Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War Illness

Gulf War Illness (GWI) affects 25% of veterans from the 1990–1991 Gulf War (GW) and is accompanied by damage to the brain regions involved in memory processing. After twenty-five years, the chronic pathobiology of GWI is still unexplained. To address this problem, we examined the long-term consequences of GW exposures in an established GWI mouse model to identify biological processes that are relevant to the chronic symptoms of GWI. Three-month old male C57BL6 mice were exposed for 10 days to GW agents (pyridostigmine bromide and permethrin). Barnes Maze testing conducted at 15- and 16-months post-exposure revealed learning and memory impairment. Immunohistochemical analyses showed astroglia and microglia activation in the hippocampi of exposed mice. Proteomic studies identified perturbation of mitochondria function and metabolomics data showed decreases in the Krebs cycle compounds, lactate, β-hydroxybutyrate and glycerol-3 phosphate in the brains of exposed mice. Lipidomics data showed decreases in fatty acids, acylcarnitines and phospholipids, including cardiolipins in the brains of exposed mice. Pilot biomarker studies showed that plasma from exposed mice and veterans with GWI had increases in odd-chain, and decreases in long-chain, acylcarnitines compared to their respective controls. Very long-chain acylcarnitines were decreased in veterans with GWI compared to controls. These studies suggest that mitochondrial lipid disturbances might be associated with GWI and that further investigation is required to determine its role in the pathophysiology of this illness. Targeting mitochondrial function may provide effective therapies for GWI, and that lipid abnormalities could serve as biomarkers of GWI

Mapping innate immune host and viral gene interactions in monocytes/macrophages, in particular for IL1β and the LTR region of HIV-1

<p>Pathway diagrams describing the regulation of Interferon-beta and the Major Immediate Early Promotor (MIE) of human Cytomegalovirus, obtained from a review of the published literature as part of the project work for our MSc in Genomics and Pathway Biology. The pathways are presented in SBGN notation. This document has not been peer reviewed.</p

THAP1 : Role in Mouse Embryonic Stem Cell Survival and Differentiation

THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression

Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness

<div><p>Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.</p></div

PB + PER exposure altered astrocytic activation in the hili of hippocampi and cerebral cortices of mice.

<p>PB + PER exposure significantly increased astrocytic activation in the hili of the hippocampi of exposed mice (B, D) compared to controls (A, C) at 5 months post exposure (Welch t-test = 5.57, DF = 1, p = 0.03). PB + PER exposure significantly increased astrocytic activation in the cerebral cortices (F, H) of Long-term Cohort mice (see inset in H), as compared to controls (E, G) at 5 months post exposure (Welch t-test = 3.14, DF = 1, p = 0.04). Representative images used 10X (A, B, E, F), and 40X (C, D, G, H) objectives, (scale bars represent 100 μm, and 20 μm respectively). Histograms depict the quantification of the GFAP stain in the hili of the hippocampi and cerebral cortices from control and exposed mice, as % Area per microscopic field, and error bars represent standard error of the mean (SEM).</p

PB + PER exposure decreased SYP staining in the hippocampi and cerebral cortices of exposed mice.

<p>Differences in SYP staining was observed in the CA3 region of exposed mice (B) versus controls (A) at 5 months post exposure (Welch’s t-test = 12.7, DF = 1, p < 0.01). In addition, significantly reduced SYP staining was evident in the cerebral cortices of exposed mice (D), as compared to controls (C) (Welch’s t-test = 10.26, DF = 1, p = 0.03). Representative images were taken at 60X magnification (scale bars represent 1 mm). Inset depicts positive SYP staining showing dark brown pre-synaptic vesicles stained within the cell soma (see insets in A and C). Histograms depict the quantification of the SYP stain in the hippocampi, and cerebral cortices, as % Area per microscopic field, and error bars represent standard error of the mean (SEM).</p

Impairment for long-term memory formation was observed at day 106 days-post acute exposure to PB + PER.

<p>Frequency (#) and Primary Error Rate (#) were examined for exposed and control mice during Barnes Maze probe trials. For the frequency of nose-pokes into the target hole (A), we observed a significant interaction between the exposure and days post-exposure (Wald = 6.15, df = 2, p = 0.05), a main effect of post-exposure days (Wald = 28.67, df = 2, p < 0.001) and no main effect of exposure (Wald = 0.94, df = 1, p = 0.33). For the primary error rate, there was no main effect of exposure (F = 0.85, DF = 1, 74.29, p = 0.36), and no interaction effect between the exposure and days post-exposure (F = 0.10, DF = 1, 52.27, p = 0.91) that was observed during probe trials. SPSS 21.0 was used to test the true value of the parameter based on the sample estimate. All graphs are depicted as means and error bars show standard error of the mean (SEM).</p

No overall behavioral differences were observed in exposed mice, 11–14 days post-exposure to PB + PER.

<p>Control and exposed mice from the Short-term and Long-term Cohorts (n = 48) behaved similarly when we examined (A) cumulative distance traveled to the target hole (F = 0.94, DF = 1, 167, p = 0.33), (B) escape latency (F = 0.32, DF = 1, 167, p = 0.57), and (C) velocity (F = 0.50, DF = 1, 148, p = 0.48), over a 4-day period. The data sets for Cumulative Distance to TH (cm), Escape latency (s), and Velocity (cm/s) were normally distributed. Therefore, a Mixed Linear Model (MLM) regression was run using SPSS 21.0 software. All graphs are depicted as means and error bars show standard error of the mean (SEM).</p