Ketones Improves Apolipoprotein E4-Related Memory Deficiency Via Sirtuin 3

Background: Apolipoprotein E4 (ApoE4) is the major genetic risk factor of Alzheimer\u27s disease (AD). ApoE4 carriers have cerebral hypometabolism which is thought as a harbinger of AD. Our previous studies indicated ketones improved mitochondria energy metabolism via sirtuin 3 (Sirt3). However, it is unclear whether ketones upregulate Sirt3 and improve ApoE4-related learning and memory deficits. Results: Ketones improved learning and memory abilities of ApoE4 mice but not ApoE3 mice. Sirt3, synaptic proteins, the NAD+/ NADH ratio, and ATP production were significantly increased in the hippocampus and the cortex from ketone treatment. Methods: Human ApoE3 and ApoE4 transgenic mice (9-month-old) were treated with either ketones or normal saline by daily subcutaneous injections for 3 months (ketones, beta-hydroxybutyrate (BHB): 600 mg/kg/day; acetoacetate (ACA): 150 mg/kg/day). Learning and memory ability of these mice were assessed. Sirt3 protein, synaptic proteins (PSD95, Synaptophysin), the NAD+/ NADH ratio, and ATP levels were measured in the hippocampus and the cortex. Conclusion: Our current studies suggest that ketones improve learning and memory abilities of ApoE4 transgenic mice. Sirt3 may mediate the neuroprotection of ketones by increasing neuronal energy metabolism in ApoE4 transgenic mice. This provides the foundation for Sirt3\u27s potential role in the prevention and treatment of AD

Sirtuin 3 Attenuates Amyloid-Beta Induced Neuronal Hypometabolism

Alzheimer\u27s disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy

Interleukin-17 Inhibits Adult Hippocampal Neurogenesis

Interleukin 17(A) (IL-17) is a potent pro-inflammatory cytokine that acts as a central regulator of inflammatory response within the brain, but its physiological roles under non-inflammatory conditions remain elusive. Here we report that endogenous IL-17 ablates neurogenesis in the adult dentate gyrus (DG) of hippocampus. Genetic deletion of IL-17 increased the number of adult-born neurons in the DG. Further, we found that IL-17 deletion altered cytokine network, facilitated basal excitatory synaptic transmission, enhanced intrinsic neuronal excitability, and increased expression of proneuronal genes in neuronal progenitor cells (NPCs). Our findings suggest a profound role of IL-17 in the negative regulation of adult hippocampal neurogenesis under physiology conditions

The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide Pathology and Cognition in Mice and Rhesus Macaques

Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer\u27s disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/6 mice, the performance was decreased at age 24-26 month whereas in hAPP transgenic mice, it was decreased as early as 9-12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies

Spontaneous Thalamic Hemorrhage as the First Presentation of Anaplastic Astrocytoma: A Case Report

The purpose of the study was to heighten awareness of anaplastic astrocytoma and the incidence of tumor apoplexy. A 47-year-old man with spontaneous thalamic hemorrhage as the first presentation of anaplastic astrocytoma was studied. Examination of the biopsy specimen revealed an anaplastic astrocytoma (WHO grade 3). Anaplastic astrocytoma rarely occurs as the first presentation in the thalamus with spontaneous intracranial hemorrhage. Misdiagnosis of tumor as stroke more commonly occurs in patients with a vascular risk factor, but with no history of neoplasia

BG-LoA: A Benchmarking Framework for BIM/GIS Data Integration based on Meta-Modelling Theory

There are various studies on the integration of building information modelling (BIM) and geographic information system (GIS) that convert BIM data into GIS data. These studies used different technologies, data models, and data formats such as RDF (Resource Description Framework), graph, CityGML, and Shapefile to address the data incompatibility problem between BIM and GIS. This makes it difficult to compare these studies for the purpose of assessing research innovation, and sometimes, improper comparisons were carried out between studies. To solve this problem, this study adopted the metamodeling theory used in model-driven software engineering (MDSE) and extended its 4-layer framework of level of abstraction. The new benchmarking framework, referred to as level of abstraction for BIM/GIS data integration (BG-LoA), has 5 levels, including meta metamodel (M3), metamodel (M2), model (M1), reality (data) (M0), and reality (real world) (M00). The common types of IFC (Industry Foundation Classes) conversion were analysed using the new framework, including IFC-to-CityGML, IFC-to-CityJSON, IFC-to-Shapefile, IFC-to-GML, IFC-to-3DTiles, IFC-to-RDF, IFC-to-IfcGraph, and IFC-to-UML. The result shows that the new framework can show the difference between those conversion types, which makes it easier for future studies to benchmark their work and assess level of contribution to the body of knowledge.Marie Skłodowska-Curie grant agreement No 10103433

High-level productivity of alpha,omega-dodecanedioic acid with a newly isolated Candida viswanathii strain

alpha,omega-Dicarboxylic acids (DC) are versatile chemical intermediates with different chain lengths, which are well-known as polymer building block. In this work, a new strain with high productivity of DC was isolated from oil-contaminated soil. Based on the morphology and phylogenetic analyses of the internal transcribed spacer sequences, it was characterized as Candida viswanathii. It was found that the contribution of carbon flux to the cell growth and DC production from n-dodecane could be regulated by the sucrose and yeast extract concentrations in the medium, and besides the broth pH, a suitable proportioning of sucrose and yeast extract was the key to achieve the optimal transition from cell growth phase to DC production phase. By optimizing culture conditions in a 7.5-L bioreactor, a higher DC productivity of 1.59 g center dot L-1 h(-1) with a corresponding concentration of 181.6 g/L was obtained. After the purification of DC from the culture, the results from gas chromatography-mass spectrometry, infrared spectroscopy and H-1-NMR showed that alpha,omega-dodecanedioic acid (DC12) was the major product of C. viswanathii ipe-1 using pure n-dodecane as substrate. For the first time, we reported that a high productivity of DC12 could be produced by C. viswanathii.</p

Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD(+)/NADH ratio. In this study, we investigated whether mitochondrial NAD(+)-dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD(+)-dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway

alpha, omega-Dodecanedioic acid production by Candida viswanathii ipe-1 with co-utilization of wheat straw hydrolysates and n-dodecane

Candida viswanathii ipe-1 was used to produce alpha, omega-dodecanedioic acid (DC12), which showed capability to ferment xylose and glucose simultaneously, while arabinose utilization was less efficient. A low concentration of furfural enhanced cell growth, and the addition of 4.0 g/L sodium acetate largely increased DC12 production. It indicated that detoxification of the wheat straw hydrolysates was not necessary for the biosynthesis of DC12. Based on the promising features of our strain, an efficient process was developed to produce DC12 from co-utilization of wheat straw hydrolysates and n-dodecane. Using this process, 129.7 g/L DC12 with a corresponding productivity of 1.13 g.L-1.h(-1) could be produced, which was increased by 40.0% compared with a sole carbon of glucose. The improved DC12 yield by the coutilization of wheat straw hydrolysates and n-dodecane using C. viswanathii ipe-1 demonstrates the great potential of using biomass as a feedstock in the production of DC12. (C) 2017 Elsevier Ltd. All rights reserved.</p