RESUMO
The abnormal aggregation of extracellular amyloid-ß(Aß) in senile plaques resulting in calcium Ca+2 dyshomeostasis is one of the primary symptoms of Alzheimer's disease (AD). Significant research efforts have been devoted in the past to better understand the underlying molecular mechanisms driving Aß deposition and Ca+2 dysregulation. Importantly, synaptic impairments, neuronal loss, and cognitive failure in AD patients are all related to the buildup of intraneuronal Aß accumulation. Moreover, increasing evidence show a feed-forward loop between Aß and Ca+2 levels, i.e. Aß disrupts neuronal Ca+2 levels, which in turn affects the formation of Aß. To better understand this interaction, we report a novel stochastic model where we analyze the positive feedback loop between Aß and Ca+2 using ADNI data. A good therapeutic treatment plan for AD requires precise predictions. Stochastic models offer an appropriate framework for modelling AD since AD studies are observational in nature and involve regular patient visits. The etiology of AD may be described as a multi-state disease process using the approximate Bayesian computation method. So, utilizing ADNI data from 2-year visits for AD patients, we employ this method to investigate the interplay between Aß and Ca+2 levels at various disease development phases. Incorporating the ADNI data in our physics-based Bayesian model, we discovered that a sufficiently large disruption in either Aß metabolism or intracellular Ca+2 homeostasis causes the relative growth rate in both Ca+2 and Aß, which corresponds to the development of AD. The imbalance of Ca+2 ions causes Aß disorders by directly or indirectly affecting a variety of cellular and subcellular processes, and the altered homeostasis may worsen the abnormalities of Ca+2 ion transportation and deposition. This suggests that altering the Ca+2 balance or the balance between Aß and Ca+2 by chelating them may be able to reduce disorders associated with AD and open up new research possibilities for AD therapy.
RESUMO
This study investigates the factors such as knowledge management capacities and their positive influence on firm competitive advantage or the supply chain agility of the firm and the underlying mechanisms (supply chain agility) that facilitate the firm's performance and leads to firm competitive advantage. It also explores the moderating role of inter-functional integration. We have collected the data from the 308 supply chain managers of pharmaceutical firms in Pakistan and questionnaires were used for data collection with multi-item scales already developed and validated. The findings suggest that knowledge management capacities significantly influence a firm's competitive advantage or supply chain agility. The supply chain agility fully mediates between absorptive capacity, transformative capacity, and firm competitive advantage. Further, supply chain agility partially mediates between inventive capacity and firm competitive advantage. Meanwhile, inter-functional integration moderates the relationship between supply chain agility and firm competitive advantage, with their positive relationship strengthening when inter-functional integration is high. The study provides empirical evidence that knowledge management capacities (such as absorptive capacity, transformative capacity, and inventive capacity), supply chain agility, and inter-functional can be important factors in improving firm performance.
Assuntos
Comércio , Gestão do Conhecimento , Invenções , Paquistão , Preparações FarmacêuticasRESUMO
Exosomes are nano-sized extracellular vesicles that perform a variety of biological functions linked to the pathogenesis of various neurodegenerative disorders. In Alzheimer's disease (AD), for examples, exosomes are responsible for the release of Aß oligomers, and their extracellular accumulation, although the underpinning molecular machinery remains elusive. We propose a novel model for Alzheimer's Aß accumulation based on Ca 2+-dependent exosome release from astrocytes. Moreover, we exploit our model to assess how temperature dependence of exosome release could interact with Aß neurotoxicity. We predict that voltage-gated Ca 2+ channels (VGCCs) along with the transient-receptor potential M8 (TRPM8) channel are crucial molecular components in Alzheimer's progression.
