Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury

Exposure to hypoxic-ischemic insults during the neonatal or perinatal developmental periods produces various forms of pathology. Injuries that occur in response to these events often manifest as severe cognitive and/or motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of hypoxic-ischemic injury, there is a growing need for effective therapies that can be delivered at delayed time points. Much of the research into mechanisms of neural injury has focused on molecular targets associated with excitotoxicity and free oxygen radicals. Despite repeated success in animal models, these compounds have failed to show efficacy in clinical trials. Increasing evidence indicates that hypoxic-ischemic injury in the neonate is progressive, and the resulting neuropathies are linked to the activation of neuroinflammatory processes that occur in response to the initial wave of cell death. Understanding this latter response, therefore, will be critical in the development of novel therapies to block the progression of the injury. In this review, we summarize emerging concepts from rodent models concerning the regulation of various cytokines, chemokines, and matrix metalloproteinases in response to ischemia, and the various ways in which the delayed neuroinflammatory response may contribute to the progressive nature of neonatal hypoxic-ischemic injury in rat. Finally, we discuss data that supports the potential to target these neuroinflammatory signals at clinically relevant time points

Neuroprotective Activity of Leukemia Inhibitory Factor Is Relayed through Myeloid Zinc Finger-1 in a Rat Model of Stroke

The aim of this study was to determine whether leukemia inhibitory factor (LIF) exerts its neuroprotective effects through signal transduction of the transcription factor myeloid zinc finger-1 (MZF-1). According to the hypothesis of this study, MZF-1 mediates LIF-induced neuroprotective signaling during ELVO through increased expression and transcriptional activity. To determine the in vivo role of MZF-1 in LIF-induced neuroprotection, we used Genomatix software was used to MZF-1 sites in the promoter region of the rat superoxide dismutase 3 (SOD3) gene. Stroke was induced via middle cerebral artery occlusion, and animals were administered PBS or 125 μg/kg LIF at 6, 24, and 48 h after the injury. MZF-1 binding activity was measured using electrophoretic mobility shift assay (EMSA) and its expression/localization were determined using western blot and immunohistochemical analysis. To determine whether MZF-1 relays LIF-induced neuroprotection in vitro, primary cultured neurons were subjected to oxygen-glucose deprivation (OGD) after treatment with PBS or LIF. MZF-1 expression was measured in vitro using real time PCR and immunohistochemical staining. Transfection with siRNA was used to determine whether LIF protected cultured neurons against OGD after silencing MZF-1 expression. Four MZF-1 binding sites were identified by Genomatix, and EMSA confirmed in vivo binding activity in brain after MCAO. LIF significantly increased MZF-1 protein levels compared to PBS treatment at 72 h post-MCAO. In vivo nuclear localization of MZF-1 as well as co-localization of SOD3 and MZF-1 was observed in the cortical neurons of LIF-treated rats. Primary cultured neurons treated with LIF had significantly higher levels of MZF-1 mRNA and protein after LIF treatment compared to neurons treated with PBS. Finally, knockdown MZF-1 using siRNA counteracted the neuroprotective effects of LIF in vitro. These data demonstrate that LIF-mediated neuroprotection is dependent upon MZF-1 activity. Furthermore, these findings identify a novel neuroprotective pathway that employs MZF-1, a transcription factor associated with hematopoietic gene expression

Delayed administration of a matrix metalloproteinase inhibitor limits progressive brain injury after hypoxia-ischemia in the neonatal rat

<p>Abstract</p> <p>Background</p> <p>Hypoxia-ischemia (H-I) can produce widespread neurodegeneration and deep cerebral white matter injury in the neonate. Resident microglia and invading leukocytes promote lesion progression by releasing reactive oxygen species, proteases and other pro-inflammatory mediators. After injury, expression of the gelatin-degrading matrix metalloproteinases (MMPs), MMP-2 and MMP-9, are thought to result in the proteolysis of extracellular matrix (ECM), activation of cytokines/chemokines, and the loss of vascular integrity. Thus, therapies targeting ECM degradation and progressive neuroinflammation may be beneficial in reducing H-I – induced neuropathy. Minocycline has MMP-inhibitory properties and is both anti-inflammatory and neuroprotective. AG3340 (prinomastat) is an MMP inhibitor with high selectivity for the gelatinases. The purpose of this study was to determine whether these compounds could limit H-I – induced injury when administered at a delayed time point.</p> <p>Methods</p> <p>Sprague-Dawley rats were exposed to H-I at postnatal day 7 (P7), consisting of unilateral carotid artery ligation followed by 90 min exposure to 8% O₂. Minocycline, AG3340, or vehicle were administered once daily for 6 days, beginning 24 hours after insult. Animals were sacrificed at P14 for neurohistological assessments. Immunohistochemistry was performed to determine the degree of reactive astrogliosis and immune cell activation/recruitment. Neural injury was detected using the Fluoro-Jade stain, a marker that identifies degenerating cells.</p> <p>Results</p> <p>CD11b and glial fibrillary acidic protein (GFAP) immunopositive cells increased in ipsilateral cortex after treatment with vehicle alone, demonstrating microglia/macrophage recruitment and reactive astrogliosis, respectively. Fluoro-Jade staining was markedly increased throughout the fronto-parietal cortex, striatum and hippocampus. Treatment with minocycline or AG3340 inhibited microglia/macrophage recruitment, attenuated astrogliosis and reduced Fluoro-Jade staining when compared to vehicle alone.</p> <p>Conclusion</p> <p>The selective gelatinase inhibitor AG3340 showed equal efficacy in reducing neural injury and dampening neuroinflammation when compared to the anti-inflammatory compound minocycline. Thus, MMP-2 and MMP-9 may be viable therapeutic targets to treat neonatal brain injury.</p

Internationale Beziehungen und Soziologie : das ‚Scharnier’ der Differenzierung

Meta-analysis of the heterogeneous symptoms of obsessive-compulsive disorder (OCD) has found a four-factor structure of symptom dimensions consisting of cleaning, forbidden thoughts, symmetry, and hoarding. Research into age of onset of symptom dimensions has yielded inconsistent results, and it is unknown whether symptoms along these dimensions differ in their clinical course. We assessed age of onset and clinical course of different OCD symptom dimensions in a large cohort of adult patients. Nine-hundred fifty-five subjects were assessed using the Dimensional Yale-Brown Obsessive-Compulsive Scale. For age of onset analysis, we tested across three methods of classification: (1) primary (more severe) symptom dimension (2) clinically significant symptoms within a dimension or (3) any symptoms within a dimension. Age of onset was defined as the earliest age of onset reported for any individual item within a symptom dimension. For analysis of different types of clinical course, we used chi-square tests to assess for differences between primary symptom dimensions. OCD symptoms in the symmetry dimension had an earlier age of onset than other OCD symptom dimensions. These findings remained significant across all three methods of classification and controlling for gender and comorbid tics. No significant differences were found between the other dimensions. Subjects with primary OCD symptoms in the forbidden thoughts dimension were more likely to report a waxing-and-waning course, whereas symmetry symptoms were less likely to be associated with a waxing-and-waning course. © 2013

Energetic Ion Moments and Polytropic Index in Saturn’s Magnetosphere using Cassini/MIMI Measurements: A Simple Model Based on κ‐Distribution Functions

Moments of the charged particle distribution function provide a compact way of studying the transport, acceleration, and interactions of plasma and energetic particles in the magnetosphere. We employ κ‐distributions to describe the energy spectra of H+ and O+, based on >20 keV measurements by the three detectors of Cassini’s Magnetospheric Imaging Instrument, covering the time period from DOY 183/2004 to 016/2016, 5 < L < 20. From the analytical spectra we calculate the equatorial distributions of energetic ion moments inside Saturn’s magnetosphere and then focus on the distributions of the characteristic energy (Ec=IE/In), temperature, and κ‐index of these ions. A semiempirical model is utilized to simulate the equatorial ion moments in both local time and L‐shell, allowing the derivation of the polytropic index (Γ) for both H+ and O+. Primary results are as follows: (a) The ∼9 < L < 20 region corresponds to a local equatorial acceleration region, where subadiabatic transport of H+ (Γ∼1.25) and quasi‐isothermal behavior of O+ (Γ∼0.95) dominate the ion energetics; (b) energetic ions are heavily depleted in the inner magnetospheric regions, and their behavior appears to be quasi‐isothermal (Γ<1); (c) the (quasi‐) periodic energetic ion injections in the outer parts of Saturn’s magnetosphere (especially beyond 17–18 RS) produce durable signatures in the energetic ion moments; (d) the plasma sheet does not seem to have a ground thermodynamic state, but the extended neutral gas distribution at Saturn provides an effective cooling mechanism that does not allow the plasma sheet to behave adiabatically.Key PointsDerivation of energetic ion moments, κ‐index, characteristic energy, temperature, and polytropic index in Saturn’s magnetospherePresentation of a semiempirical analytical model for the 20 keV energetic ion Pressure, density, and temperatureThe neutral gas at Saturn provides an effective cooling mechanism and does not allow the plasma sheet to behave adiabaticallyPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146558/1/jgra54546.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146558/2/jgra54546_am.pd

Translational Evaluation of Acid/Base and Electrolyte Alterations in Rodent Model of Focal Ischemia

BACKGROUND AND PURPOSE: Acid/base and electrolytes could provide clinically valuable information about cerebral infarct core and penumbra. We evaluated associations between acid/base and electrolyte changes and outcomes in 2 rat models of stroke, permanent, and transient middle cerebral artery occlusion. METHODS: Three-month old Sprague-Dawley rats underwent permanent or transient middle cerebral artery occlusion. Pre- and post-middle cerebral artery occlusion venous samples for permanent and transient models provided pH, carbon dioxide, oxygen, glucose, and electrolyte values of ionized calcium, potassium, and sodium. Multiple regression determined predictors of infarct volume from these values, and Kaplan-Meier curve analyzed morality between permanent and transient middle cerebral artery occlusion models. RESULTS: Analysis indicated significant differences in the blood gas and electrolytes between pre- to post-middle cerebral artery occlusion. A decrease in pH and sodium with increases in carbon dioxide, potassium, ionized calcium, and glucose changes were found in both middle cerebral artery occlusion models; while hematocrit and hemoglobin were significant in the transient model. pH and ionized calcium were predictors of infarct volume in the permanent model, as changes in pH and ionized calcium decreased, infarct volume increased. CONCLUSIONS: There are acute changes in acid/base balance and electrolytes during stroke in transient and permanent rodent models. Additionally, we found pH and ionized calcium changes predicted stroke volume in the permanent middle cerebral artery occlusion model. These preliminary findings are novel, and warrant further exploration in human conditions

The JWST Hubble Sequence: The Rest-frame Optical Evolution of Galaxy Structure at 1.5 < z < 6.5

© 2023. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by/4.0/We present results on the morphological and structural evolution of a total of 3956 galaxies observed with JWST at 1.5 109 M ⊙ at z > 3 are not dominated by irregular and peculiar structures, either visually or quantitatively, as previously thought. We find a strong dominance of morphologically selected disk galaxies up to z = 6 in this mass range. We also find that the stellar mass and star formation rate densities are dominated by disk galaxies up to z ∼ 6, demonstrating that most stars in the Universe were likely formed in a disk galaxy. We compare our results to theory to show that the fraction of types we find is predicted by cosmological simulations, and that the Hubble Sequence was already in place as early as one billion years after the Big Bang. Additionally, we make our visual classifications public for the community.Peer reviewe

Seeing sharper and deeper: JWST's first glimpse of the photometric and spectroscopic properties of galaxies in the epoch of reionisation

We analyse the photometric and spectroscopic properties of four galaxies in the epoch of reionisation (EoR) within the SMACS 0723 JWST Early Release Observations field. Given the known spectroscopic redshifts of these sources, we investigated the accuracy with which photometric redshifts can be derived using NIRCam photometry alone, finding that F115W imaging is essential to distinguish between z~8 galaxies with high equivalent width (EW) [O III] {\lambda}5007 emission and z~10 Balmer break galaxies. We find that all four sources exhibit strong (> 0.6 mag) F356W-F444W colours, which sit at the extreme end of theoretical predictions from numerical simulations. We find that these galaxies deviate (by roughly 0.5 dex) from the local correlation between [O III] {\lambda}5007/H\beta and [Ne III] {\lambda}3869/[O II], which is consistent with the predictions from simulations of high-redshift galaxies. We measure the [O III] {\lambda}5007 rest-frame equivalent widths both directly from the spectroscopy, and indirectly as inferred from the strong F356W-F444W colours, finding large [O III] {\lambda}5007 EWs of 400-1000 {\AA}. The [O III] {\lambda}5007 and H\beta EWs are consistent with those seen in extreme, intensely star-forming dwarf galaxies in the local Universe. Our structural analysis indicates that these galaxies are resolved, exhibiting irregular shapes with bright clumps and colour gradients. In line with the predictions from the FLARES hydrodynamic simulations, such intense star formation and extreme nebular conditions are likely the norm, rather than the exception, in the EoR. Finally, although star-forming galaxies and AGN often occupy similar regions within the [O III] {\lambda}5007/H\beta-[O II]/H{\delta} plane, we find that AGN exhibit distinct, red colours in the F150W-F200W, F200W-F277W plane.Comment: 14 pages, 8 figure

Estimation of Reduction in Influenza Vaccine Effectiveness Due to Egg-Adaptation Changes—Systematic Literature Review and Expert Consensus

Background: Influenza vaccines are the main tool to prevent morbidity and mortality of the disease; however, egg adaptations associated with the choice of the manufacturing process may reduce their effectiveness. This study aimed to estimate the impact of egg adaptations and antigenic drift on the effectiveness of trivalent (TIV) and quadrivalent (QIV) influenza vaccines. Methods: Nine experts in influenza virology were recruited into a Delphi-style exercise. In the first round, the experts were asked to answer questions on the impact of antigenic drift and egg adaptations on vaccine match (VM) and influenza vaccine effectiveness (IVE). In the second round, the experts were presented with the data from a systematic literature review on the same subject and aggregated experts’ responses to round one questions. The experts were asked to review and confirm or amend their responses before the final summary statistics were calculated. Results: The experts estimated that, across Europe, the egg adaptations reduce, on average, VM to circulating viruses by 7–21% and reduce IVE by 4–16%. According to the experts, antigenic drift results in a similar impact on VM (8–24%) and IVE (5–20%). The highest reduction in IVE was estimated for the influenza virus A(H3N2) subtype for the under 65 age group. When asked about the frequency of the phenomena, the experts indicated that, on average, between the 2014 and 19 seasons, egg adaptation and antigenic drift were significant enough to impact IVE that occurred in two and three out of five seasons, respectively. They also agreed that this pattern is likely to reoccur in future seasons. Conclusions: Expert estimates suggest there is a potential for 9% on average (weighted average of “All strains” over three age groups adjusted by population size) and up to a 16% increase in IVE (against A(H3N2), the <65 age group) if egg adaptations that arise when employing the traditional egg-based manufacturing process are avoided