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Inflammasome links traumatic brain injury, 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 juan Pablo de Rivero Vaccari jennifer C.Munoz Pareja 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 Project 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 injury, 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 injury, 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 injury, 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 injury, 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 injury

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

Iodoacetic acid exposure alters the transcriptome in mouse ovarian antral follicles

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journal of Environmental Sciences 2022年第7期34卷 46-57页

作者： Andressa Gonsioroski Mary laws Vasiliki E.Mourikes Alison Neff jenny Drnevich Michael j.Plewa jodi A.Flaws Department of Comparative Biosciences University of Illinois Urbana-ChampaignUrbanaIllinois 61801USA Roy j.Carver Biotechnology Center University of Illinois Urbana-ChampaignUrbanaIllinois 61801USA Department of Crop Sciences and the Safe Global Water Institute University of Illinois Urbana-ChampaignUrbanaIllinois 61801USA

Iodoacetic acid(IAA) is an unregulated water disinfection byproduct that is an ovarian toxicant. However, the mechanisms of action underlying IAA toxicity in ovarian follicles remain unclear. Thus, we determined whether IAA alters gene expression in ovarian follicles in mice. Adult female mice were dosed with water or IAA(10 or 500 mg/L) in the water for 35-40 days. Antral follicles were collected for RNA-sequencing analysis and sera were collected to measure estradiol. RNA-sequencing analysis identified 1063 differentially expressed genes(DEGs) in the 10 and 500 mg/L IAA groups(false discovery rate FDR < 0.1), respectively, compared to controls. Gene Ontology Enrichment analysis showed that DEGs were involved with RNA processing and regulation of angiogenesis(10 mg/L) and the cell cycle and cell division(500 mg/L). Pathway Enrichment analysis showed that DEGs were involved in the phosphatidylinositol 3-kinase and protein kinase B(PI3K-Akt), gonadotropin-releasing hormone(Gn RH), estrogen, and insulin signaling pathways(10 mg/L). Pathway Enrichment analysis showed that DEGs were involved in the oocyte meiosis, Gn RH, and oxytocin signaling pathways(500 mg/L). RNA-sequencing analysis identified 809 DEGs when comparing the 500 and 10 mg/L IAA groups(FDR < 0.1). DEGs were related to ribosome, translation, m RNA processing, oxidative phosphorylation, chromosome, cell cycle, cell division, protein folding, and the oxytocin signaling pathway. Moreover, IAA exposure significantly decreased estradiol levels(500 mg/L) compared to control. This study identified key candidate genes and pathways involved in IAA toxicity and can help to further understand the molecular mechanisms of IAA toxicity in ovarian follicles.

关键词： Disinfection byproducts Iodoacetic acid Ovary Ovarian follicles Steroidogenesis Endocrine disruptors

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 subjected 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 objective 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

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 jamming 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 major force transmission network contains fewer mechanically stable particles and a less stable force transmission *** causes jamming of the granular assembly at a lower solid *** force transmission networks,however,are fragile and disintegrate quickly upon relaxation.

关键词： jamming transition jamming density Strain rate dependency Boundary effects

Sensory sacrifices when we mass-produce mass produce

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Horticulture Research 2016年第1期3卷 167-172页

作者： kevin M Folta Harry j Klee Horticultural Sciences Department Plant Innovation Center and The Graduate Program for Plant Molecular and Cellular BiologyUniversity of FloridaGainesville32606FLUSA

Plant breeders have been extremely successful at driving genetic improvements in ***,‘improvements’are truly a question of *** the last one-hundred years most plant genetic innovations have been driven by industry *** fruits,heavier yields,uniformity,increased resistance to disease and better shipping quality are just a few of the traits that have ensured profits on the farm and affordable food for ***,these milestones have come at the expense of sensory qualities,which have been sacrificed in exchange for practical production *** a base of industry-sufficient genetics,today’s breeders can now turn to the consumer for guidance in defining critical *** approaches to plant breeding start with the analysis of consumer preferences,and then merge them with modern genomics and analytical chemistry *** result is the next generation of crops that meet supply chain demands while presenting improvements in flavor,nutrition,color,aroma and *** review analyzes the approach of consumer-assisted selection as it has been applied to tomato and strawberry,two complementary annual crops that have been intensively bred to meet industry *** breeding efforts start with the consumer,with the objective of reclaiming lost sensory qualities.

关键词： crops breeding driving

The effects of sun exposure on carotenoid accumulation and oxidative stress in the retina of the House Finch(Haemorhous mexicanus)

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Chinese Birds 2016年第1期7卷 56-67页

作者： Matthew B.Toomey kevin j.McGraw School of Life Sciences Arizona State University Department of Pathology and Immunology Washington University Medical School

Background: Diet-derived carotenoid pigments are concentrated in the retinas of birds and serve a variety of functions, including photoprotection. In domesticated bird species(e.g., chickens and quail), retinal carotenoid pigmentation has been shown to respond to large manipulations in light exposure and provide protection against photodamage. However, it is not known if or how wild birds respond to ecologically relevant variation in sun ***: We manipulated the duration of natural sunlight exposure and dietary carotenoid levels in wild-caught captive House Finches(Haemorhous mexicanus), then measured carotenoid accumulation and oxidative stress in the ***: We found no significant effects of sun exposure on retinal levels of carotenoids or lipid peroxidation, in replicate experiments, in winter(jan–Mar) and spring/summer(May–june). Dietary carotenoid supplementation in the spring/summer experiment led to significantly higher retinal carotenoid levels, but did not affect lipid peroxidation. Carotenoid levels differed significantly between the winter and spring/summer experiments, with higher retinal and lower plasma carotenoid levels in birds from the later ***: Our results suggest that variation in the duration of exposure to direct sunlight have limited influence on intraspecific variation in retinal carotenoid accumulation, but that accumulation may track other seasonal–environmental cues and physiological processes.

关键词： Carotenoids Haemorhous mexicanus House Finch Photostress Vision

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

Overcoming the limitations of gallium oxide through heterogeneous integration

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Science China(Physics,Mechanics & Astronomy) 2021年第1期64卷 118-119页

作者： Yuhao Zhang kevin jChen Center for Power Electronics Systems Virginia Polytechnic and State UniversityBlacksburgVA24060USA Departmnet of Electronic and Computer Engineering The Hong Kong University of Science and TechnologyHong KongChina

Power electronics,processing over 50%of world's electric energy,enables very efficient electric energy conversion for a wide range of applications such as electric vehicles,data centers,autonomous driving,robotics and smart *** availability of low-cost,efficient,and reliable power semiconductor devices that can conduct high current,block high voltage,and switch at high frequencies are key to improving the performance of power electronics systems.

关键词： integration enable autonomous