Repeat-Accumulate Codes for Reconciliation in Continuous Variable Quantum Key Distribution

This paper investigates the design of low-complexity error correction codes for the verification step in continuous variable quantum key distribution (CVQKD) systems. We design new coding schemes based on quasi-cyclic repeat-accumulate codes which demonstrate good performances for CVQKD reconciliation

Apolipoprotein E in Diabetic Dyslipidemia and Atherosclerosis

Each year, cardiovascular disease (CVD) kills more Americans than any other cause of death. The majority of the diseases contributing to CVD can be traced back to the pathological process of atherosclerosis, in which fatty material collects along the walls of arteries, limiting flexibility and obstructing blood flow. Plasma lipids, particularly in the form of low-density lipoprotein (LDL) cholesterol, contribute significantly to the formation of atherosclerotic plaques and are important determinants of CVD risk. Thus, it is critical to understand the roles of the crucial components of normal lipoprotein metabolism that regulate plasma lipids, such as apolipoprotein (apo) B, apoE and the LDL receptor. In addition, patients with diabetes are two to four times as likely to develop CVD as non-diabetic patients. One important reason for this discrepancy is the process of diabetic dyslipidemia - a cluster of harmful changes to normal lipoprotein metabolism commonly seen in patients with diabetes. ApoE is the primary ligand for several lipoprotein receptors, making it a crucial component in the clearance of lipid from the circulation and a major determinant of plasma cholesterol and cardiovascular disease risk. The APOE gene is polymorphic, resulting in three common isoforms: ApoE2, E3, and E4. In addition to its role in lipoprotein metabolism, recent findings have also suggested a role for ApoE in glucose metabolism. In Chapter 2, I examine the role of apoE3 and apoE4 during the process of diabetic dyslipidemia and atherosclerosis. Similarly, Chapter 3 focuses on the crucial interaction between apoE and the LDLR in the background of diabetes. In Chapter 4, I explore the increased risk of CVD in patients with diabetes in detail, focusing on the various models of diabetic atherosclerosis available to researchers and how they may help understand the cause of this risk. Finally, in Chapter 6 I provide a supplemental examination of the the role of apoB, and in particular the LDLR binding region of apoB100, in the development of hyperlipidemia and atherosclerosis. Together, this work highlights the importance and interconnectedness of glucose and lipid metabolism, and sheds new light on the critical role of apolipoprotein E in the development of dyslipidemia and atherosclerosis during diabetes

\u3cem\u3eAPOE\u3c/em\u3e and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD), and is associated with impairments in cerebral metabolism and cerebrovascular function. A substantial body of literature now points to E4 as a driver of multiple impairments seen in AD, including blunted brain insulin signaling, mismanagement of brain cholesterol and fatty acids, reductions in blood brain barrier (BBB) integrity, and decreased cerebral glucose uptake. Various neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been instrumental in characterizing these metabolic and vascular deficits associated with this important AD risk factor. In the current mini-review article, we summarize the known effects of APOE on cerebral metabolism and cerebrovascular function, with a special emphasis on recent findings via neuroimaging approaches

\u3ci\u3eAPOE\u3c/i\u3e Genetics Influence Murine Gut Microbiome

Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously, we and others reported an association between APOE alleles and the gut microbiome. Here, we evaluated effects of APOE heterozygosity and tested whether these overall results extended to mice maintained under ideal conditions for microbiome analyses. To model human APOE alleles, this study used APOE targeted replacement (TR) mice on a C57Bl/6 background. To minimize genetic drift, homozygous APOE3 mice were crossed to homozygous APOE2 or homozygous APOE4 mice prior to the study, and the resulting heterozygous progeny crossed further to generate the study mice. To maximize environmental homogeneity, mice with mixed genotypes were housed together and used bedding from the cages was mixed and added back as a portion of new bedding. Fecal samples were obtained from mice at 3-, 5- and 7-months of age, and microbiota analyzed by 16S ribosomal RNA gene amplicon sequencing. Linear discriminant analysis of effect size (LefSe) identified taxa associated with APOE status, depicted as cladograms to show phylogenetic relatedness. The influence of APOE status was tested on alpha-diversity (Shannon H index) and beta-diversity (principal coordinate analyses and PERMANOVA). Individual taxa associated with APOE status were identified by classical univariate analysis. Whether findings in the APOE mice were replicated in humans was evaluated by using published microbiome genome wide association data. Cladograms revealed robust differences with APOE in male mice and limited differences in female mice. The richness and evenness (alpha-diversity) and microbial community composition (beta-diversity) of the fecal microbiome was robustly associated with APOE status in male but not female mice. Classical univariate analysis revealed individual taxa that were significantly increased or decreased with APOE, illustrating a stepwise APOE2-APOE3–APOE4 pattern of association with heterozygous animals trending as intermediate in the stepwise pattern. The relative abundance of bacteria from the class Clostridia, order Clostridiales, family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of Erysipelotrichia increased with APOE4 status, a finding that extended to humans. In this study, wherein mice were maintained in an ideal fashion for microbiome studies, gut microbiome profiles were strongly and significantly associated with APOE status in male APOE-TR mice. Erysipelotrichia are increased with APOE4 in both mice and humans. APOE allelic effects appeared generally intermediate in heterozygous animals. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on disease-relevant phenotypes, will be necessary to determine if alterations in the gut microbiome represent a novel mechanism whereby APOE alleles impact disease

Mitochondrial Metabolism in Major Neurological Diseases

Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell’s ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation–functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation and possibly disease manifestation. This review will discuss the basic functions of mitochondria and how alterations in mitochondrial activity lead to neurological disease progression

Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome

Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in hippocampal-dependent spatial learning and memory were exaggerated in E4 mice. Combining genome-wide measures of DNA hydroxymethylation with comprehensive untargeted metabolomics, we identified novel alterations in purine metabolism, glutamate metabolism, and the pentose phosphate pathway. Finally, in E4 mice, the metabolic and cognitive deficiencies caused by HFD were rescued by switching to a low fat diet for one month, suggesting a functional role was associated with reversal of the same metabolic pathways described above. These results suggest a susceptibility of E4 carriers to metabolic impairments brought on by IR, and may guide development of novel therapies for cognitive decline and dementia

Oral Gavage Delivery of Stable Isotope Tracer for in Vivo Metabolomics

Stable isotope-resolved metabolomics (SIRM) is a powerful tool for understanding disease. Advances in SIRM techniques have improved isotopic delivery and expanded the workflow from exclusively in vitro applications to in vivo methodologies to study systemic metabolism. Here, we report a simple, minimally-invasive and cost-effective method of tracer delivery to study SIRM in vivo in laboratory mice. Following a brief fasting period, we orally administered a solution of [U-13C] glucose through a blunt gavage needle without anesthesia, at a physiological dose commonly used for glucose tolerance tests (2 g/kg bodyweight). We defined isotopic enrichment in plasma and tissue at 15, 30, 120, and 240 min post-gavage. 13C-labeled glucose peaked in plasma around 15 min post-gavage, followed by period of metabolic decay and clearance until 4 h. We demonstrate robust enrichment of a variety of central carbon metabolites in the plasma, brain and liver of C57/BL6 mice, including amino acids, neurotransmitters, and glycolytic and tricarboxylic acid (TCA) cycle intermediates. We then applied this method to study in vivo metabolism in two distinct mouse models of diseases known to involve dysregulation of glucose metabolism: Alzheimer’s disease and type II diabetes. By delivering [U-13C] glucose via oral gavage to the 5XFAD Alzheimer’s disease model and the Lepob/ob type II diabetes model, we were able to resolve significant differences in multiple central carbon pathways in both model systems, thus providing evidence of the utility of this method to study diseases with metabolic components. Together, these data clearly demonstrate the efficacy and efficiency of an oral gavage delivery method, and present a clear time course for 13C enrichment in plasma, liver and brain of mice following oral gavage of [U-13C] glucose—data we hope will aid other researchers in their own 13C-glucose metabolomics study design

Apolipoprotein E4 Mediates Insulin Resistance-Associated Cerebrovascular Dysfunction and the Post-Prandial Response

Metabolic dysfunction, commonly a result of diets high in saturated fats and sugar, is associated with impaired cognitive function and an increased risk of age-related cognitive decline (ACD) and Alzheimer’s disease (AD). Compared to the E3 isoform of apolipoprotein (apoE), the E4 isoform is a major genetic risk factor for ACD, AD, and for developing cognitive impairments following various environmental challenges, including dietary challenges such as a high-fat diet (HFD). Both insulin resistance (IR) and E4 are associated with metabolic and vascular impairments. Deficits in cerebral metabolism and cerebrovascular function have been proposed as initiating events leading to these impairments. In the current study, we employed a model of human apoE targeted replacement mice and HFD-induced obesity to study the potential link between E4 and IR, at rest and following a postprandial challenge. HFD-induced IR was associated with impaired cognition, reduced cerebral blood volume and decreased glucose uptake. These effects were more profound in E4 than E3 mice. Furthermore, the cognitive, metabolic and cerebrovascular responses to an exogenous glucose load showed an apoE isoform-dependent response, with E4, but not E3 mice, acutely benefiting from a spike in blood glucose