Targeting Lipid Metabolism as a Therapeutic Approach for Gulf War Illness

Upon returning from the 1991 Gulf War (GW), veterans from this conflict exhibited a persistent multisymptomatic illness which is now defined as Gulf War Illness (GWI). There is ample evidence that the presentation of GWI is associated with exposure to an anti-nerve agent pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), that were used as prophylactic measures by veterans during the war. The prevalence of GWI is about 30% in US veterans and 15% in UK veterans who were deployed during this conflict. Clinical presentation of GWI is heterogenous, and veterans with this condition display a wide range of symptoms such as memory impairment, fatigue, gastrointestinal disorder and chronic pain. Current treatment strategies for GWI are limited and provide only symptomatic relief. Due to the multifactorial nature of this illness, quest for appropriate treatment strategies is difficult and further complicated by the fact that many of the GW veterans are also facing age-related chronic health problems. I utilized a mouse model of GWI previously developed using combined exposure to PB and PER (GWI mice) which exhibits neurobehavioral features that are similar to the symptoms reported by GWI veterans. This model displays glia activation and neuroinflammation, pathological features that are reported in other GWI rodent models, representing a common chronic outcome associated with GW chemical exposure. The main objectives of this thesis are to find effective therapies against GWI that target the underlying pathology of GWI. Many clinical and imaging studies have suggested a possible central nervous system (CNS) involvement in GWI. However, even after two decades, there is no approved medication for treating the CNS pathology of GWI. Much of our previous work suggests dysregulation of lipid homeostasis and metabolism. These results pointed to both mitochondrial and peroxisomal abnormalities in GWI mice as well as in veterans with GWI. As part of my thesis work, I explored whether targeting mitochondrial and peroxisomal function can reduce abnormal brain lipid accumulation and improve chronic neurobehavioral deficits and the accompanying neuropathology in a mouse model of GW chemical exposure. I examined oleoylethanolamide, which targets peroxisome function via activation of peroxisome proliferator-activated receptors (PPAR) and also decreases inflammation. I examined another strategy using two different treatment regimens, nicotinamide riboside and a ketogenic diet, both of which target different aspects of mitochondrial bioenergetics. In addition to peroxisome and mitochondria dysfunction, recent evidence suggests that the symptoms of GWI resemble those of patients with autoimmune disorders, but it is unknown how GW chemicals could have caused immune dysfunction in GWI. Therefore, I focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), which is previously shown to form adducts with endogenous proteins. I observed the presence of 3-PBA modified lysine on protein peptides in GWI mice acutely post-exposure and also detected autoantibodies against 3-PBA-albumin conjugates in plasma of GWI mice and in veterans with GWI at chronic post-exposure timepoints. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI. I hope that the work described in this thesis provides novel avenues for the development of objective biomarkers and therapies for GWI

Rateless Codes for Near-Perfect Load Balancing in Distributed Matrix-Vector Multiplication

Large-scale machine learning and data mining applications require computer systems to perform massive matrix-vector and matrix-matrix multiplication operations that need to be parallelized across multiple nodes. The presence of straggling nodes -- computing nodes that unpredictably slowdown or fail -- is a major bottleneck in such distributed computations. Ideal load balancing strategies that dynamically allocate more tasks to faster nodes require knowledge or monitoring of node speeds as well as the ability to quickly move data. Recently proposed fixed-rate erasure coding strategies can handle unpredictable node slowdown, but they ignore partial work done by straggling nodes thus resulting in a lot of redundant computation. We propose a \emph{rateless fountain coding} strategy that achieves the best of both worlds -- we prove that its latency is asymptotically equal to ideal load balancing, and it performs asymptotically zero redundant computations. Our idea is to create linear combinations of the $m$ rows of the matrix and assign these encoded rows to different worker nodes. The original matrix-vector product can be decoded as soon as slightly more than $m$ row-vector products are collectively finished by the nodes. We conduct experiments in three computing environments: local parallel computing, Amazon EC2, and Amazon Lambda, which show that rateless coding gives as much as $3\times$ speed-up over uncoded schemes

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

High prevalence of alpha thalassemia in the tribal community of the western part of India! Reality or myth? Can simple hematology parameters; MCV and MCH act as screening tools at birth?

Background: The majority of adult tribal subjects in the western part of India, show microcytic hypochromic red cells, and borderline anemia with a normal iron profile, suggesting a high prevalence of thalassemia in this population. Methods: The current study was designed to perform qualitative (to screen for Hb Bart’s) and quantitative (to estimate percentage of Hb Bart’s) hemoglobin electrophoresis with modification of the method, to evaluate the prevalence of α thalassemia and to determine gene frequency of α+ thal gene. Furthermore, the present study also aimed to evaluate common hematology parameters like MCV and MCH as screening tools to suspect α thalassemia at birth. Results: Based on hemoglobin electrophoresis, the prevalence of α thalassemia in all its forms was found to be 66.66%. The estimated gene frequency for α+ thal was found to be 0.7453 and based on that, the extrapolated prevalence of α thalassemia was 93.52% (55.55% homozygous and 37.97% heterozygous). MCV<100 fl and MCH<31 pg were found to be reliable screening tools to predict α thalassemia at birth in full-term uncomplicated pregnancy. Conclusions: Tribal community in the western part of India bears a very high prevalence of α thalassemia, it’s a reality and not a myth. Simple hematological parameters like MCV (<100 fl) and MCH (<31 pg) measured at birth can prove to be cost-effective surrogate markers for α thalassemia. Large scale study using confirmatory genetic analysis is required to validate the findings.

Author Correction: Oleoylethanolamide treatment reduces neurobehavioral deficits and brain pathology in a mouse model of Gulf War Illness

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper

A permethrin metabolite is associated with adaptive immune responses in Gulf War Illness

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood and liver of pyridostigmine bromide (PB) and  PER (PB+PER) exposed mice at acute and chronic post-exposure timepoints. We tested whether 3-PBA-haptenated albumin (3-PBA-albumin) can activate immune cells since it is known that chemically haptenated proteins can stimulate immune responses. We detected autoantibodies against 3-PBA-albumin in plasma from PB + PER exposed mice and veterans with GWI at chronic post-exposure timepoints. We also observed that in vitro treatment of blood with 3-PBA-albumin resulted in the activation of B- and T-helper lymphocytes and that these immune cells were also increased in blood of PB + PER exposed mice and veterans with GWI. These immune changes corresponded with elevated levels of infiltrating monocytes in the brain and blood of PB + PER exposed mice which coincided with alterations in the markers of blood-brain barrier disruption, brain macrophages and neuroinflammation. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI

Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma

A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders. [Abstract copyright: Published by Elsevier Inc.

Exogenous lipase administration alters gut microbiota composition and ameliorates Alzheimer’s disease-like pathology in APP/PS1 mice

Alzheimer’s disease (AD) represents the most common form of dementia in the elderly with no available disease modifying treatments. Altered gut microbial composition has been widely acknowledged as a common feature of AD, which potentially contributes to progression or onset of AD. To assess the hypothesis that Candida rugosa lipase (CRL), which has been shown to enhance gut microbiome and metabolite composition, can rebalance the gut microbiome composition and reduce AD pathology, the treatment effects in APPswe/PS1de9 (APP/PS1) mice were investigated. The analysis revealed an increased abundance of Acetatifactor and Clostridiales vadin BB60 genera in the gut; increased lipid hydrolysis in the gut lumen, normalization of peripheral unsaturated fatty acids, and reduction of neuroinflammation and memory deficits post treatment. Finally, we demonstrated that the evoked benefits on memory could be transferred via fecal matter transplant (FMT) into antibiotic-induced microbiome-depleted (AIMD) wildtype mice, ameliorating their memory deficits. The findings herein contributed to improve our understanding of the role of the gut microbiome in AD’s complex networks and suggested that targeted modification of the gut could contribute to amelioration of AD neuropathology