Search

Supplementary Material 6

Supplementary Material 1

Supplementary Material 4

Supplementary Material 2

Background: Alzheimer’s disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. Objective: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. Methods: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. Results: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. Conclusion: DA4-JC is a promising drug for the treatment of AD.

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. Objective: The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice. Methods: Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aβ plaques and neuroinflammation in the brain. IL-1β, TNF-α, and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting. Results: DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aβ deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1β and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κB activation in the hippocampus of APP/PS1 mice. Conclusion: DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD.

Additional file 1: Supplementary Figure 1. Quantitative analysis of gray values. Supplementary Table 1. Summary of WES Data and Data Quality Control. Supplementary Table 2. Summary Statistics for SNPs. Supplementary Table 3. Summary Statistics for InDels.

Microplastics are being widely discussed as an emerging global environmental contaminant. Microplastic pollution usually originates from land-based sources, which are then mainly transported through hydrological and atmospheric pathways and accumulated in terrestrial, freshwater and marine ecosystems. Urban environments represent a condensed area of human activities (including the production and use of plastic materials), and urban rivers may therefore be a key transporter of microplastic pollution. Understanding microplastic abundances in urban rivers is potentially important in finding effective means of reducing fluvial microplastic discharge. This study quantified microplastic abundances in surface waters along the Fenghua River, Ningbo, a coastal megacity in East China. Microplastic pollution was distributed unevenly along the river, with concentrations ranging from 300 n/m3 to 4000 n/m3 (0.3 – 4.0 n/L). Average concenterations were 1620.16 ± 878.22 n/m3 (1.62 ± 0.88 n/L) in summer (43 sampling points) and 1696.08 ± 983.52 n/m3 (1.70 ± 0.98 n/L) in winter (17 sampling points). The most common microplastic shapes, sizes, colors and types of polymers were fiber

Soil organic matter (SOM) content is an effective indicator of desertification; thus, monitoring its spatial‒temporal changes on a large scale is important for combating desertification. However, mapping SOM content in desertified land is challenging owing to the heterogeneous landscape, relatively low SOM content and vegetation coverage. Here, we modeled the SOM content in topsoil (0–20 cm) of desertified land in northern China by employing a high spatial resolution dataset and machine learning methods, with an emphasis on quarterly green and non-photosynthetic vegetation information, based on the Google Earth Engine (GEE). The results show: 1) the machine learning model performed better than the traditional multiple linear regression model (MLR) for SOM content estimation, and the Random Forest (RF) model was more accurate than the Support Vector Machine (SVM) model; 2) the quarterly information regarding green vegetation and non-photosynthetic were identified as key covariates for estimating the SOM content in desertified land, and an obvious improvement could be observed after simultaneously combining the Dead Fuel Index (DFI) and Normalized Difference Vegetation Index (NDVI) of the four quarters (R2 increased by 0.06, the root mean square error decreased by 0.05, the ratio of prediction deviation increased by 0.2, and the ratio of performance to interquartile distance increased by 0.5). In particular, the effects of the DFI in Q1 (the first quarter) and Q2 (the second quarter) on estimating low SOM content (

Circadian rhythm disturbance (CRD) is one of the iconic manifestations in Alzheimer’s disease (AD), a disease tightly associated with age, but the characteristics and gender difference of CRD occurred in AD have not been well demonstrated. Using 6-month-old triple transgenic AD mouse model (3xTg-AD) without obvious brain pathological changes, we demonstrated the gender difference of CRD at this age. We further showed abnormal Per gene expression in the central clock suprachiasmatic nucleus (SCN) of the 3xTg-AD mice. Specifically, compared with the wide type (WT) mice, the 3xTg-AD mice showed disrupted circadian locomotor rhythms both at LD (light-dark 12 h:12 h) and DD (constant dark) conditions, such as increased activities in the resting phase, decreased and scattered activities in the active phase, decreased overall activity intensities, amplitude, robustness, and increased intradaily variability. We further observed that 3xTg-AD female mice showed obviously less CRD compared with the 3xTg-AD male mice, and female mice of both WT and 3xTg-AD were more active in locomotor activity. Accordingly, 3xTg-AD mice showed a phase delay in the expression of Per1 and Per2 mRNA in the SCN, with the levels of Per1 and Per2 mRNA were significantly lower than that of WT mice at specific time points. We conclude that 3xTg-AD mice exhibit behavioral CRD at the age of six months with male gender preference, and these phenomena are at least partly associated with the alteration of Per1 and Per2 transcription patterns in the SCN.

Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD.

Julian Barnes is famous in contemporary literary world. His works have attracted many readers all over the world for his variety of writing style and his unceasing exploration of the truth of history and memory. As the Man Booker Prize winning novel in 2011, The Sense of an Ending mainly tells the story of the protagonist Tony Webster’s love relationship with Veronica Ford and his friendship with Adrian Finn through recalling the past. Taking the changing relationship among Tony, Veronica and Adrian as the main line, this paper mainly analyzes the different interpretive, ethical and aesthetic judgments and re-judgments made by Tony, the protagonist and the first person narrator, and the reader on the love and friendship in the novel in the light of James Phelan’s theory of narrative judgments. Through analysis, this paper shows the organic connections between the three types of narrative judgments, which not only promotes the narrative progression of the novel, but also realizes the perfect integration of the novel in narrative form, narrative ethics and narrative aesthetics. This process shows Barnes’ doubts about the reliability of human memory, which provides a better way for readers to understand the novel and appreciate Barnes’ superb narrative art.

Immunotherapy for Alzheimer's disease (AD) remains promising in the improvement of cognition and memory via the clearing of amyloid-β protein (Aβ) in the AD brain, despite some side effects. Our previous studies demonstrated that the 31-35 sequence of the Aβ molecule was the shortest active center and that polyclonal anti-Aβ31-35 antibody reduced neuronal apoptosis and cognitive impairments induced with acute Aβ application. The present study designed a novel single-chain variable fragment (scFv) monoclonal anti-Aβ31-35 antibody (scFv17) that specifically recognized extracellular Aβ and observed protective effects of scFv17 on pathological impairments in APP/PS1 transgenic mice. We also investigated its cellular and molecular mechanisms and found that scFv17 and 6E10 (a positive control) exhibited similar Aβ-clearing ability and that scFv17 produced a stronger effect in clearing Aβ oligomers than 6E10. scFv17, but not 6E10, enhanced anti-inflammatory responses with significant increases in IL-10 and TGF-β. 6E10 decreased BACE1 levels, and scFv17 significantly increased the level of secreted amyloid precursor protein-α (sAPPα), which is an important physiological neurotrophin from APP generated by α-secretase. 6E10 and scFv17, especially the latter, dramatically down-regulated the expression of neprilysin, which is an enzyme expressed in proportion to Aβ concentration. Therefore, the present study demonstrated that the novel monoclonal anti-Aβ31-35 antibody scFv17 effectively reduced pathological impairments in APP/PS1 transgenic mice via modulation of inflammatory cytokines and Aβ-related enzymes, which supports scFv17 as a new alternative in the current immunotherapy of AD.

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.

Apolipoprotein E4 (APOE4) allele located on chromosome 19 is a major genetic risk factor for developing Alzheimer’s disease (AD). However, the direct effects of ApoE4 on the cognitive function and long-term synaptic plasticity have not fully investigated. At the same time, although amyloid beta protein (Aβ)-ApoE complexes are principal components of AD-associated brain damage, there is still lack of in vivo study on the effects of co-existed Aβ1-40 and ApoE4. In the present study, we examined the effects of ApoE4 on the spatial memory and hippocampal long term potentiation (LTP) by using Morris water maze test and in vivo field potential recording, compared the neurotoxicity of Aβ1-40 and ApoE4, and investigated the effects of co-application of Aβ1-40 and ApoE4 on cognitive behavior and synaptic plasticity. The results showed that intracerebrovenrticular (i.c.v.) injection of Aβ1-40 or ApoE4 significantly and similarly impaired spatial learning and memory, and depressed the high-frequency stimulus (HFS) induced LTP. Importantly, compared to the effects of Aβ1-40 or ApoE4 alone, co-injection of Aβ1-40 and ApoE4 produced much heavier damages in cognitive behaviors and long term synaptic plasticity. These results demonstrated that ApoE4 not only exerted direct neurotoxicity but also enhanced the neurotoxicity of Aβ1-40 on spatial cognitive function and hippocampal LTP, which maybe partly elucidates the mechanism by which APOE4 allele exerted negative effects as a major genetic risk factor for developing AD.

This paper introduces an acoustic emission sensor using PVDF Piezoelectric film which is c onvenient to use in the field. In order to verify the reliability of GIS fault fast positioning system ba sed on PVDF piezoelectric film sensor, four different kinds of typical defects were set, and the practical research on GIS flashover positioning was carried out. The result shows that by comparing s ound intensity of different gas rooms, GIS fault fast positioning system based on PVDF piezoelectric film sensor, the fault location can be found accurately. I ntroduction In AC withstand voltage test of GIS, restricted by field condition, The location of the GIS flashover and puncture was mainly judged by human ear or ultrasonic locator and ultra high frequency locator. Ultrasonic locator and ultra high frequency locator were mostly limited by the number of sensor channels, meanwhile, the cost of the instrument was high and inconvenient to carry. Therefore, they can not be widely used in the field. As a result, it is urgent to study a flashover and breakdown of the gas chamber fault location system which can locate accurately and is practical, low power consumption, portable, and with signal displaying. Compared with the conventional piezoelectric materials, PVDF piezoelectric film materials have m any advantages such as: wide frequency response, high mechanical performance, light weight, good flexibility, less susceptible to pollution by water and chemicals, strong plasticity and so on, have been widely used in various industry fields(1-3). Extensive applications showed that the sensor made of this material has high sensitivity, overload resistance, good anti- interference simple operation, small v olume, and light weight(4,5). This paper designs a kind of flashover positioning system based on PVDF piezoelectric film sensor, which can quickly and accurately locate the discharge position by collecting and comparing the intensity of the acoustic signal from different sensor when the breakdown or flashover happened.