCm)is a common but underrecognized complication of patients with diabetes mellitus(Dm).Although the pathobiology of other cardiac complications of diabetes such as ischemic heart disease and cardiac autonomic neuropathy are mostly known with reasonable therapeutic options,the mechanisms and management options for DbCm are still not fully *** its early stages,DbCm presents with diastolic dysfunction followed by heart failure(HF)with preserved ejection fraction that can progress to systolic dysfunction and HF with reduced ejection fraction in its advanced stages unless appropriately *** from prompt control of Dm with lifestyle changes and antidiabetic medications,disease-modifying therapy for DbCm includes prompt control of hypertension and dyslipidemia inherent to patients with Dm as in other forms of heart diseases and the use of treatments with proven efficacy in HF.A basic study by Zhang et al,in a recent issue of the World Journal of Diabetes elaborates the potential pathophysiological alterations and the therapeutic role of teneligliptin in diabetic mouse models with *** this preliminary basic study might help to improve our understanding of DbCm and offer a potential new management option for patients with the disease,the positive results from such animal models might not always translate to clinical practice as the pathobiology of DbCm in humans could be ***,such experimental studies can encourage more scientific efforts to find a better solution to treat patients with this enigmatic disease.

关键词： Diabetic cardiomyopathy Diabetic cardiomyopathy Heart failure Pathobiology Teneligliptin

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Non-pharmacological interventions for diabetic peripheral neuropathy:Are we winning the battle?

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World Journal of Diabetes 2024年第4期15卷 579-585页

作者： Dania Blaibel Cornelius james Fernandez Joseph m Pappachan Department of Endocrinology and metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Department of Endocrinology&metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine&HealthThe University of ManchesterManchester M139PLUnited Kingdom

Despite the advent of relatively reliable modalities of diagnosing diabetic peripheral neuropathy(DPN),such as nerve conduction studies,there is still a knowledge gap about the pathophysiology,and thus limited available in-terventions for symptom control and curtailing disease *** pharma-cologic aspect of management is mainly centred on pain control,however,there are several important aspects of DPN such as loss of vibration sense,pressure sense,and proprioception which are associated with risks to lower limb health,which pharmacotherapy does not ***,published evidence suggests non-pharmacologic interventions such as glycaemic control through dietary modification and exercise need to be combined with other measures such as psychotherapy,to reach a desired,however modest *** is emerging as an important treatment modality for several chronic medical conditions including neuropathic and other pain *** their study published in the World Journal of Diabetes on the potential of acupuncture to reduce DPN symptoms and enhance nerve conduction parameters,Hoerder et al have been able to demonstrate that acupuncture improves sensory function and that this effect is likely sustained two months after treatment *** previous studies also support these findings,larger multi-center randomized control trials including a sham-controlled arm accounting for a placebo effect are ***,given the satisfactory safety profile and the positive results found in these studies,it is likely that acupuncture may become an important aspect of the repertoire of effective DPN management.

关键词： Diabetic peripheral neuropathy Diabetes mellitus Pharmacotherapy Acupuncture Neuropathic pain Nonpharmacological intervention

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Diabetes and tuberculosis:An emerging dual threat to healthcare

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World Journal of Diabetes 2024年第7期15卷 1409-1416页

作者： Sahana Shetty Joseph m Pappachan Cornelius james Fernandez Department of Endocrinology Kasturba Medical CollegeManipalManipal Academy of Higher EducationManipal 576104KarnatakaIndia Department of Endocrinology and metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine and HealthThe University of ManchesterManchester M139PLUnited Kingdom Department of Endocrinology&metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom

Tuberculosis(TB)remains a huge global healthcare challenge even in the 21^(st) century though the prevalence has dropped in developed countries in recent *** mellitus(Dm)is an important risk factor for the development and perpetuation of TB owing to the immune dysfunction in patients with *** coexistence of both diseases in the same individual also aggravates disease severity,complications,and chance of treatment failure because of gross immune alterations posed by Dm as well as *** complex cellular and humoral immunological factors are involved in the dangerous interaction between TB and Dm,some of which remain unknown even *** is highly important to identify the risk factors for TB in patients with Dm,and vice versa,to ensure early diagnosis and management to prevent complications from this ominous *** their research study published in the recent issue of the World Journal of Diabetes,Shi et al elaborate on the factors associated with the development of TB in a large cohort of Dm patients from *** such research output from different regions of the world is expected to improve our knowledge to fight the health devastation posed by TB in patients with diabetes.

关键词： Tuberculosis Diabetes mellitus Immune dysfunction Treatment failure multi-drug resistant tuberculosis

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The development of a high-performance Ni-superalloy additively manufactured heat pipe

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Advances in manufacturing 2022年第4期10卷 610-624页

作者： Sheng Li Khamis Essa james Carr States Chiwanga Andrew Norton moataz m.Attallah School of Electromechanical Engineering Guangdong University of TechnologyGuangzhou 510006People’s Republic of China School of Engineering University of BirminghamEdgbastonBirmingham B152TTUK Henry moseley X-ray Imaging Facility Henry Royce Institute for Advanced MaterialsDepartment of MaterialsUniversity of ManchesterManchester M139PLUK European Thermodynamics Ltd 8 Priory Business ParkWistow RoadKibworthLeicestershire LE80RXUK Rolls-Royce plc P.O.Box 31Derby DE248BJUK School of metallurgy and materials University of BirminghamEdgbastonBirmingham B152TTUK

Additively manufacturing(Am)has been used to manufacture fine structures with structured/engineered porosity in heat management *** this study,laser powder bed fusion(LPBF)was used to manufacture a high-performance Ni-superalloy heat pipe,through tailoring LPBF process parameters to fabricate thin wall and *** using novel laser scanning strategies,wick structure heat pipes with maximised surface-area-to-volume ratio,fine features size around 100µm,and controlled porosity were successfully *** and X-ray microtomography(micro-CT)were used to investigate the 3D structure of the void space within the *** test results showed that most of the heat pipes made by LPBF had better performance than the conventionally manufactured *** study also investigated the influences of the process parameters on the porosity volume fraction and the feature *** results showed that LPBF process could fabricate thin structure due to the change of melt pool contact *** relationship between process parameters and bead size reported in this study could help design and manufacture heat pipe with complex fine structure.

关键词： Laser powder bed fusion(LPBF) Heat pipe melt pool microtomography(micro-CT)

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