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

Dynamic imaging using Motion-Compensated SmooThness Regularization on Manifolds (MoCo-SToRM)

We introduce an unsupervised motion-compensated reconstruction scheme for high-resolution free-breathing pulmonary MRI. We model the image frames in the time series as the deformed version of the 3D template image volume. We assume the deformation maps to be points on a smooth manifold in high-dimensional space. Specifically, we model the deformation map at each time instant as the output of a CNN-based generator that has the same weight for all time-frames, driven by a low-dimensional latent vector. The time series of latent vectors account for the dynamics in the dataset, including respiratory motion and bulk motion. The template image volume, the parameters of the generator, and the latent vectors are learned directly from the k-t space data in an unsupervised fashion. Our experimental results show improved reconstructions compared to state-of-the-art methods, especially in the context of bulk motion during the scans

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

Power-Based Droop Control in DC Microgrids Enabling Seamless Disconnection From Upstream Grids

This paper proposes a local power-based droop controller for distributed energy resource converters in dc microgrids that are connected to upstream grids by grid-interface converters. During normal operation, the grid-interface converter imposes the microgrid bus voltage, and the proposed controller allows power flow regulation at distributed energy resource converters\u2019 output. On the other hand, during abnormal operation of the grid-interface converter (e.g., due to faults in the upstream grid), the proposed controller allows bus voltage regulation by droop control. Notably, the controller can autonomously convert from power flow control to droop control, without any need of bus voltage variation detection schemes or communication with other microgrid components, which enables seamless transitions between these two modes of operation. Considering distributed energy resource converters employing the power-based droop control, the operation modes of a single converter and of the whole microgrid are defined and investigated herein. The controller design is also introduced. Furthermore, the power sharing performance of this control approach is analyzed and compared with that of classical droop control. The experimental results from a laboratory-scale dc microgrid prototype are reported to show the final performances of the proposed power-based droop control

Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.This work was supported by the NIH (Grants AI124474 and AI131639 to R.P. and Grant AI136534 to R.M.T.). It was also supported in part by NIH National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards Grant UL1 TR002535. The contents are the authors’sole responsibility anddo not necessarily represent official NIH views.S

Systemic Administration of Antiretrovirals Prior to Exposure Prevents Rectal and Intravenous HIV-1 Transmission in Humanized BLT Mice

Successful antiretroviral pre-exposure prophylaxis (PrEP) for mucosal and intravenous HIV-1 transmission could reduce new infections among targeted high-risk populations including discordant couples, injection drug users, high-risk women and men who have sex with men. Targeted antiretroviral PrEP could be particularly effective at slowing the spread of HIV-1 if a single antiretroviral combination were found to be broadly protective across multiple routes of transmission. Therefore, we designed our in vivo preclinical study to systematically investigate whether rectal and intravenous HIV-1 transmission can be blocked by antiretrovirals administered systemically prior to HIV-1 exposure. We performed these studies using a highly relevant in vivo model of mucosal HIV-1 transmission, humanized Bone marrow/Liver/Thymus mice (BLT). BLT mice are susceptible to HIV-1 infection via three major physiological routes of viral transmission: vaginal, rectal and intravenous. Our results show that BLT mice given systemic antiretroviral PrEP are efficiently protected from HIV-1 infection regardless of the route of exposure. Specifically, systemic antiretroviral PrEP with emtricitabine and tenofovir disoproxil fumarate prevented both rectal (Chi square = 8.6, df = 1, p = 0.003) and intravenous (Chi square = 13, df = 1, p = 0.0003) HIV-1 transmission. Our results indicate that antiretroviral PrEP has the potential to be broadly effective at preventing new rectal or intravenous HIV transmissions in targeted high risk individuals. These in vivo preclinical findings provide strong experimental evidence supporting the potential clinical implementation of antiretroviral based pre-exposure prophylactic measures to prevent the spread of HIV/AIDS

Deep Sequencing of the Mexican Avocado Transcriptome, an Ancient Angiosperm with a High Content of Fatty Acids

Background: Avocado (Persea americana) is an economically important tropical fruit considered to be a good source of fatty acids. Despite its importance, the molecular and cellular characterization of biochemical and developmental processes in avocado is limited due to the lack of transcriptome and genomic information. Results: The transcriptomes of seeds, roots, stems, leaves, aerial buds and flowers were determined using different sequencing platforms. Additionally, the transcriptomes of three different stages of fruit ripening (pre-climacteric, climacteric and post-climacteric) were also analyzed. The analysis of the RNAseqatlas presented here reveals strong differences in gene expression patterns between different organs, especially between root and flower, but also reveals similarities among the gene expression patterns in other organs, such as stem, leaves and aerial buds (vegetative organs) or seed and fruit (storage organs). Important regulators, functional categories, and differentially expressed genes involved in avocado fruit ripening were identified. Additionally, to demonstrate the utility of the avocado gene expression atlas, we investigated the expression patterns of genes implicated in fatty acid metabolism and fruit ripening. Conclusions: A description of transcriptomic changes occurring during fruit ripening was obtained in Mexican avocado, contributing to a dynamic view of the expression patterns of genes involved in fatty acid biosynthesis and the fruit ripening process

Equivalence of three-dimensional spacetimes

A solution to the equivalence problem in three-dimensional gravity is given and a practically useful method to obtain a coordinate invariant description of local geometry is presented. The method is a nontrivial adaptation of Karlhede invariant classification of spacetimes of general relativity. The local geometry is completely determined by the curvature tensor and a finite number of its covariant derivatives in a frame where the components of the metric are constants. The results are presented in the framework of real two-component spinors in three-dimensional spacetimes, where the algebraic classifications of the Ricci and Cotton-York spinors are given and their isotropy groups and canonical forms are determined. As an application we discuss Goedel-type spacetimes in three-dimensional General Relativity. The conditions for local space and time homogeneity are derived and the equivalence of three-dimensional Goedel-type spacetimes is studied and the results are compared with previous works on four-dimensional Goedel-type spacetimes.Comment: 13 pages - content changes and corrected typo

Atypical Q Fever in US Soldiers

Q fever is an emerging infectious disease among US soldiers serving in Iraq. Three patients have had atypical manifestations, including 2 patients with acute cholecystitis and 1 patient with acute respiratory distress syndrome. Providers must be aware of Q fever’s signs and symptoms to avoid delays in treatment