Role of Membrane GM1 on Early Neuronal Membrane Actions of Aβ During Onset of Alzheimer\u27s Disease

The ability of beta-amyloid peptide (Aβ) to disrupt the plasma membrane through formation of pores and membrane breakage has been previously described. However, the molecular determinants for these effects are largely unknown. In this study, we examined if the association and subsequent membrane perforation induced by Aβ was dependent on GM1levels. Pretreatment of hippocampal neurons with D-PDMP decreased GM1 and Aβ clustering at the membrane (Aβ fluorescent-punctas/20 μm, control = 16.2 ± 1.1 vs. D-PDMP = 6.4 ± 0.4, p \u3c 0.001). Interestingly, membrane perforation with Aβ occurred with a slower time course when the GM1 content was diminished (time to establish perforated configuration (TEPC) (min): control = 7.8 ± 2 vs. low GM1 = 12.1 ± 0.5, p \u3c 0.01), suggesting that the presence of GM1 in the membrane can modulate the distribution and the membrane perforation by Aβ. On the other hand, increasing GM1 facilitated the membrane perforation (TEPC: control = 7.8 ± 2 vs. GM1 = 6.2 ± 1 min, p \u3c 0.05). Additionally, using Cholera Toxin Subunit-B (CTB) to block the interaction of Aβ with GM1 attenuated membrane perforation significantly. Furthermore, pretreatment with CTB decreased the membrane association of Aβ (fluorescent-punctas/20 μm, Aβ: control = 14.8 ± 2.5 vs. CTB = 8 ± 1.4, p \u3c 0.05), suggesting that GM1 also plays a role in both association of Aβ with the membrane and in perforation. In addition, blockade of the Aβ association with CTB inhibited synaptotoxicity. Taken together, our results strongly suggest that membrane lipid composition can affect the ability of Aβ to associate and subsequently perforate the plasma membrane thereby modulating its neurotoxicity in hippocampal neurons

LEED studies of lead on copper (100)

Lead layers on copper (100) at coverages from 0.5 to 0.6 were investigated by quantitative LEED and AES measurements and dynamical LEED calculations. Comparisons of intensity measurements with dynamical calculations for the (Wurzel2 x Wurzel2)R45° structure show that the Pb atoms are adsorbed in hollow sites. The Cu---Pb distance is close to the sum of both metallic radii. The dense lead monolayer at a coverage of 0.6 exhibits a c(5 Wurzel2 x Wurzel2)R45° superstructure with cmm symmetry of the diffraction pattern. Calculations for five models were performed under variation of several geometric parameters. Most analogies were found for regular arrangements of distorted (Wurzel2 x Wurzel2)R45° domains, separated by antiphase boundaries. This result is in consistency with observations of poorly ordered (Wurzel2 x Wurzel2)R45° antiphase domains at intermediate coverages

Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel

Fernando D. González-Nilo and Wendy González. Centro de Bioinformática y Simulación Molecular, Universidad de Talca, 2 Norte 685, Talca 346-0000, Chile.Potassium channels share a common selectivity filter that determines the conduction characteristics of the pore. Diversity in K+ channels is given by how they are gated open. TASK-2, TALK-1, and TALK-2 are two-pore region (2P) KCNK K+ channels gated open by extracellular alkalinization. We have explored the mechanism for this alkalinization-dependent gating using molecular simulation and site-directed mutagenesis followed by functional assay. We show that the side chain of a single arginine residue (R224) near the pore senses pH in TASK-2 with an unusual pKa of 8.0, a shift likely due to its hydrophobic environment. R224 would block the channel through an electrostatic effect on the pore, a situation relieved by its deprotonation by alkalinization. A lysine residue in TALK-2 fulfills the same role but with a largely unchanged pKa, which correlates with an environment that stabilizes its positive charge. In addition to suggesting unified alkaline pH-gating mechanisms within the TALK subfamily of channels, our results illustrate in a physiological context the principle that hydrophobic environment can drastically modulate the pKa of charged amino acids within a protein.PNAS Sponsored This article contains supporting information online at www.pnas.org/cgi/content/full/0606173104/DC1

Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property

The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the development of disease-modifying therapies. One working hypothesis of AD is that Aβ excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes. Here we show that similar to other pore forming toxins, Aβ induces perforation of neuronal membranes causing an increase in membrane conductance, intracellular calcium and ethidium bromide influx. These data reveal that the target of Aβ is not another membrane protein, but that Aβ itself is the cellular target thereby explaining the failure of current therapies to interfere with the course of AD. We propose that this novel effect of Aβ could be useful for the discovery of anti AD drugs capable of blocking these “Aβ perforates”. In addition, we demonstrate that peptides that block Aβ neurotoxicity also slow or prevent the membrane-perforating action of Aβ

Electronic educational resources: how to estimate quality?

Article is devoted to questions of an assessment of quality of electronic educational resources. Authors provide the list of innovative qualities which electronic educational resources, the principles of an assessment of these qualities, and also the main stages of carrying out technical and technological, psychology and pedagogical and design ergonomic examination of an assessment of quality have to possessСтатья посвящена вопросам оценки качества электронных образовательных ресурсов. Авторы приводят перечень инновационных качеств, которыми должны обладать электронные образовательные ресурсы, принципы оценки данных качеств, а также основные этапы проведения технико-технологической, психолого-педагогической и дизайн-эргономической экспертизы оценки качеств

Self-regulation learning as active inference: dynamic causal modeling of an fMRI neurofeedback task

Introduction: Learning to self-regulate brain activity by neurofeedback has been shown to lead to changes in the brain and behavior, with beneficial clinical and non-clinical outcomes. Neurofeedback uses a brain-computer interface to guide participants to change some feature of their brain activity. However, the neural mechanism of self-regulation learning remains unclear, with only 50% of the participants succeeding in achieving it. To bridge this knowledge gap, our study delves into the neural mechanisms of self-regulation learning via neurofeedback and investigates the brain processes associated with successful brain self-regulation. Methods: We study the neural underpinnings of self-regulation learning by employing dynamical causal modeling (DCM) in conjunction with real-time functional MRI data. The study involved a cohort of 18 participants undergoing neurofeedback training targeting the supplementary motor area. A critical focus was the comparison between top-down hierarchical connectivity models proposed by Active Inference and alternative bottom-up connectivity models like reinforcement learning. Results: Our analysis revealed a crucial distinction in brain connectivity patterns between successful and non-successful learners. Particularly, successful learners evinced a significantly stronger top-down effective connectivity towards the target area implicated in self-regulation. This heightened top-down network engagement closely resembles the patterns observed in goal-oriented and cognitive control studies, shedding light on the intricate cognitive processes intertwined with self-regulation learning. Discussion: The findings from our investigation underscore the significance of cognitive mechanisms in the process of self-regulation learning through neurofeedback. The observed stronger top-down effective connectivity in successful learners indicates the involvement of hierarchical cognitive control, which aligns with the tenets of Active Inference. This study contributes to a deeper understanding of the neural dynamics behind successful self-regulation learning and provides insights into the potential cognitive architecture underpinning this process

Blended wing body with boundary layer ingestion conceptual design in a multidisciplinary design analysis optimization environment

This paper introduces the GENUS multidisciplinary concept level aircraft design and analysis environment developed by Cranfield University in recent years and it has been applied to the conceptual design of blended wing body (BWB) aircraft. Analytical disciplines include a variety of low-to-medium fidelity, physics-based and empirical methods, and aerodynamic analysis of high-order panel method. Boundary layer ingestion (BLI), as a special module, has been incorporated into the aerodynamic and propulsion analysis. The results of the Cranfield BW-11 are presented. In the highly-constrained design space, a type of highly fuel- efficient BWB concept can be studied, and the advantages of the BLI concept can also be explored based on this framework

Comparison of Phylogenetically Distinct Histoplasma Strains Reveals Evolutionarily Divergent Virulence Strategies

ABSTRACTInfection with the dimorphic fungus Histoplasma capsulatum results from the inhalation of contaminated soil. Disease outcome is variable and depends on the immune status of the host, number of organisms inhaled, and the H.capsulatum strain. H.capsulatum is divided into seven distinct clades based on phylogenetic analyses, and strains from two separate clades have been identified in North America (denoted as NAm strains). We characterized an H.capsulatum isolate (WU24) from the NAm 1 lineage in relation to two other well-characterized Histoplasma isolates, the Panamanian strain G186A and the NAm 2 strain G217B. We determined that WU24 is a chemotype II strain and requires cell wall α-(1,3)-glucan for successful in vitro infection of macrophages. In a mouse model of histoplasmosis, WU24 exhibited a disease profile that was very similar to that of strain G186A at a high sublethal dose; however, at this dose G217B had markedly different kinetics. Surprisingly, infection with a lower dose mitigated many of the differences during the course of infection. The observed differences in fungal burden, disease kinetics, symptomology, and cytokine responses all indicate that there is a sophisticated relationship between host and fungus that drives the development and progression of histoplasmosis.IMPORTANCEHistoplasmosis has a wide range of clinical manifestations, presenting as mild respiratory distress, acute respiratory infection, or a life-threatening disseminated disease most often seen in immunocompromised patients. Additionally, the outcome appears to be dependent on the amount and strain of fungus inhaled. In this study, we characterized a recent clinical H.capsulatum isolate that was collected from an HIV+ individual in North America. In contrast to other isolates from the same lineage, this strain, WU24, infected both macrophages and wild-type mice. We determined that in contrast to many other North American strains, WU24 infection of macrophages is dependent on the presence of cell wall α-(1,3)-glucan. Surprisingly, comparison of WU24 with two previously characterized isolates revealed that many conclusions regarding relative strain virulence and certain hallmarks of histoplasmosis are dependent on the inoculum size

Accuracy of Trace Formulas

Using quantum maps we study the accuracy of semiclassical trace formulas. The role of chaos in improving the semiclassical accuracy, in some systems, is demonstrated quantitatively. However, our study of the standard map cautions that this may not be most general. While studying a sawtooth map we demonstrate the rather remarkable fact that at the level of the time one trace even in the presence of fixed points on singularities the trace formula may be exact, and in any case has no logarithmic divergences observed for the quantum bakers map. As a byproduct we introduce fantastic periodic curves akin to curlicues.Comment: 20 pages, uuencoded and gzipped, 1 LaTex text file and 9 PS files for figure