Traumatic brain injury triggers multiple cell death pathways, possibly including ferroptosis-a recently described cell death pathway that results from accumulation of 15-lipoxygenase-mediated lipid ...oxidation products, specifically oxidized phosphatidylethanolamine containing arachidonic or adrenic acid. This study aimed to investigate whether ferroptosis contributed to the pathogenesis of in vitro and in vivo traumatic brain injury, and whether inhibition of 15-lipoxygenase provided neuroprotection.
Cell culture study and randomized controlled animal study.
University research laboratory.
HT22 neuronal cell line and adult male C57BL/6 mice.
HT22 cells were subjected to pharmacologic induction of ferroptosis or mechanical stretch injury with and without administration of inhibitors of ferroptosis. Mice were subjected to sham or controlled cortical impact injury. Injured mice were randomized to receive vehicle or baicalein (12/15-lipoxygenase inhibitor) at 10-15 minutes postinjury.
Pharmacologic inducers of ferroptosis and mechanical stretch injury resulted in cell death that was rescued by prototypical antiferroptotic agents including baicalein. Liquid chromatography tandem-mass spectrometry revealed the abundance of arachidonic/adrenic-phosphatidylethanolamine compared with other arachidonic/adrenic acid-containing phospholipids in the brain. Controlled cortical impact resulted in accumulation of oxidized phosphatidylethanolamine, increased expression of 15-lipoxygenase and acyl-CoA synthetase long-chain family member 4 (enzyme that generates substrate for the esterification of arachidonic/adrenic acid into phosphatidylethanolamine), and depletion of glutathione in the ipsilateral cortex. Postinjury administration of baicalein attenuated oxidation of arachidonic/adrenic acid-containing-phosphatidylethanolamine, decreased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus, and improved spatial memory acquisition versus vehicle.
Biomarkers of ferroptotic death were increased after traumatic brain injury. Baicalein decreased ferroptotic phosphatidylethanolamine oxidation and improved outcome after controlled cortical impact, suggesting that 15-lipoxygenase pathway might be a valuable therapeutic target after traumatic brain injury.
Traumatic brain injury (TBI) leads to changes in ion fluxes, alterations in mitochondrial function, and increased generation of reactive oxygen species, resulting in secondary tissue damage. ...Mitochondria play important signaling roles in coordination of multiple metabolic platforms in addition to their well‐known role in bioenergetics. Mitochondrial signaling strongly depends on cardiolipin (CL), a mitochondria‐specific structurally unusual anionic phospholipid containing four fatty acyl chains. While our previous reports indicated that CL is selectively oxidized and presents itself as a target for the redox therapy following TBI, the topography of changes of CL in the injured brain remained to be defined. Here, we present a matrix‐assisted laser desorption/ionization imaging study which reports regio‐specific changes in CL, in a controlled cortical impact model of TBI in rats. Matrix‐assisted laser desorption/ionization imaging revealed that TBI caused early decreases in CL in the contusional cortex, ipsilateral hippocampus, and thalamus with the most highly unsaturated CL species being most susceptible to loss. Phosphatidylinositol was the only other lipid species that exhibited a significant decrease, albeit to a lesser extent than CL. Signals for other lipids remained unchanged. This is the first study evaluating the spatial distribution of CL loss after acute brain injury. We propose that the CL loss may constitute an upstream mechanism for CL‐driven signaling in different brain regions as an early response mechanism and may also underlie the bioenergetic changes that occur in hippocampal, cortical, and thalamic mitochondria after TBI.
Traumatic brain injury (TBI) leads to changes in ion fluxes and alterations in mitochondrial function. Mitochondrial signaling strongly depends on cardiolipin (CL), which is selectively oxidized and presents itself as a target for redox therapy following TBI. We describe a mass spectrometric lipid imaging study that reports regio‐specific changes in rat brain CL in a controlled cortical impact (CCI) model of traumatic brain injury (TBI). While MALDI‐MS imaging revealed that TBI caused decreases in CL in the contusional area 3 h after injury, it also revealed decreases extending well beyond the area of impact into histologically normal tissue in the hippocampus and thalamic regions. The more unsaturated CL species were most susceptible to loss.
Mild traumatic brain injury (mTBI) in children is a common and serious public health problem. Traditional neuroimaging findings in children who sustain mTBI are often normal, putting them at risk for ...repeated mTBI (rmTBI). There is a need for more sensitive imaging techniques capable of detecting subtle neurophysiological alterations after injury. We examined neurochemical and white matter changes using diffusion tensor imaging of the whole brain and proton magnetic resonance spectroscopy of the hippocampi at 7 Tesla in 18-day-old male rats at 7 days after mTBI and rmTBI. Traumatic axonal injury was assessed by beta-amyloid precursor protein accumulation using immunohistochemistry. A significant decrease in fractional anisotropy and increase in axial and radial diffusivity were observed in several brain regions, especially in white matter regions, after a single mTBI versus sham and more prominently after rmTBI. In addition, we observed accumulation of beta-amyloid precursor protein in the external capsule after mTBI and rmTBI. mTBI and rmTBI reduced the N-acetylaspartate/creatine ratio (NAA/Cr) and increased the myoinositol/creatine ratio (Ins/Cr) versus sham. rmTBI exacerbated the reduction in NAA/Cr versus mTBI. The choline/creatine (Cho/Cr) and (lipid/Macro Molecule 1)/creatine (Lip/Cr) ratios were also decreased after rmTBI versus sham. Diffusion tensor imaging findings along with the decrease in Cho and Lip after rmTBI may reflect damage to axonal membrane. NAA and Ins are altered at 7 days after mTBI and rmTBI likely reflecting neuro-axonal damage and glial response, respectively. These findings may be relevant to understanding the extent of disability following mTBI and rmTBI in the immature brain and may identify possible therapeutic targets.
Contemporary public managers find themselves under pressure on many fronts. Coming off a sustained period of growth in their funding and some complacency about their performance, they now face an ...environment of ferocious competitiveness abroad and austerity at home. Public managers across Australia and New Zealand are finding themselves wrestling with expenditure reduction, a smaller public sector overall, sustained demands for productivity improvement, and the imperative to think differently about the optimal distribution of responsibilities between states, markets and citizens. Given ever-shrinking resources, in terms of staffing, budgets and time, how can public managers and public services become more productive, more outcome-driven and more agile? How can we achieve better alignment between ever-growing citizen expectations and the realities of constrained service provision? What can we learn from the best combination of innovation and austerity already being delivered in other countries and sectors, including harnessing the grounded wisdom of frontline service delivery practitioners? This book focuses on practical ways public managers at home and abroad are dealing with these shared dilemmas. It brings together renowned scholars in the fields of public sector productivity, performance management, ‘frugal innovation’ and budget stringency, with leading international and Australasian practitioners sharing their successes and challenges.
Traumatic brain injury (TBI) alters microbial populations present in the gut, which may impact healing and tissue recovery. However, the duration and impact of these changes on outcome from TBI are ...unknown. Short-chain fatty acids (SCFAs), produced by bacterial fermentation of dietary fiber, are important signaling molecules in the microbiota gut-brain axis. We hypothesized that TBI would lead to a sustained reduction in SCFA producing bacteria, fecal SCFAs concentration, and administration of soluble SCFAs would improve functional outcome after TBI. Adult mice (
= 10) had the controlled cortical impact (CCI) model of TBI performed (6 m/sec, 2-mm depth, 50-msec dwell). Stool samples were collected serially until 28 days after CCI and analyzed for SCFA concentration by high-performance liquid chromatography-mass spectrometry/mass spectrometry and microbiome analyzed by 16S gene sequencing. In a separate experiment, mice (
= 10/group) were randomized 2 weeks before CCI to standard drinking water or water supplemented with the SCFAs acetate (67.5 mM), propionate (25.9 mM), and butyrate (40 mM). Morris water maze performance was assessed on post-injury Days 14-19. Alpha diversity remained stable until 72 h, at which point a decline in diversity was observed without recovery out to 28 days. The taxonomic composition of post-TBI fecal samples demonstrated depletion of bacteria from
,
, and
families, and enrichment of bacteria from the
family. Analysis from paired fecal samples revealed a reduction in total SCFAs at 24 h and 28 days after TBI. Acetate, the most abundant SCFA detected in the fecal samples, was reduced at 7 days and 28 days after TBI. SCFA administration improved spatial learning after TBI versus standard drinking water. In conclusion, TBI is associated with reduced richness and diversity of commensal microbiota in the gut and a reduction in SCFAs detected in stool. Supplementation of soluble SCFAs improves spatial learning after TBI.
Asphyxial cardiac arrest (CA) is a significant cause of death and disability in children. Using juvenile Osteogenic disorder Shionogi (ODS) rats that, like humans, do not synthesize ascorbate, we ...tested the effect of ascorbate deficiency on functional and histological outcome after CA.
Postnatal day 16-18 milk-fed ODS and wild-type Wistar rats underwent 9-min asphyxial CA (n = 8/group) or sham surgery (n = 4/group). ODS mothers received ascorbate in drinking water to prevent scurvy. Levels of ascorbate and glutathione (GSH) were measured in plasma and hippocampus at baseline and after CA. Neurologic deficit score (NDS) was measured at 3, 24, and 48 h and hippocampal neuronal counts, neurodegeneration, and microglial activation were assessed at day 7.
ODS rats showed depletion of plasma and hippocampal ascorbate, attenuated hippocampal neurodegeneration and microglial activation, and increased CA1 hippocampal neuron survival vs. Wistar rats while NDS were similar. Hippocampal GSH levels were higher in ODS vs. Wistar rats at baseline and 10 min, whereas hypoxia-inducible factor-1α levels were higher in Wistar vs. ODS rats at 24 , after CA.
Ascorbate-deficient juvenile ODS rats appear resistant to neurodegeneration produced by asphyxia CA, possibly related to upregulation of the endogenous antioxidant GSH in brain.
Like humans and unlike other rodents, osteogenic disorder Shionogi (ODS) rats do not synthesize ascorbate, and thus may serve as a useful model for studying the role of ascorbate in human disease. Conflicting evidence exists regarding ascorbate's protective versus detrimental effects in animal models and clinical studies. Ascorbate-deficient ODS rats are resistant to neurodegeneration after experimental cardiac arrest.
Although classified under the business umbrella, advertising is also used as manipulative tool to persuade consumers in order to achieve the bottom-line in business. It is dependent upon design and ...psychological undertones inherent of human-centered communication theory to influence specific behaviors from potential consumers effectively to achieve the bottom line. While following traditional Phenomenological inquiry, during analysis of sample students' interpretations of actualizing Internet advertising, responses were found to be indicative of both the human-centered, communication theory of Sense-making and advertising's Hierarchy of Effects model. Theoretical analysis parameters of the SenseMaking tenets, situation, gap/bridge, use (Dervin; Savolainen; Kari; & Murphy, T., Daudi, & Heimlich,) and the Hierarchy of Effects model's stages of cognition, affectation, and conation (Ilfeld & Winer; Hoekstra & Huizingh) are isomorphic, as well as descriptive of the psychological process individuals undertake while encountering Internet advertising phenomena. The primary research revealed that, although SUNYIT students react negatively to unsolicited Internet advertising, considering them invasive and intrusive, the ads do achieve the advertiser's intended effects of awareness, recognition, and often purchases. Secondary sources provided reinforcement of the sample population's responses.
Students participating in special programs funded under Title I of the Elementary and Secondary Education Act may experience a fragmented and disjointed instructional program. Case studies of ten ...schools in New York City were conducted to identify the ways in which special programs were coordinated with classroom instruction. Summaries of the case study data include information on instructional goals, school organization, special programs, coordination of instruction in the schools, staff training, district coordination of instruction, parent advisory councils, and concerns about special programs stated by district and school personnel. Factors which influence program coordination at the district and school levels are also discussed. Constraints on instructional coordination, particularly those related to school organization, are examined. Recommendations for change at the Federal, State, district, and school levels are made. (RLV)
Accurate numerical modeling of clouds and precipitation is essential for weather forecasting and climate change research. While size-resolved (bin) cloud microphysics models predict particle size ...distributions without imposing shapes, results are subject to artificial size distribution broadening owing to numerical diffusion associated with various processes. Whereas Part 1 addressed collision-coalescence, here we investigate numerical diffusion that occurs in solving condensation and evaporation. In a parcel model framework, all of the numerical schemes examined converge to one solution of condensation and evaporation as the mass grid is refined, and the advection-based schemes are recommended over the reassigning schemes. Including Eulerian vertical advection in a column limits the convergence to some extent, but that limitation occurs at a sufficiently fine mass grid, and the number of iterations in solving vertical advection should be minimized to reduce numerical diffusion. Insubstantial numerical diffusion in solving condensation can be amplified if collision-coalescence is also active, which in turn can be substantially diminished if turbulence effects on collision are incorporated. Large-eddy simulations of a drizzling stratocumulus field reveal that changes in moments of Doppler spectra obtained using different mass grids are consistent with those obtained from the simplified framework, and that spectral moments obtained using a mass grid designed to effectively reduce numerical diffusion are generally closer to observations. Notable differences between the simulations and observations still exist, and our results suggest a need to consider whether factors other than numerical diffusion in the fundamental process schemes employed can cause such differences.
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