The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory

The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer's disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II-VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology

Mean Shift versus Variance Inflation Approach for Outlier Detection—A Comparative Study

Outlier detection is one of the most important tasks in the analysis of measured quantities to ensure reliable results. In recent years, a variety of multi-sensor platforms has become available, which allow autonomous and continuous acquisition of large quantities of heterogeneous observations. Because the probability that such data sets contain outliers increases with the quantity of measured values, powerful methods are required to identify contaminated observations. In geodesy, the mean shift model (MS) is one of the most commonly used approaches for outlier detection. In addition to the MS model, there is an alternative approach with the model of variance inflation (VI). In this investigation the VI approach is derived in detail, truly maximizing the likelihood functions and examined for outlier detection of one or multiple outliers. In general, the variance inflation approach is non-linear, even if the null model is linear. Thus, an analytical solution does usually not exist, except in the case of repeated measurements. The test statistic is derived from the likelihood ratio (LR) of the models. The VI approach is compared with the MS model in terms of statistical power, identifiability of actual outliers, and numerical effort. The main purpose of this paper is to examine the performance of both approaches in order to derive recommendations for the practical application of outlier detection

Digitalisierung in der Immobilienwirtschaft

DIGITALISIERUNG IN DER IMMOBILIENWIRTSCHAFT Digitalisierung in der Immobilienwirtschaft / Bölting, Torsten (Rights reserved) ( -

Influence of fiber undulation on the mechanical properties of fiber reinforced plastics

The classical lamination theory is widely used for the calculation of the mechanical properties of reinforced plastics and stress distribution inside laminates. The resulting Young’s moduli along the fiber direction are close to the achievable properties of unidirectional reinforced laminates [1]. However in most applications woven fabrics are used that lower the stiffness of the composites [2]. The influence of undulation and waviness of the fibers on the mechanical properties is yet to be explicitly specified. This article deals with the description of fiber undulation as well as the coherence between the geometry of fabrics and the achievable laminate properties. In order to get improved estimations for the Young’s modulus, a new, easily applicable method is introduced to consider the undulation of fibers in the calculation process of the classical lamination theory (CLT). The results show that the given method leads to diminishing the error of the ordinary process

Flash-Disks fur das schnelle Commit in Oracle

In diesem Beitrag werden Einsatzmöglichkeiten von Flash-Disks (auch Solid State Disks bzw. SSDs genannt) in DBMS-basierten Systemen betrachtet. Anhand des DBMS Oracle diskutieren wir eine Idee, durch Flash-Disk-Einsatz das Commit in DBMS zu beschleunigen. Für detaillierte Messungen wird derzeit ein Testframe entwickelt. Erste Versuche und Messungen demonstrieren das Verhalten von SSDs zur Speicherung von Transaktionslogs

Vestibular dysfunction in the adult CBA/CaJ mouse after lead and cadmium treatment

Objectives: The vestibular system allows the perception of position and motion and its dysfunction presents as motion impairment, vertigo and balance abnormalities, leading to debilitating psychological discomfort and difficulty performing daily tasks. Although declines and deficits in vestibular function have been noted in rats exposed to lead (Pb) and in humans exposed to Pb and cadmium (Cd), no studies have directly examined the pathological and pathophysiological effects upon the vestibular apparatus of the inner ear. Methods: Eighteen young adult mice were exposed through their drinking water (3 mM Pb, 300 µM Cd, or a control treatment) for 10 weeks. Before and after treatment, they underwent a vestibular assessment, consisting of a rotarod performance test and a novel head stability test to measure the vestibulocolic reflex. At the conclusion of the study, the utricles were analyzed immunohistologically for condition of hair cells and nerve fibers. Results: Increased levels of Pb exposure correlated with decreased head stability in space; no significant decline in performance on rotarod test was found. No damage to the hair cells or the nerve fibers of the utricle was observed in histology. Conclusions: The young adult CBA/CaJ mouse is able to tolerate occupationally‐relevant Pb and Cd exposure well, but the correlation between Pb exposure and reduced head stability suggests that Pb exposure causes a decline in vestibular function. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 869–876, 2017.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136249/1/tox22286_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136249/2/tox22286.pd

Midlife vascular risk factors and risk of incident dementia:Longitudinal cohort and Mendelian randomization analyses in the UK Biobank

Introduction Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. Methods Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia. Results Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI;0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]). Discussion These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk

KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia

i3 Evaluation (Valid 45) Addendum Report

This project was supported by the US Department of Education, Institute for Education Sciences, Investing in Innovation (i3) fund.The evaluation of LISTO involved a multisite cluster randomized trial (CRT) designed to meet the Every Student Succeeds Act (ESSA) Tier 2 standards for “moderate” evidence, as well as the What Works Clearinghouse (WWC) standards "with reservations." The study estimated program impacts on both student and teacher outcomes and documented the fidelity of implementation and educators’ perceptions of program quality. Schools with participating fifth grade science teachers were randomly assigned to either the treatment or control condition. Schools were randomly assigned within district blocks when more than one school in a district chose to participate in the study. Fifth grade science teachers may have participated in the intervention for either one or two years over the 2017–18 and 2018–19 school years, and some teachers were allowed to join the study after the random assignment of schools. Students were exposed to the intervention only in their fifth-grade year, either in the 2017–18 or 2018–19 school year. Again, data for the year 2017–18 reflected a low fidelity of implementation for the entire first semester, due to the reasons previously discussed. The resulting impacts included delaying the beginning of year testing, curriculum implementation, baseline observations, and professional development schedules for the original confirmatory group. Outcomes collected in the 2017–18 school year were considered to be exploratory, given the timing of Hurricane Harvey, which hit Texas in August of 2017, as mentioned earlier. Outcomes in the 2018–19 school year served as the confirmatory contrasts. In both school years, students were exposed to the program through their teachers in only their fifth-grade year. One year of exposure for students may have been insufficient to increase student achievement in science or reading, yet some impacts were observed. And, due to the COVID-19 pandemic, in Year 3, only BISA, ITBS science, and science interest survey scores were collected and only in the fall of the 2019–20 school year. STAAR Science and Reading scores were not collected during Year 3 (2019–20). Thus, the only contrasts we were able to conduct on student achievement were those focusing on Year 4 administrations of STAAR Science and Reading, BISA, ITBS Science, and the science interest survey.US Department of Education, award number U411B160011

Connectomics and molecular imaging in neurodegeneration.

Our understanding on human neurodegenerative disease was previously limited to clinical data and inferences about the underlying pathology based on histopathological examination. Animal models and in vitro experiments have provided evidence for a cell-autonomous and a non-cell-autonomous mechanism for the accumulation of neuropathology. Combining modern neuroimaging tools to identify distinct neural networks (connectomics) with target-specific positron emission tomography (PET) tracers is an emerging and vibrant field of research with the potential to examine the contributions of cell-autonomous and non-cell-autonomous mechanisms to the spread of pathology. The evidence provided here suggests that both cell-autonomous and non-cell-autonomous processes relate to the observed in vivo characteristics of protein pathology and neurodegeneration across the disease spectrum. We propose a synergistic model of cell-autonomous and non-cell-autonomous accounts that integrates the most critical factors (i.e., protein strain, susceptible cell feature and connectome) contributing to the development of neuronal dysfunction and in turn produces the observed clinical phenotypes. We believe that a timely and longitudinal pursuit of such research programs will greatly advance our understanding of the complex mechanisms driving human neurodegenerative diseases.The Molecular Imaging of Neurodegeneration Cologne (MINC) Symposium was partly funded by the Deutsche Forschungsgemeinschaft (DFG) awarded to Dr. Thilo van Eimeren (EI 892/5-1). The Deutsche Forschungsgemeinschaft (DFG) also awarded funding to Dr. Alexander Drzezga (DR442/91)