FAD Mutations in Amyloid Precursor Protein Do Not Directly Perturb Intracellular Calcium Homeostasis

Disturbances in intracellular calcium homeostasis are likely prominent and causative factors leading to neuronal cell death in Alzheimer's disease (AD). Familial AD (FAD) is early-onset and exhibits autosomal dominant inheritance. FAD-linked mutations have been found in the genes encoding the presenilins and amyloid precursor protein (APP). Several studies have shown that mutated presenilin proteins can directly affect calcium release from intracellular stores independently of Aβ production. Although less well established, there is also evidence that APP may directly modulate intracellular calcium homeostasis. Here, we directly examined whether overexpression of FAD-linked APP mutants alters intracellular calcium dynamics. In contrast to previous studies, we found that overexpression of mutant APP has no effects on basal cytosolic calcium, ER calcium store size or agonist-induced calcium release and subsequent entry. Thus, we conclude that mutated APP associated with FAD has no direct effect on intracellular calcium homeostasis independently of Aβ production

Requirement of biphasic calcium release from the endoplasmic reticulum for Fas-mediated apoptosis

Fas receptor is a member of the tumor necrosis factor-α family of death receptors that mediate physiologic apoptotic signaling. To investigate the molecular mechanisms regulating calcium mobilization during Fas-mediated apoptosis, we have analyzed the sequential steps leading to altered calcium homeostasis and cell death in response to activation of the Fas receptor. We show that Fas-mediated apoptosis requires endoplasmic reticulum–mediated calcium release in a mechanism dependent on phospholipase C-γ1 (PLC-γ1) activation and Ca2+ release from inositol 1,4,5-trisphosphate receptor (IP3R) channels. The kinetics of Ca2+ release were biphasic, demonstrating a rapid elevation caused by PLC-γ1 activation and a delayed and sustained increase caused by cytochrome c binding to IP3R. Blocking either phase of Ca2+ mobilization was cytoprotective, highlighting PLC-γ1 and IP3R as possible therapeutic targets for disorders associated with Fas signaling

Assessing Sustainability in the Shipbuilding Supply Chain 4.0: A Systematic Review

The supply chain is currently taking on a very important role in organizations seeking to improve the competitiveness and profitability of the company. Its transversal character mainly places it in an unbeatable position to achieve this role. This article, through a study of each of the key enabling technologies of Industry 4.0, aims to obtain a general overview of the current state of the art in shipbuilding adapted to these technologies. To do so, a systematic review of what the scientific community says is carried out, dividing each of the technologies into different categories. In addition, the global vision of countries interested in each of the enabling technologies is also studied. Both studies present a general vision to the companies of the concerns of the scientific community, thus encouraging research on the subject that is focused on the sustainability of the shipbuilding supply chain

New therapeutic targets in Alzheimer's disease: brain deregulation of calcium and zinc

The molecular determinants of Alzheimer's (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca2+) and zinc (Zn2+). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-β dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca2+ and Zn2+ dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca2+ and Zn2+ rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca2+ and Zn2+ dyshomeostasis may offer a great opportunity for disease-modifying strategies