The Mechanics and Thermodynamics of Amyloid Beta Protein Aggregation in Competing Pathways

The primary purpose of this paper is to investigate the mechanics of Aβ protein aggregation within the brain through mathematical modeling and simulation. Aggregation of Aβ is the cause of plaques within the brain of Alzheimer’s Disease sufferers. Because the pathways of aggregation from monomer to oligomer to polymer are numerous and complex, we have had to simplify our model to a limited number of species. Of great concern, too, is the process by which Aβ can form as “off-pathway” species, which is when Aβ reacts with fatty acid micelles. It is this species of Aβ, which due to its toxicity to neurons, that is now believed to cause Alzheimer’s Disease. Although the precise mechanism of Aβ aggregation continues to be heavily debated, evidence suggests a rate-limiting mechanism. Thus we will use Mass Action Kinetics to write a system of differential equations for the purpose of simulating aggregation of the Aβ protein in its different forms. We will analyze the stability of the system under different reaction rate regimes, as well as the system’s preferences for particular equilibrium states. Finally, we will examine the thermodynamics of the system

Fatty Acid Concentration and Phase Transitions Modulate Aβ Aggregation Pathways

Aggregation of amyloid β (Aβ) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Aβ homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules. In this context, we investigate the heterotypic interactions between Aβ and fatty acids (FAs) by two independent tool-sets such as reduced order modelling (ROM) and ensemble kinetic simulation (EKS). We observe that FAs influence Aβ dynamics distinctively in three broadly-defined FAconcentration regimes containing non-micellar, pseudo-micellar or micellar phases. While the non-micellar phase promotes on-pathway fibrils, pseudo-micellar and micellar phases promote predominantly off-pathway oligomers, albeit via subtly different mechanisms. Importantly off-pathway oligomers saturate within a limited molecular size, and likely with a different overall conformation than those formed along the on-pathway, suggesting the generation of distinct conformeric strains of Aβ, which may have profound phenotypic outcomes. Our results validate previous experimental observations and provide insights into potential influence of biological interfaces in modulating Aβ aggregation pathways

A Game-Theoretic Approach to Deciphering the Dynamics of Amyloid-Beta Aggregation Along Competing Pathways

Aggregation of amyloid-β (Aβ) peptides is a significant event that underpins Alzheimer\u27s disease (AD). Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behaviour. In this paper, we use our previously established results on heterotypic interactions between Aβ and fatty acids (FAs) to investigate off-pathway aggregation under the control of FA concentrations to develop a mathematical framework that captures the mechanism. Our framework to define and simulate the competing on- and off-pathways of Aβ aggregation is based on the principles of game theory. Together with detailed simulations and biophysical experiments, our models describe the dynamics involved in the mechanisms of Aβ aggregation in the presence of FAs to adopt multiple pathways. Specifically, our reduced-order computations indicate that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constants, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on using FA as a heterotypic partner to modulate the temporal parameters. Predicting spatio-temporal landscape along competing pathways for a given heterotypic partner such as lipids is a first step towards simulating scenarios in which the generation of specific ‘conformer strains’ of Aβ could be predicted. This approach could be significant in deciphering the mechanisms of amyloid aggregation and strain generation, which are ubiquitously observed in many neurodegenerative diseases

Mechanisms of manipulation:a systematic review of the literature on immediate anatomical structural or positional changes in response to manually delivered high-velocity, low-amplitude spinal manipulation

Background: Spinal manipulation (SM) has been claimed to change anatomy, either in structure or position, and that these changes may be the cause of clinical improvements. The aim of this systematic review was to evaluate and synthesise the peer-reviewed literature on the current evidence of anatomical changes in response to SM. Methods: The review was registered with PROSPERO (CRD42022304971) and reporting was guided by the standards of the PRISMA Statement. We searched Medline, Embase, CINAHL, AMED, Cochrane Library all databases, PEDro, and the Index to Chiropractic Literature from inception to 11 March 2022 and updated on 06 June 2023. Search terms included manipulation, adjustment, chiropractic, osteopathy, spine and spine-related structures. We included primary research studies that compared outcomes with and without SM regardless of study design. Manipulation was defined as high-velocity, low-amplitude thrust delivered by hand to the spine or directly related joints. Included studies objectively measured a potential change in an anatomical structure or in position. We developed a novel list of methodological quality items in addition to a short, customized list of risk of bias (RoB) items. We used quality and RoB items together to determine whether an article was credible or not credible. We sought differences in outcomes between SM and control groups for randomised controlled trials and crossover studies, and between pre- and post-SM outcomes for other study designs. We reported, in narrative form, whether there was a change or not. Results: The search retrieved 19,572 articles and 20 of those were included for review. Study topics included vertebral position (n = 3) facet joint space (n = 5), spinal stiffness (n = 3), resting muscle thickness (n = 6), intervertebral disc pressure (n = 1), myofascial hysteresis (n = 1), and further damage to already damaged arteries (n = 1). Eight articles were considered credible. The credible articles indicated that lumbar facet joint space increased and spinal stiffness decreased but that the resting muscle thickness did not change. Conclusion: We found few studies on this topic. However, there are two promising areas for future study: facet joint space and spinal stiffness. A research strategy should be developed with funding for high quality research centres

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

The APEX Quantitative Proteomics Tool: Generating protein quantitation estimates from LC-MS/MS proteomics results

Mass spectrometry (MS) based label-free protein quantitation has mainly focused on analysis of ion peak heights and peptide spectral counts. Most analyses of tandem mass spectrometry (MS/MS) data begin with an enzymatic digestion of a complex protein mixture to generate smaller peptides that can be separated and identified by an MS/MS instrument. Peptide spectral counting techniques attempt to quantify protein abundance by counting the number of detected tryptic peptides and their corresponding MS spectra. However, spectral counting is confounded by the fact that peptide physicochemical properties severely affect MS detection resulting in each peptide having a different detection probability. Lu et al. (2007) described a modified spectral counting technique, Absolute Protein Expression (APEX), which improves on basic spectral counting methods by including a correction factor for each protein (called O(i) value) that accounts for variable peptide detection by MS techniques. The technique uses machine learning classification to derive peptide detection probabilities that are used to predict the number of tryptic peptides expected to be detected for one molecule of a particular protein (O(i)). This predicted spectral count is compared to the protein's observed MS total spectral count during APEX computation of protein abundances. Results: The APEX Quantitative Proteomics Tool, introduced here, is a free open source Java application that supports the APEX protein quantitation technique. The APEX tool uses data from standard tandem mass spectrometry proteomics experiments and provides computational support for APEX protein abundance quantitation through a set of graphical user interfaces that partition thparameter controls for the various processing tasks. The tool also provides a Z-score analysis for identification of significant differential protein expression, a utility to assess APEX classifier performance via cross validation, and a utility to merge multiple APEX results into a standardized format in preparation for further statistical analysis. Conclusion: The APEX Quantitative Proteomics Tool provides a simple means to quickly derive hundreds to thousands of protein abundance values from standard liquid chromatography-tandem mass spectrometry proteomics datasets. The APEX tool provides a straightforward intuitive interface design overlaying a highly customizable computational workflow to produce protein abundance values from LC-MS/MS datasets.National Institute of Allergy and Infectious Diseases (NIAID) N01-AI15447National Institutes of HealthNational Science Foundation, the Welsh and Packard FoundationsInternational Human Frontier Science ProgramCenter for Systems and Synthetic Biolog