Modifications of lysozyme by substituted benzoquinones

Amyloidosis, which involves the precipitation of mis-folded protein aggregates, is a prominent process that occurs in many neurodegenerative conditions such as Alzheimer\u27s disease and Parkinson\u27s disease; the protein aggregates being amyloid-β for Alzheimer’s disease and α-synuclein for Parkinson’s disease. This study has focused on lysozyme modifications induced by metabolites of the commonly found pollutants known as polycyclic aromatic hydrocarbons (PAHs). PAHs are found in substances ranging from grilled meats to cigarette smoke to cosmetics, and they can be metabolized into a family of biological toxins known as benzoquinones. The molecules of interest for this study were 1,4-benzoquinone (pBQ), 2-chloro-1,4-benzoquinone (CBQ), and 2-methyl-1,4- benzoquinone (MBQ). The effect these benzoquinones had on lysozyme was studied by first creating samples through time- and concentration-dependent incubations in physiologic conditions. These samples were then examined through SDS-PAGE analysis, fluorescence assays, and UV-Vis spectroscopy to determine the products created through this modification. Our findings revealed the effective oligomerization and aggregation of lysozyme modified by benzoquinones

Diesel exhaust impairs TREM2 to dysregulate neuroinflammation

BACKGROUND: Air pollution has been linked to neurodegenerative diseases, including Alzheimer's disease (AD), and the underlying neuroimmune mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglia (DAM) cells, where loss-of-function TREM2 mutations are associated with an increased risk of AD. At present, the basic function of TREM2 in neuroinflammation is a point of controversy. Further, the impact of air pollution on TREM2 and the DAM phenotype is largely unknown. Using diesel exhaust (DE) as a model of urban air pollution exposure, we sought to address its impact on TREM2 expression, the DAM phenotype, the association of microglia with the neurovasculature, and the role of TREM2 in DE-induced neuroinflammation. METHODS: WYK rats were exposed for 4 weeks to DE (0, 50, 150, 500 μg/m3) by inhalation. DE particles (DEP) were administered intratracheally once (600 μg/mouse) or 8 times (100 μg/mouse) across 28 days to male mice (Trem2+/+, Trem2-/-, PHOX+/+, and PHOX-/-). RESULTS: Rats exposed to DE exhibited inverted-U patterns of Trem2 mRNA expression in the hippocampus and frontal cortex, while TREM2 protein was globally diminished, indicating impaired TREM2 expression. Analysis of DAM markers Cx3Cr1, Lyz2, and Lpl in the frontal cortex and hippocampus showed inverted-U patterns of expression as well, supporting dysregulation of the DAM phenotype. Further, microglial-vessel association decreased with DE inhalation in a dose-dependent manner. Mechanistically, intratracheal administration of DEP increased Tnf (TNFα), Ncf1 (p47PHOX), and Ncf2 (p67PHOX) mRNA expression in only Trem2+/+ mice, where Il1b (IL-1β) expression was elevated in only Trem2-/- mice, emphasizing an important role for TREM2 in DEP-induced neuroinflammation. CONCLUSIONS: Collectively, these findings reveal a novel role for TREM2 in how air pollution regulates neuroinflammation and provides much needed insight into the potential mechanisms linking urban air pollution to AD

Circulating HMGB1 is elevated in veterans with Gulf War Illness and triggers the persistent pro-inflammatory microglia phenotype in male C57Bl/6J mice

Gulf War Illness (GWI) is a chronic, multi-symptom peripheral and CNS condition with persistent microglial dysregulation, but the mechanisms driving the continuous neuroimmune pathology are poorly understood. The alarmin HMGB1 is an autocrine and paracrine pro-inflammatory signal, but the role of circulating HMGB1 in persistent neuroinflammation and GWI remains largely unknown. Using the LPS model of the persistent microglial pro-inflammatory response, male C57Bl/6J mice injected with LPS (5 mg/kg IP) exhibited persistent changes in microglia morphology and elevated pro-inflammatory markers in the hippocampus, cortex, and midbrain 7 days after LPS injection, while the peripheral immune response had resolved. Ex vivo serum analysis revealed an augmented pro-inflammatory response to LPS when microglia cells were cultured with the 7-day LPS serum, indicating the presence of bioactive circulating factors that prime the microglial pro-inflammatory response. Elevated circulating HMGB1 levels were identified in the mouse serum 7 days after LPS administration and in the serum of veterans with GWI. Tail vein injection of rHMGB1 in male C57Bl/6 J mice elevated TNFα mRNA levels in the liver, hippocampus, and cortex, demonstrating HMGB1-induced peripheral and CNS effects. Microglia isolated at 7 days after LPS injection revealed a unique transcriptional profile of 17 genes when compared to the acute 3 H LPS response, 6 of which were also upregulated in the midbrain by rHMGB1, highlighting a distinct signature of the persistent pro-inflammatory microglia phenotype. These findings indicate that circulating HMGB1 is elevated in GWI, regulates the microglial neuroimmune response, and drives chronic neuroinflammation that persists long after the initial instigating peripheral stimulus

A New Class of High-Mass X-ray Binaries: Implications for Core Collapse and Neutron-Star Recoil

We investigate an interesting new class of high-mass X-ray binaries (HMXBs) with long orbital periods (P_orb > 30 days) and low eccentricities (e <~ 0.2). The orbital parameters suggest that the neutron stars in these systems did not receive a large impulse, or ``kick,'' at the time of formation. We develop a self-consistent phenomenological picture wherein the neutron stars born in the observed wide HMXBs receive only a small kick (<~ 50 km/s), while neutron stars born in isolation, in the majority of low-mass X-ray binaries, or in many of the well-known HMXBs with P_orb <~ 30 days receive the conventional large kicks, with a mean speed of ~ 300 km/s. We propose that the magnitude of the natal kick to a neutron star born in a binary system depends on the rotation rate of the pre-collapse core. We further suggest that the rotation rate of the core is a strong, well-defined function of the evolutionary path of the progenitor star.Comment: 13 pages, 5 figures (2 color), submitted to Ap

Inhalation Triggers Neuroimmune, Glial, and Neuropeptide Transcriptional Changes

Increasing evidence associates indoor fungal exposure with deleterious central nervous system (CNS) health, such as cognitive and emotional deficits in children and adults, but the specific mechanisms by which it might impact the brain are poorly understood. Mice were exposed to filtered air, heat-inactivated Aspergillus versicolo r (3 × 10 5 spores), or viable A. versicolo r (3 × 10 5 spores) via nose-only inhalation exposure 2 times per week for 1, 2, or 4 weeks. Analysis of cortex, midbrain, olfactory bulb, and cerebellum tissue from mice exposed to viable A. versicolo r spores for 1, 2, and 4 weeks revealed significantly elevated pro-inflammatory ( Tnf and Il1b ) and glial activity ( Gdnf and Cxc3r1 ) gene expression in several brain regions when compared to filtered air control, with the most consistent and pronounced neuroimmune response 48H following the 4-week exposure in the midbrain and frontal lobe. Bulk RNA-seq analysis of the midbrain tissue confirmed that 4 weeks of A. versicolo r exposure resulted in significant transcriptional enrichment of several biological pathways compared to the filtered air control, including neuroinflammation, glial cell activation, and regulation of postsynaptic organization. Upregulation of Drd1 , Penk , and Pdyn mRNA expression was confirmed in the 4-week A. versicolo r exposed midbrain tissue, highlighting that gene expression important for neurotransmission was affected by repeated A. versicolor inhalation exposure. Taken together, these findings indicate that the brain can detect and respond to A. versicolo r inhalation exposure with changes in neuroimmune and neurotransmission gene expression, providing much needed insight into how inhaled fungal exposures can affect CNS responses and regulate neuroimmune homeostasis

Projected land ice contributions to twenty-first-century sea level rise.

The land ice contribution to global mean sea level rise has not yet been predicted1 using ice sheet and glacier models for the latest set of socio-economic scenarios, nor using coordinated exploration of uncertainties arising from the various computer models involved. Two recent international projects generated a large suite of projections using multiple models2-8, but primarily used previous-generation scenarios9 and climate models10, and could not fully explore known uncertainties. Here we estimate probability distributions for these projections under the new scenarios11,12 using statistical emulation of the ice sheet and glacier models. We find that limiting global warming to 1.5&nbsp;degrees Celsius would halve the land ice contribution to twenty-first-century sea level rise, relative to current emissions pledges. The median decreases from 25&nbsp;to 13&nbsp;centimetres sea level equivalent (SLE) by 2100, with glaciers responsible for half the sea level contribution. The&nbsp;projected Antarctic contribution does not show a clear response to the emissions scenario, owing to&nbsp;uncertainties in the competing processes of increasing ice loss and snowfall accumulation in a warming climate. However, under risk-averse (pessimistic) assumptions, Antarctic ice loss could be five times higher, increasing the median land ice contribution to 42&nbsp;centimetres SLE under current policies and pledges, with the 95th percentile projection exceeding half a metre even under 1.5&nbsp;degrees Celsius warming. This would severely limit the possibility of mitigating future coastal flooding. Given this large range (between 13&nbsp;centimetres SLE using the main projections under 1.5&nbsp;degrees Celsius warming and 42&nbsp;centimetres SLE using risk-averse projections under current pledges), adaptation planning for twenty-first-century sea level rise must account for a factor-of-three uncertainty in the land ice contribution until climate policies and the Antarctic response are further constrained

Projected land ice contributions to 21st century sea level rise

The land ice contribution to global mean sea level rise has not yet been predicted1 using ice sheet and glacier models for the latest set of socio-economic scenarios, nor using coordinated exploration of uncertainties arising from the various computer models involved. Two recent international projects generated a large suite of projections using multiple models2,3,4,5,6,7,8, but primarily used previous-generation scenarios9 and climate models10, and could not fully explore known uncertainties. Here we estimate probability distributions for these projections under the new scenarios11,12 using statistical emulation of the ice sheet and glacier models. We find that limiting global warming to 1.5 degrees Celsius would halve the land ice contribution to twenty-first-century sea level rise, relative to current emissions pledges. The median decreases from 25 to 13 centimetres sea level equivalent (SLE) by 2100, with glaciers responsible for half the sea level contribution. The projected Antarctic contribution does not show a clear response to the emissions scenario, owing to uncertainties in the competing processes of increasing ice loss and snowfall accumulation in a warming climate. However, under risk-averse (pessimistic) assumptions, Antarctic ice loss could be five times higher, increasing the median land ice contribution to 42 centimetres SLE under current policies and pledges, with the 95th percentile projection exceeding half a metre even under 1.5 degrees Celsius warming. This would severely limit the possibility of mitigating future coastal flooding. Given this large range (between 13 centimetres SLE using the main projections under 1.5 degrees Celsius warming and 42 centimetres SLE using risk-averse projections under current pledges), adaptation planning for twenty-first-century sea level rise must account for a factor-of-three uncertainty in the land ice contribution until climate policies and the Antarctic response are further constrained