scholarly journals Characterization of Intermediate Steps in Amyloid Beta (Aβ) Production under Near-native Conditions

2013 ◽  
Vol 289 (3) ◽  
pp. 1540-1550 ◽  
Author(s):  
Fredrik Olsson ◽  
Staffan Schmidt ◽  
Veit Althoff ◽  
Lisa M. Munter ◽  
Shaobo Jin ◽  
...  
Keyword(s):  
Relative Increase ◽  
Aβ Peptides ◽  
Pharmacological Modulation ◽  
Native Cell ◽  
Familial Alzheimer Disease ◽  
Transmembrane Sequence ◽  
Aβ Generation ◽  
The Impact ◽  
Aβ Production

Processing of the amyloid precursor protein (APP) by γ-secretase results in generation of Aβ peptides of different lengths ranging from 51 to 30 residues. Accumulation of Aβ and in particular Aβ42 is enhanced by familial Alzheimer disease (FAD) causing mutations in APP and is believed to play a pivotal role. The molecular mechanism underlying normal Aβ production, the impact of FAD mutations on this process and how anti-amyloidogenic γ-secretase modulators (GSMs) cause a selective decrease in Aβ40 and Aβ42 and an increase in shorter Aβ peptides, however, is poorly understood. By using a combined immuno- and LC-MS-based assay we identify several major intermediates, i.e. 3- and 4-peptides that line up head to head across the entire APP transmembrane sequence from Aβ51 to Aβ31/Aβ30 and from Aβ49 to Aβ30/31. FAD APP mutations displayed a relative increase in 3- and 4-peptides from Aβ48 to Aβ38 compared with Aβ49 to Aβ37. These findings correlate with an increase in the Aβ42/40 ratio. GSMs caused a decrease in Aβ40 and Aβ42 and an increase in Aβ37 and Aβ38 paralleled by an increase of the intermediates Aβ40–38 and Aβ42–39. Collectively, these data provide a thorough characterization of all intermediate steps in Aβ production in native cell membranes and provide key mechanistic insights to genetic and pharmacological modulation of Aβ generation.

scholarly journals Plasmalogens Inhibit APP Processing by Directly Affectingγ-Secretase Activity in Alzheimer’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Tatjana L. Rothhaar ◽  
Sven Grösgen ◽  
Viola J. Haupenthal ◽  
Verena K. Burg ◽  
Benjamin Hundsdörfer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vicious Cycle ◽  
Aβ Peptides ◽  
App Processing ◽  
Secretase Activity ◽  
Brain Phospholipids ◽  
Plasmalogen Level ◽  
The Impact ◽  
Aβ Production

Lipids play an important role as risk or protective factors in Alzheimer’s disease (AD). Previously it has been shown that plasmalogens, the major brain phospholipids, are altered in AD. However, it remained unclear whether plasmalogens themselves are able to modulate amyloid precursor protein (APP) processing or if the reduced plasmalogen level is a consequence of AD. Here we identify the plasmalogens which are altered in human ADpostmortembrains and investigate their impact on APP processing resulting in Aβ production. All tested plasmalogen species showed a reduction in γ-secretase activity whereas β- and α-secretase activity mainly remained unchanged. Plasmalogens directly affected γ-secretase activity, protein and RNA level of the secretases were unaffected, pointing towards a direct influence of plasmalogens on γ-secretase activity. Plasmalogens were also able to decrease γ-secretase activity in humanpostmortemAD brains emphasizing the impact of plasmalogens in AD. In summary our findings show that decreased plasmalogen levels are not only a consequence of AD but that plasmalogens also decrease APP processing by directly affecting γ-secretase activity, resulting in a vicious cycle: Aβ reduces plasmalogen levels and reduced plasmalogen levels directly increase γ-secretase activity leading to an even stronger production of Aβ peptides.

scholarly journals The Alzheimer’s disease associated bacterial protease RgpB from P. gingivalis activates the alternative β-secretase meprin β thereby increasing Aβ generation

2019 ◽  
Author(s):  
Fred Armbrust ◽  
Cynthia Colmorgen ◽  
Claus U. Pietrzik ◽  
Christoph Becker-Pauly
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Reactive Microglia ◽  
Aβ Peptides ◽  
Bacterial Protease ◽  
Whole Exome ◽  
Aβ Generation ◽  
The Impact

AbstractAlzheimer’s disease (AD) is the most common type of dementia and characterized by tau hyperphosphorylation, oxidative stress, reactive microglia and amyloid-β (Aβ) deposits. A recent study revealed that Porphyromonas gingivalis infection is associated with amyloid β generation in Alzheimer’s disease. Increased Aβ levels, tau degradation and neuronal toxicity were observed as a consequence of ginigipain R (RgpB) activity, a cysteine protease constitutively secreted by P. gingivalis. Of note, we previously identified RgpB as a potent activator of the metalloproteinase meprin β. Interestingly, meprin β is an alternative β-secretase of the amyloid precursor protein (APP), which together with the γ-secretase leads to the generation of aggregation-prone N-terminally truncated Aβ2-x peptides. Importantly, identification of a risk gene variant of meprin β (rs173032) for Alzheimer’s disease using whole-exome sequencing of the BDR cohort further supports the impact of this alternative β-secretase. Thus, we wondered if increased Aβ levels as a consequence of P. gingivalis colonization into the brain might be due to meprin β activation by RgpB. Here, we demonstrate that i) upon incubation with RgpB the proteolytic activity of meprin β at the cell surface of transfected HEK cells or of endogenously expressed enzyme in SH-SY5Y neuroblastoma cells was significantly increased, and that ii) RgpB-mediated increase in meprin β activity leads to massive generation of Aβ-peptides. In conclusion, our findings would further explain the pathogenesis of P. gingivalis in AD brain.

The Analyses of Learning Strategies in English as a Second Language: Theoretical Classification and Measurement Test

2020 ◽  
Vol 4 (2) ◽  
pp. 118-129
Author(s):  
Asti Gumartifa ◽  
◽  
Indah Windra Dwie Agustiani
Keyword(s):  
Language Learning ◽  
Learning Outcomes ◽  
Learning Strategies ◽  
Learning Process ◽  
English Learners ◽  
English Language ◽  
Point Of View ◽  
Effective Learning ◽  
The Impact

Gaining English language learning effectively has been discussed all years long. Similarly, Learners have various troubles outcomes in the learning process. Creating a joyful and comfortable situation must be considered by learners. Thus, the implementation of effective learning strategies is certainly necessary for English learners. This descriptive study has two purposes: first, to introduce the classification and characterization of learning strategies such as; memory, cognitive, metacognitive, compensation, social, and affective strategies that are used by learners in the classroom and second, it provides some questionnaires item based on Strategy of Inventory for Language Learning (SILL) version 5.0 that can be used to examine the frequency of students’ learning strategies in the learning process. The summary of this study explains and discusses the researchers’ point of view on the impact of learning outcomes by learning strategies used. Finally, utilizing appropriate learning strategies are certainly beneficial for both teachers and learners to achieve the learning target effectively.

scholarly journals Modulation of Gut Microbiota and Oxidative Status by β-Carotene in Late Pregnant Sows

2020 ◽  
Vol 7 ◽  
Author(s):  
Xupeng Yuan ◽  
Jiahao Yan ◽  
Ruizhi Hu ◽  
Yanli Li ◽  
Ying Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Dietary Supplementation ◽  
Basal Diet ◽  
Fecal Microbiota ◽  
Control Group ◽  
Metabolic Activities ◽  
The Impact ◽  
Positive Effect ◽  
Β Carotene

Recent evidences suggest that gut microbiota plays an important role in regulating physiological and metabolic activities of pregnant sows, and β-carotene has a potentially positive effect on reproduction, but the impact of β-carotene on gut microbiota in pregnant sows remains unknown. This study aimed to explore the effect and mechanisms of β-carotene on the reproductive performance of sows from the aspect of gut microbiota. A total of 48 hybrid pregnant sows (Landrace × Yorkshire) with similar parity were randomly allocated into three groups (n = 16) and fed with a basal diet or a diet containing 30 or 90 mg/kg of β-carotene from day 90 of gestation until parturition. Dietary supplementation of 30 or 90 mg/kg β-carotene increased the number of live birth to 11.82 ± 1.54 and 12.29 ± 2.09, respectively, while the control group was 11.00 ± 1.41 (P = 0.201). Moreover, β-carotene increased significantly the serum nitric oxide (NO) level and glutathione peroxidase (GSH-Px) activity (P < 0.05). Characterization of fecal microbiota revealed that 90 mg/kg β-carotene increased the diversity of the gut flora (P < 0.05). In particular, β-carotene decreased the relative abundance of Firmicutes including Lachnospiraceae AC2044 group, Lachnospiraceae NK4B4 group and Ruminococcaceae UCG-008, but enriched Proteobacteria including Bilophila and Sutterella, and Actinobacteria including Corynebacterium and Corynebacterium 1 which are related to NO synthesis. These data demonstrated that dietary supplementation of β-carotene may increase antioxidant enzyme activity and NO, an important vasodilator to promote the neonatal blood circulation, through regulating gut microbiota in sows.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

scholarly journals Exploring the Characteristics and Influencing Factors of Leisure Walking Based on the Demand of Behavior

2021 ◽  
Vol 13 (8) ◽  
pp. 4105
Author(s):  
Yupei Jiang ◽  
Honghu Sun
Keyword(s):  
Health Benefits ◽  
Health Benefit ◽  
Public Health Research ◽  
Space Time ◽  
Time Behavior ◽  
Walking Behavior ◽  
Face To Face ◽  
Residential Neighborhood ◽  
The Impact

Leisure walking has been an important topic in space-time behavior and public health research. However, prior studies pay little attention to the integration and the characterization of diverse and multilevel demands of leisure walking. This study constructs a theoretical framework of leisure walking behavior demands from three different dimensions and levels of activity participation, space-time opportunity, and health benefit. On this basis, through a face-to-face survey in Nanjing, China (N = 1168, 2017–2018 data), this study quantitatively analyzes the characteristics of leisure walking demands, as well as the impact of the built environment and individual factors on it. The results show that residents have a high demand for participation and health benefits of leisure walking. The residential neighborhood provides more space opportunities for leisure walking, but there is a certain constraint on the choice of walking time. Residential neighborhood with medium or large parks is more likely to satisfy residents’ demands for engaging in leisure walking and obtaining high health benefits, while neighborhood with a high density of walking paths tends to limit the satisfaction of demands for space opportunity and health benefit. For residents aged 36 and above, married, or retired, their diverse demands for leisure walking are more likely to be fulfilled, while those with high education, medium-high individual income, general and above health status, or children (<18 years) are less likely to be fulfilled. These finding that can have important implications for the healthy neighborhood by fully considering diverse and multilevel demands of leisure walking behavior.

scholarly journals Size-resolved characterization of organic aerosol in the North China Plain: new insights from high resolution spectral analysis

2021 ◽  
Author(s):  
Weiqi Xu ◽  
Chun Chen ◽  
Yanmei Qiu ◽  
Conghui Xie ◽  
Yunle Chen ◽  
...  
Keyword(s):  
Radiative Forcing ◽  
North China Plain ◽  
North China ◽  
Fine Particles ◽  
Large Fraction ◽  
Organic Aerosol ◽  
Size Distributions ◽  
The North ◽  
The Impact

Organic aerosol (OA), a large fraction of fine particles, has a large impact on climate radiative forcing and human health, and the impact depends strongly on size distributions. Here we...

scholarly journals Performance Analysis of Indentation Punch on High Energy Lithium Pouch Cells and Simulated Model Improvement

Polymers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 1971
Author(s):  
Lihua Ye ◽  
Muhammad Muzamal Ashfaq ◽  
Aiping Shi ◽  
Syyed Adnan Raheel Shah ◽  
Yefan Shi
Keyword(s):  
Short Circuit ◽  
Lithium Ion ◽  
Mechanical Deformation ◽  
High Energy ◽  
State Of Charge ◽  
Punch Test ◽  
Short Course ◽  
Model Cell ◽  
The Impact

In this research, the aim relates to the material characterization of high-energy lithium-ion pouch cells. The development of appropriate model cell behavior is intended to simulate two scenarios: the first is mechanical deformation during a crash and the second is an internal short circuit in lithium-ion cells during the actual effect scenarios. The punch test has been used as a benchmark to analyze the effects of different state of charge conditions on high-energy lithium-ion battery cells. This article explores the impact of three separate factors on the outcomes of mechanical punch indentation experiments. The first parameter analyzed was the degree of prediction brought about by experiments on high-energy cells with two different states of charge (greater and lesser), with four different sizes of indentation punch, from the cell’s reaction during the indentation effects on electrolyte. Second, the results of the loading position, middle versus side, are measured at quasi-static speeds. The third parameter was the effect on an electrolyte with a different state of charge. The repeatability of the experiments on punch loading was the last test function analyzed. The test results of a greater than 10% state of charge and less than 10% state of charge were compared to further refine and validate this modeling method. The different loading scenarios analyzed in this study also showed great predictability in the load-displacement reaction and the onset short circuit. A theoretical model of the cell was modified for use in comprehensive mechanical deformation. The overall conclusion found that the loading initiating the cell’s electrical short circuit is not instantaneously instigated and it is subsequently used to process the development of a precise and practical computational model that will reduce the chances of the internal short course during the crash.

scholarly journals Impact of COVID-19 pandemic on stroke admissions in Qatar

2021 ◽  
Vol 3 (1) ◽  
pp. e000084
Author(s):  
Naveed Akhtar ◽  
Salman Al Jerdi ◽  
Ziyad Mahfoud ◽  
Yahia Imam ◽  
Saadat Kamran ◽  
...  
Keyword(s):  
Hospital Admissions ◽  
Small Vessel Disease ◽  
Tertiary Care ◽  
Relative Increase ◽  
Large Vessel ◽  
Tertiary Care Centre ◽  
Transient Ischaemic Attacks ◽  
Stroke Mimics ◽  
Coronary Syndromes ◽  
The Impact

IntroductionThe COVID-19 pandemic has resulted in a dramatic unexplained decline in hospital admissions due to acute coronary syndromes and stroke. Several theories have emerged aiming to explain this decline, mostly revolving around the fear of contracting the disease and thus avoiding hospital visits.AimsIn this study, we aim to examine the impact of the COVID-19 pandemic on stroke admissions to a tertiary care centre in Qatar.MethodsThe Hamad General Hospital stroke database was interrogated for stroke admissions between September 2019 and May 2020. The number of stroke admissions, stroke subtypes and short-term outcomes was compared between the ‘pre-COVID-19’ period (September 2019 to February 2020) and the COVID-19 pandemic period (March to May 2020).ResultsWe observed a significant decline in monthly admissions in March (157), April (128) and May (135) compared with the pre-COVID-19 6-month average (229) (p=0.024). The reduction in admissions was most evident in functional stroke mimics. The average admissions decreased from 87 to 34 per month (p=0.0001). Although there were no significant differences in admissions due to ischaemic stroke (IS), intracranial haemorrhage or transient ischaemic attacks between the two periods, we noted a relative decrease in IS due to small vessel disease and an increase in those due to large vessel atherosclerosis in March to May 2020.ConclusionsThe decline in overall stroke admissions during the COVID-19 pandemic is most likely related to concerns of contracting the infection, evidenced mainly by a decline in admissions of stroke mimics. However, a relative increase in large vessel occlusions raises suspicion of pathophysiological effects of the virus, and requires further investigation.

Sign in / Sign up

Export Citation Format

Share Document