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A Cell-Penetrating Peptide for Inhibiting MAPKAP Kinase 2-Mediated Inflammatory Cytokine Release Following Glial Cell Activation

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World j.urnal of Neuroscience 2015年第2期5卷 115-130页

作者： j.mes R. Wodicka Nnadozie I. Onunkwo Andrew j. Woolley Alyssa Panitch kevin j. otto Weldon School of Biomedical Engineering Purdue University West Lafayette USA Indiana University School of Medicine Indianapolis USA Department of Biological Sciences Purdue University West Lafayette USA Department of Biomedical Engineering University of Florida Gainesville USA

Central nervous system (CNS) inj.ry initializes a reactive tissue response, which is characterized by a cascade of signals that result in inflammatory cytokine release and neuroinflammation. These signals are induced in part by activated microglia that migrates to the inj.ry site in an attempt to remove dead tissue and promote healing. The ability to control the reactive tissue response is of significant importance to a variety of applications, such as neuroprostheses, whose functional lifespan is limited by glial cell activation. A possible strategy to mitigate glial cell activation is to reduce the release of inflammatory cytokines following a brain inj.ry. One pathway that facilitates inflammatory cytokine release is the mitogen-activated protein kinase-activated protein kinase 2 (MK2) pathway, which increases cytokine mRNA synthesis, stability and translation following activation. Therefore, inhibiting MK2-mediated cytokine release can reduce microglial activationfollowing CNS inj.ry. Through?in vitro?studies, we demonstrate the ability of a cell-penetrating peptide inhibitor of MK2 (MK2i) to reduce MK2-mediated cytokine release in mixed cortical cultures.?Immunocytochemistry, enzyme-linked immunosorbent assay (ELISA), and cytotoxicity assays in 7- -10-day-old E17 Sprague-Dawley rat mixed cortical cultures showed that MK2i treatment significantly lowered inflammatory cytokine production and increased cortical cell viability following?glial cell activation with tumor necrosis factor-α(TNF-α) and lipopolysaccharide (LPS). Results suggest that MK2i may reduce damage caused by activated glia in the inflamed CNS.

关键词： Inj.ry Mitigation Treatment Drug MK2i

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Inflammasome links traumatic brain inj.ry, chronic traumatic encephalopathy, and Alzheimer's disease

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Neural Regeneration Research 2025年第6期20卷 1644-1664页

作者： Gabriela Seplovich Yazan Bouchi j.an Pablo de Rivero Vaccari j.nnifer C.Munoz Parej. Andrew Reisner Laura Blackwell Yehia Mechref kevin K.Wang j.Adrian Tyndall Binu Tharakan Firas Kobeissy Department of Surgery Morehouse School of MedicineAtlantaGAUSA Department of Neurobiology Center for NeurotraumaMultiomics&Biomarkers(CNMB)Neuroscience InstituteMorehouse School of MedicineAtlantaGAUSA Department of Neurological Surgery and the Miami Proj.ct to Cure Paralysis University of Miami Miller School of MedicineMiamiFLUSA Division of Pediatric Critical Care Department of PediatricsUniversity of Miami Miller School of MedicineMiamiFLUSA Department of Pediatrics Emory UniversityAtlantaGAUSA Department of Neurosurgery Children’s Healthcare of AtlantaAtlantaGAUSA Department of Chemistry and Biochemistry Texas Tech UniversityLubbockTXUSA Morehouse School of Medicine AtlantaGAUSA

Traumatic brain inj.ry, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain inj.ry, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain inj.ry, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain inj.ry, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

关键词： Alzheimer's disease caspase-1 chronic traumatic encephalopathy inflammasomes neurodegeneration neuroinflammation NLRP1 NLRP3 pyroptosis tauopathy traumatic brain inj.ry

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FEARCF a multidimensional free energy method for investigating conformational landscapes and chemical reaction mechanisms

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Science China Chemistry 2011年第12期54卷 1962-1973页

作者： NAIDOO kevin j. Scientific Computing Research Unit and Department of Chemistry University of Cape Town

The development and implementation of a computational method able to produce free energies in multiple dimensions,descriptively named the free energies from adaptive reaction coordinate forces(FEARCF) method is described in this *** the method can be used to calculate free energies of association,conformation and reactivity here it is shown in the context of chemical reaction landscapes.A reaction free energy surface for the Claisen rearrangement of chorismate to prephenate is used as an illustration of the method's efficient *** simulations are shown to achieve flat histograms for complex multidimensional free energy *** sampling efficiency by which it produces multidimensional free energies is demonstrated on the complex puckering of a pyranose ring,that is described by a three dimensional W(θ1,θ2,θ3) potential of mean force.

关键词： free energy calculations reaction dynamics reaction surfaces multidimensional free energy surfaces

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FEARCF a multidimensional free energy method for investigating conformational landscapes and chemical reaction mechanisms

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中国科学：化学 2012年第1期42卷 119-120页

作者： NAIDOO kevin j. Scientific Computing Research Unit and Department of Chemistry. University of Cape Town. South Africa 7701

关键词：化学反应机理自由能景观多维能量法适应性反应反应势能面采样效率

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Implementation of rotational resistance models＇ A critical appraisal

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Particuology 2017年第5期15卷 14-23页

作者： Xin Huang kevin j. Hanley Catherine O'Sullivan Chung-Yee Kwok a Department of Geotechnical Engineering Tongji University Shanghai 200092 China Key Laboratory of Geotechnical and Underground Engineering of Ministry of Education Tongji University Shanghai 200092 China Institute for Infrastructure and Environment School of Engineering The University of Edinburgh Edinburgh EH9 3JL United Kingdom Skempton Building Department of Civil and Environmental Engineering Imperial College London London SW72AZ United Kingdom Haking Wong Building Department of Civil and Environmental Engineering The University ofHong Kong Hong Kong China

Contact models that simulate rotational resistance at particle contacts have been proposed as a means to capture the effect of shape in DEM simulations. This contribution critically explores some key issues related to the implementation of rotational resistance models; these include the need for physically meaningful model parameters, the impact of the model on the overall numerical stability/critical time increment for the DEM model, model validation, and the assessment of model performance relative to real physical materials. The discussion is centred around a rotational resistance model that captures the resistance provided by interlocking asperities on the particle surface. An expression for the maximum permissible integration time step to ensure numerical stability is derived for DEM simulations when rotational resistance is incorporated. Analytical solutions for some single-contact scenarios are derived for model validation. The ability of this type of model to provide additional fundamental insight into granular material behaviour is demonstrated using particle-scale analysis of triaxial compression simulations to examine the roles that contact rollin~ and slidin~ have on the stability of stron：~ force chains.

关键词： Granular mediaParticle shapeDiscrete element methodRollingTwistingRotational resistance

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Discrete element modelling of the quasi-static uniaxial compression of individual infant formula agglomerates

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Particuology 2012年第5期10卷 523-531页

作者： kevin j.Hanley Catherine O'Sullivan Edmond P.Byrne kevin Cronin Department of Process and Chemical Engineering University College CorkCorkIreland Department of Civil and Environmental Engineering Skempton BuildingImperial College LondonLondon SW7 2AZ United Kingdom

Infant formula is usually produced in an agglomerated powder form. These agglomerates are subj.cted to many transient forces following their manufacture. These can be difficult to quantify experimentally because of their small magnitudes and short durations, Numerical models have the potential to address this gap in the experimental data. The obj.ctive of the research described here was to calibrate a discrete element model for these agglomerates using experimental data obtained for quasi-static loading, and to use this model to study the mechanics of the particle response in detail. The Taguchi method was previously proposed as a viable calibration approach for discrete element models. In this work, the method was assessed for calibration of the model parameters （e.g., bond stiffnesses and strengths） considering three responses： the force at failure, strain at failure and agglomerate stiffness. The Weibull moduli for the simulation results and the experimental data were almost identical following calibration and the 37% characteristic stresses were similar. An analysis of the energy terms in the model provided useful insight into the model response. The bond energy and the normal force exerted on the platens were strongly correlated, and bond breakage events coincided with the highest energy dissipation rates.

关键词： Discrete element modellingUniaxial compressionQuasi-static crushingSimulationGranular materialsTaguchi methods

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The organization of societal conflicts by pavement ants Tetramorium caespitum： an agent-based model of amine-mediated decision making

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Current Zoology 2016年第3期62卷 277-284页

作者： kevin M. HOOVER Andrew N. BUBAK Isaac j. LAW j.zmine D. W. YAEGER Kenneth j. RENNER j.hn G. SWALLOW Michael j. GREENE Department of Integrative Biology University of Colorado Denver Denver CO 80217-3364 USA Neuroscience Program University of Colorado Anschutz Medical Campus Aurora CO 80045 USA Department of Biology University of South Dakota Vermillion South Dakota 57069 USA

Ant colonies self-organize to solve complex problems despite the simplicity of an individual ant＇s brain. Pavement ant Tetramorium caespitum colonies must solve the problem of defending the ter- ritory that they patrol in search of energetically rich forage. When members of 2 colonies randomly interact at the territory boundary a decision to fight occurs when： 1） there is a mismatch in nest- mate recognition cues and 2） each ant has a recent history of high interaction rates with nestmate ants. Instead of fighting, some ants will decide to recruit more workers from the nest to the fighting location, and in this way a positive feedback mediates the development of colony wide wars. In ants, the monoamines serotonin （5-HT） and octopamine （OA） modulate many behaviors associated with colony organization and in particular behaviors associated with nestmate recognition and ag- gression. In this article, we develop and explore an agent-based model that conceptualizes how in- dividual changes in brain concentrations of 5-HT and OA, paired with a simple threshold-based de- cision rule, can lead to the development of colony wide warfare. Model simulations do lead to the development of warfare with 91% of ants fighting at the end of 1 h. When conducting a sensitivity analysis, we determined that uncertainty in monoamine concentration signal decay influences the behavior of the model more than uncertainty in the decision-making rule or density. We conclude that pavement ant behavior is consistent with the detection of interaction rate through a single timed interval rather than integration of multiple interactions.

关键词： agent-based model aggressive behavior ants decision making monoamines octopamine serotonin.

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The parallel-plate resonator:An RF probe for MR and MRI studies over a wide frequency range

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Magnetic Resonance Letters 2023年第4期3卷 306-318页

作者： Andres Ramírez Aguilera kevin j.Sanders Gillian R.Goward Bruce *** UNB MRI Centre Department of PhysicsUniversity of New BrunswickFrederictonNew BrunswickE3B 5A3Canada Department of Chemistry McMaster UniversityHamiltonOntarioL8S 4L8Canada

We explore the use of the parallel-plate resonator for the study of thin cuboid samples over a wide range of magnetic resonance *** parallel-plate resonator functions at frequencies from tens to hundreds of *** parallel-plate resonators are presented and discussed in a frequency range from 8 to 500 *** resonance experiments were performed on both horizontal and vertical bore magnet systems with lithium and hydrogen ***-plate radiofrequency(RF)probes are easy to build and easy to *** and simulations showed good sensitivity of the parallel-plate RF probe geometry with a small decrease in sensitivity at higher frequencies.

关键词： Parallel-plate resonator Optimization Magnetic resonance/magnetic resonance imaging(MR/MRI) Batteries

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Environment-dependent attack rates of cryptic and aposematic butterflies

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Current Zoology 2018年第5期64卷 663-669页

作者： Brett M. SEYMOURE Andrew RAYMUNDO kevin j. MCGRAW W. OWEN MCMILLAN Ronald L, RUTOWSKI Department of Biology Colorado State University Fort Collins CO 80523 USA School of Life Sciences Arizona State University Tempe AZ 85287 USA Smithsonian Tropical Research Institute Panama City Panama

Many organisms have evolved adaptive coloration that reduces their risk of predation. Cryptic colo- ration reduces the likelihood of detection/recognition by potential predators, while warning or aposematic coloration advertises unprofitability and thereby reduces the likelihood of attack. Although some studies show that aposematic coloration functions better at decreasing attack rate than crypsis, recent work has suggested and demonstrated that crypsis and aposematism are both successful strategies for avoiding predation. Furthermore, the visual environment （e.g., ambient lighting, background） affects the ability for predators to detect prey. We investigated these 2 related hypoth- eses using 2 well-known visually aposematic species of Heliconius butterflies, which occupy differ- ent habitats （open-canopy vs. closed-canopy）, and one palatable, cryptic, generalist species j.nonia coenia. We tested if the differently colored butterflies differ in attack rates by placing plasti- cine models of each of the 3 species in 2 different tropical habitats where the butterflies naturally occur： disturbed, open-canopy habitat and forested, closed-canopy habitat. The cryptic model had fewer attacks than one of the aposematic models. Predation rates differed between the 2 habitats, with the open habitat having much higher predation. However, we did not find an interaction between species and habitat type, which is perplexing due to the different aposematic phenotypes naturally occurring in different habitats. Our findings suggest that during the Panamanian dry sea- son avian predation on perched butterflies is not a leading cause in habitat segregation between the 2 aposematic species and demonstrate that cryptically colored animals at rest may be better than aposematic prey at avoiding avian attacks in certain environments.

关键词： avian attacks camouflage Heliconius j.nonia light environment plasticine models predation warning coloration.

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Non-uniqueness of critical solid fraction considering boundary conditions and strain-rate effects

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Particuology 2021年第1期19卷 37-49页

作者： Mingze Xu Zixin Zhang Xin Huang kevin j.Hanley Department of Geotechnical Engineering Tongji UniversityShanghai 200092China State Key Laboratory of Geotechnical Engineering Ministry of EducationTongji UniversityShanghai 200092China School of Engineering Institute for Infrastructure and EnvironmentThe University of EdinburghEdinburgh EH93JLUnited Kingdom

The critical solid fraction(ϕj.,which marks the transition between the solid and liquid phases in the j.mming diagram,is influenced by several *** this study,the dependency ofϕj.on strain rate and boundary conditions is examined through discrete element method simulations considering a frictionless polydisperse granular *** approaches are used to determineϕ*** observed boundary effect is due to the nonuniform solid fraction distribution induced by the clustering of particles close to rigid-wall boundaries at high compression *** solid fraction distribution within the sample in the rigid-wall simulations approaches that in the periodic-boundary simulations as the compression rate *** increasing compression rate,the maj.r force transmission network contains fewer mechanically stable particles and a less stable force transmission *** causes j.mming of the granular assembly at a lower solid *** force transmission networks,however,are fragile and disintegrate quickly upon relaxation.

关键词： j.mming transition j.mming density Strain rate dependency Boundary effects

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