Echoes From Ireland

https://digitalcommons.library.umaine.edu/mmb-vp/1372/thumbnail.jp

Rejuvenation of the Epigenetic Landscape of the Aged Brain Through Manipulation of Circulating Factors

The aging population of the United States is expanding at an alarming rate. The Center for Disease Control and Prevention estimates that the population of those age 65 years and older will reach over 50 million by 2020 and will double to 100 million by 2060. This will not only put a massive strain on national healthcare resources, but will also increase the number of those who are not able to live and function independently. It is becoming increasingly vital to understand how the brain changes with age and mechanisms to possibly protect and rejuvenate the aged brain to a younger, healthier phenotype to promote healthy aging. In this work, we found that there is an increase in the number and amount of pro-inflammatory cytokines in the brain with age, demonstrating that the brain becomes progressively pro-inflammatory with age. Notably, we observed an increase in IFNγ and GM-CSF which are two cytokines implicated in the detrimental priming phenotype of the aged brain. Additionally, we found that the aged brain becomes epigenetically dysregulated, with an increase in Ezh2 function and simultaneous loss of the opposing function of Jmjd3, thereby leading to a respective increase in H3K27me3 and decrease in H3K27me1 in the brain with age. Furthermore, when we examined the role of Ezh2 in primary microglia cultures in vitro, we found that inhibition of Ezh2 could simultaneously abrogate pro-inflammatory polarization and enhance anti-inflammatory polarization. Together, this data suggests that increasing function of Ezh2 may directly contribute to the pro-inflammatory phenotype of the brain with age. We also found that culturing primary microglia with plasma from healthy aged mice resulted in up-regulation of pro-inflammatory cytokines Il1b and Il6 in vitro, suggesting that circulating peripheral factors may directly influence the transition of the brain to a pro-inflammatory phenotype with age. We tested if the age-associated epigenetic dysregulation and pro-inflammatory phenotype could be reversed by utilizing the surgical model of heterochronic parabiosis. In this model, a young and aged animal are surgically attached so that the two come to share a common blood supply. Using young-young and aged-aged isochronic surgical controls, we found that young blood rejuvenates the levels of H3K27me3 to those of a younger animal. Additionally, when we induced a neuroinflammatory response in the heterochronic and aged isochronic parabionts, we found that the neuroinflammatory response of aged heterochronic animals was rejuvenated and reduced compared to aged isochronic controls. This work is the first to investigate the role of epigenetic dysregulation of Ezh2 and Jmjd3 in the brain with age. Additionally, this is the first work to examine the ability of the circulating peripheral immune system to rejuvenate the epigenetic landscape of the aged brain and functional response to a pro-inflammatory stimulus. Future identification of the specific circulating peripheral factor(s) responsible for brain aging and rejuvenation may allow for therapeutic intervention to promote healthy brain aging in older individuals

Solid-state additive manufacturing for metallized optical fiber integration

The formation of smart, Metal Matrix Composite (MMC) structures through the use of solid-state Ultrasonic Additive Manufacturing (UAM) is currently hindered by the fragility of uncoated optical fibers under the required processing conditions. In this work, optical fibers equipped with metallic coatings were fully integrated into solid Aluminum matrices using processing parameter levels not previously possible. The mechanical performance of the resulting manufactured composite structure, as well as the functionality of the integrated fibers, was tested. Optical microscopy, Scanning Electron Microscopy (SEM) and Focused Ion Beam (FIB) analysis were used to characterize the interlaminar and fiber/matrix interfaces whilst mechanical peel testing was used to quantify bond strength. Via the integration of metallized optical fibers it was possible to increase the bond density by 20–22%, increase the composite mechanical strength by 12–29% and create a solid state bond between the metal matrix and fiber coating; whilst maintaining full fiber functionality

Multifunctional metal matrix composites with embedded printed electrical materials fabricated by Ultrasonic Additive Manufacturing

This work proposes a new method for the fabrication of Multifunctional Metal Matrix Composite (MMC) structures featuring embedded printed electrical materials through Ultrasonic Additive Manufacturing (UAM). Printed electrical circuitries combining conductive and insulating materials were directly embedded within the interlaminar region of UAM aluminium matrices to realise previously unachievable multifunctional composites. A specific surface flattening process was developed to eliminate the risk of short circuiting between the metal matrices and printed conductors, and simultaneously reduce the total thickness of the printed circuitry. This acted to improve the integrity of the UAM MMC’s and their resultant mechanical strength. The functionality of embedded printed circuitries was examined via four-point probe measurement. DualBeam Scanning Electron Microscopy (SEM) and Focused Ion Beam (FIB) milling were used to investigate the microstructures of conductive materials to characterize the effect of UAM embedding energy whilst peel testing was used to quantify mechanical strength of MMC structures in combination with optical microscopy. Through this process, fully functioning MMC structures featuring embedded insulating and conductive materials were realised whilst still maintaining high peel resistances of ca. 70 N and linear weld densities of ca. 90%

Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking

Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood–brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease

Being fair and honest

This book examines how lies and cheating hurt people's lives, and stresses the importance of justice and honesty in creating a society that treats people well and provides them with the opportunities they need to succeed. History and current events topics covered include: child labor in the industrial age; drug testing in sports; freedom of speech; honesty of scientific studies; laws to protect the disabled; people who have found and returned large sums of money; Plessy v. Ferguson; racial profiling; the trail of tears; and, why people stea

The Effects of Estrogen in Ischemic Stroke

Stroke is a leading cause of death and the most common cause of long-term disability in the USA. Women have a lower incidence of stroke compared with men throughout most of the lifespan which has been ascribed to protective effects of gonadal steroids, most notably estrogen. Due to the lower stroke incidence observed in pre-menopausal women and robust preclinical evidence of neuroprotective and anti-inflammatory properties of estrogen, researchers have focused on the potential benefits of hormones to reduce ischemic brain injury. However, as women age, they are disproportionately affected by stroke, coincident with the loss of estrogen with menopause. The risk of stroke in elderly women exceeds that of men and it is clear that in some settings estrogen can have pro-inflammatory effects. This review will focus on estrogen and inflammation and its interaction with aging

Character education : being fair and honest/ Koellhoffer

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